Cancers

27 pages, 17708 KiB

Open AccessArticle

Probing the Potential of Defense Response-Associated Genes for Predicting the Progression, Prognosis, and Immune Microenvironment of Osteosarcoma

by Liangkun Huang, Fei Sun, Zilin Liu, Wenyi Jin, Yubiao Zhang, Junwen Chen, Changheng Zhong, Wanting Liang and Hao Peng

Cancers 2023, 15(8), 2405; https://doi.org/10.3390/cancers15082405 - 21 Apr 2023

Cited by 11 | Viewed by 2282

Abstract

Background: The defense response is a type of self-protective response of the body that protects it from damage by pathogenic factors. Although these reactions make important contributions to the occurrence and development of tumors, the role they play in osteosarcoma (OS), particularly in [...] Read more.

Background: The defense response is a type of self-protective response of the body that protects it from damage by pathogenic factors. Although these reactions make important contributions to the occurrence and development of tumors, the role they play in osteosarcoma (OS), particularly in the immune microenvironment, remains unpredictable. Methods: This study included the clinical information and transcriptomic data of 84 osteosarcoma samples and the microarray data of 12 mesenchymal stem cell samples and 84 osteosarcoma samples. We obtained 129 differentially expressed genes related to the defense response (DRGs) by taking the intersection of differentially expressed genes with genes involved in the defense response pathway, and prognostic genes were screened using univariate Cox regression. Least absolute shrinkage and selection operator (LASSO) penalized Cox regression and multivariate Cox regression were then used to establish a DRG prognostic signature (DGPS) via the stepwise method. DGPS performance was examined using independent prognostic analysis, survival curves, and receiver operating characteristic (ROC) curves. In addition, the molecular and immune mechanisms of adverse prognosis in high-risk populations identified by DGPS were elucidated. The results were well verified by experiments. Result: BNIP3, PTGIS, and ZYX were identified as the most important DRGs for OS progression (hazard ratios of 2.044, 1.485, and 0.189, respectively). DGPS demonstrated outstanding performance in the prediction of OS prognosis (area under the curve (AUC) values of 0.842 and 0.787 in the training and test sets, respectively, adj-p < 0.05 in the survival curve). DGPS also performed better than a recent clinical prognostic approach with an AUC value of only 0.674 [metastasis], which was certified in the subsequent experimental results. These three genes regulate several key biological processes, including immune receptor activity and T cell activation, and they also reduce the infiltration of some immune cells, such as B cells, CD8+ T cells, and macrophages. Encouragingly, we found that DGPS was associated with sensitivity to chemotherapeutic drugs including JNK Inhibitor VIII, TGX221, MP470, and SB52334. Finally, we verified the effect of BNIP3 on apoptosis, proliferation, and migration of osteosarcoma cells through experiments. Conclusions: This study elucidated the role and mechanism of BNIP3, PTGIS, and ZYX in OS progression and was well verified by the experimental results, enabling reliable prognostic means and treatment strategies to be proposed for OS patients. Full article

(This article belongs to the Special Issue Biomarkers of Tumor Metastasis and Invasiveness)

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27 pages, 6383 KiB

Open AccessArticle

Lung Micrometastases Display ECM Depletion and Softening While Macrometastases Are 30-Fold Stiffer and Enriched in Fibronectin

by Maria Narciso, África Martínez, Constança Júnior, Natalia Díaz-Valdivia, Anna Ulldemolins, Massimiliano Berardi, Kate Neal, Daniel Navajas, Ramon Farré, Jordi Alcaraz, Isaac Almendros and Núria Gavara

Cancers 2023, 15(8), 2404; https://doi.org/10.3390/cancers15082404 - 21 Apr 2023

Cited by 4 | Viewed by 2887

Abstract

Mechanical changes in tumors have long been linked to increased malignancy and therapy resistance and attributed to mechanical changes in the tumor extracellular matrix (ECM). However, to the best of our knowledge, there have been no mechanical studies on decellularized tumors. Here, we [...] Read more.

Mechanical changes in tumors have long been linked to increased malignancy and therapy resistance and attributed to mechanical changes in the tumor extracellular matrix (ECM). However, to the best of our knowledge, there have been no mechanical studies on decellularized tumors. Here, we studied the biochemical and mechanical progression of the tumor ECM in two models of lung metastases: lung carcinoma (CAR) and melanoma (MEL). We decellularized the metastatic lung sections, measured the micromechanics of the tumor ECM, and stained the sections for ECM proteins, proliferation, and cell death markers. The same methodology was applied to MEL mice treated with the clinically approved anti-fibrotic drug nintedanib. When compared to healthy ECM (~0.40 kPa), CAR and MEL lung macrometastases produced a highly dense and stiff ECM (1.79 ± 1.32 kPa, CAR and 6.39 ± 3.37 kPa, MEL). Fibronectin was overexpressed from the early stages (~118%) to developed macrometastases (~260%) in both models. Surprisingly, nintedanib caused a 4-fold increase in ECM-occupied tumor area (5.1 ± 1.6% to 18.6 ± 8.9%) and a 2-fold in-crease in ECM stiffness (6.39 ± 3.37 kPa to 12.35 ± 5.74 kPa). This increase in stiffness strongly correlated with an increase in necrosis, which reveals a potential link between tumor hypoxia and ECM deposition and stiffness. Our findings highlight fibronectin and tumor ECM mechanics as attractive targets in cancer therapy and support the need to identify new anti-fibrotic drugs to abrogate aberrant ECM mechanics in metastases. Full article

(This article belongs to the Special Issue Tumor Microenvironment: A Key Piece in the Puzzle of Cancer Heterogeneity)

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12 pages, 3310 KiB

Open AccessArticle

Immunomorphological Patterns of Chaperone System Components in Rare Thyroid Tumors with Promise as Biomarkers for Differential Diagnosis and Providing Clues on Molecular Mechanisms of Carcinogenesis

by Letizia Paladino, Radha Santonocito, Giuseppa Graceffa, Calogero Cipolla, Alessandro Pitruzzella, Daniela Cabibi, Francesco Cappello, Everly Conway de Macario, Alberto J. L. Macario, Fabio Bucchieri and Francesca Rappa

Cancers 2023, 15(8), 2403; https://doi.org/10.3390/cancers15082403 - 21 Apr 2023

Cited by 1 | Viewed by 1629

Abstract

Hurthle cell (HC), anaplastic (AC), and medullary (MC) carcinomas are low frequency thyroid tumors that pose several challenges for physicians and pathologists due to the scarcity of cases, information, and histopathological images, especially in the many areas around the world in which sophisticated [...] Read more.

Hurthle cell (HC), anaplastic (AC), and medullary (MC) carcinomas are low frequency thyroid tumors that pose several challenges for physicians and pathologists due to the scarcity of cases, information, and histopathological images, especially in the many areas around the world in which sophisticated molecular and genetic diagnostic facilities are unavailable. It is, therefore, cogent to provide tools for microscopists to achieve accurate diagnosis, such as histopathological images with reliable biomarkers, which can help them to reach a differential diagnosis. We are investigating whether components of the chaperone system (CS), such as the molecular chaperones, can be considered dependable biomarkers, whose levels and distribution inside and outside cells in the tumor tissue could present a distinctive histopathological pattern for each tumor type. Here, we report data on the chaperones Hsp27, Hsp60, and Hsp90. They presented quantitative levels and distribution patterns that were different for each tumor and differed from those of a benign thyroid pathology, goiter (BG). Therefore, the reported methodology can be beneficial when the microscopist must differentiate between HC, AC, MC, and BG. Full article

(This article belongs to the Special Issue Thyroid Cancer: New Advances from Diagnosis to Therapy)

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Classification of thyroid cancers (TCs). Thyroid tumors of follicular origin can be of two main subtypes: differentiated and undifferentiated. Papillary (PC) thyroid tumors are the most common type (80–85%) of well differentiated thyroid tumors and have the best prognosis. Follicular thyroid carcinoma (FC) accounts for about 10% of epithelial cancers and lacks diagnostic molecular features. Thyroidal oncocytic follicular cells can give origin to Hurthle cell carcinoma (HC), which constitute about 3% of all TC cancers. Among the undifferentiated subtype, anaplastic thyroid cancer (AC) is a rare and lethal form of TC, which probably derives from follicular cells, resulting from dedifferentiation, in patients with long-standing goiter. In addition to tumors derived from follicular cells, the thyroid gland also develops tumors from parafollicular cells, or C cells, such as the medullary thyroid carcinoma (MC), characterized by an elevated level of calcitonin [<a href="#B4-cancers-15-02403" class="html-bibr">4</a>]. Routinely, diagnosis and staging are carried out using fine-needle aspiration (FNA): cancer cells usually look different from normal cells, so the type of TC is determined by microscopic examination of thyroid cells found in nodules. In addition, molecular tests, such as those for RAS and BRAF mutations, can be used to help make a diagnosis when the result of a fine needle biopsy is uncertain [<a href="#B5-cancers-15-02403" class="html-bibr">5</a>]. Full article ">Figure 2
Hsp27 immunohistochemistry. Representative images of immunohistochemical results for Hsp27 in benign goiter (A,B), Hurthle cell carcinoma (C,D), medullary carcinoma (E,F) and anaplastic carcinoma (G,H). (A,C,E,G): magnification 200×, scale bar 50 µm; (B,D,F,H): magnification 400×; scale bar 20 µm. Full article ">Figure 3
Statistical analysis of Hsp27 results. The histogram shows the results for the immunohistochemical evaluation of Hsp27 in benign goiter (BG), Hurthle cell carcinoma (HC), medullary carcinoma (MC), and anaplastic carcinoma (AC). Data are presented as arithmetic mean ± standard deviation. * p ≤ 0.05 vs. BG and MC # p ≤ 0.05 vs. BG, HC and MC. Full article ">Figure 4
Hsp60 immunohistochemistry. Representative images of immunohistochemical results for Hsp60 in benign goiter (A,B), Hurthle cell carcinoma (C,D), medullary carcinoma (E,F), and anaplastic carcinoma (G,H). (A,C,E,G): magnification 200×, scale bar 50 µm; (B,D,F,H): magnification 400×, scale bar 20 µm. Full article ">Figure 5
Statistical analysis of Hsp60 results. The histogram shows statistical results for the immunohistochemical evaluation of Hsp60 in benign goiter (BG), Hurthle cell carcinoma (HC), medullary carcinoma (MC), and anaplastic carcinoma (AC). Data are presented as arithmetic mean ± standard deviation. * p ≤ 0.05 vs. BG and MC; # p ≤ 0.05 vs. BG, and MC. Full article ">Figure 6
Hsp90 immunohistochemistry. Representative images of immunohistochemical results for Hsp90 in benign goiter (A,B), Hurthle cell carcinoma (C,D), medullary carcinoma (E,F), and anaplastic carcinoma (G,H). (A,C,E,G): magnification 200×, scale bar 50 µm; (B,D,F,H): magnification 400×, scale bar 20 µm. Full article ">Figure 7
Statistical analysis of Hsp90 results. The histogram shows results for the immunohistochemical evaluation of Hsp90 in benign goiter (BG), Hurthle cell carcinoma (HC), medullary carcinoma (MC), and anaplastic carcinoma (AC). Data are presented as mean ± standard deviation. * p ≤ 0.05 vs. BG, MC, and AC; # p ≤ 0.05 vs. BG, HC, and MC. Full article ">

15 pages, 28043 KiB

Open AccessArticle

Application of Indocyanine Green Fluorescence Imaging in Assisting Biopsy of Musculoskeletal Tumors

by Siyuan He, Ang Zhong, Jun Lei, Zhouming Deng, Xiaobin Zhu, Renxiong Wei, Huayi Huang, Zhenyi Chen, Lin Cai and Yuanlong Xie

Cancers 2023, 15(8), 2402; https://doi.org/10.3390/cancers15082402 - 21 Apr 2023

Viewed by 1661

Abstract

(1) Background: Biopsies are the gold standard for the diagnosis of musculoskeletal tumors. In this study, we aimed to explore whether indocyanine green near-infrared fluorescence imaging can assist in the biopsy of bone and soft tissue tumors and improve the success rate of [...] Read more.

(1) Background: Biopsies are the gold standard for the diagnosis of musculoskeletal tumors. In this study, we aimed to explore whether indocyanine green near-infrared fluorescence imaging can assist in the biopsy of bone and soft tissue tumors and improve the success rate of biopsy. (2) Method: We recruited patients with clinically considered bone and soft tissue tumors and planned biopsies. In the test group, indocyanine green (0.3 mg/kg) was injected. After identifying the lesion, a near-infrared fluorescence camera system was used to verify the ex vivo specimens of the biopsy in real time. If the biopsy specimens were not developed, we assumed that we failed to acquire lesions, so the needle track and needle position were adjusted for the supplementary biopsy, and then real-time imaging was performed again. Finally, we conducted a pathological examination. In the control group, normal biopsy was performed. (3) Results: The total diagnosis rate of musculoskeletal tumors in the test group was 94.92% (56/59) and that in the control group was 82.36% (42/51). In the test group, 14 cases were not developed, as seen from real-time fluorescence in the core biopsy, and then underwent the supplementary biopsy after changing the puncture direction and the location of the needle channel immediately, of which 7 cases showed new fluorescence. (4) Conclusions: Using the near-infrared fluorescence real-time development technique to assist the biopsy of musculoskeletal tumors may improve the accuracy of core biopsy and help to avoid missed diagnoses, especially for some selected tumors. Full article

(This article belongs to the Section Clinical Research of Cancer)

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Research and design technology roadmap of the test group. Full article ">Figure 2
The flowchart of this trial. Full article ">Figure 3
Thirty-two-year-old male suspected to have malignant tumors of the lower limb soft tissue. (A) Under the guidance of B-ultrasound, the biopsy needle was implanted into the lesion (red arrow). (B–D) The naked-eye view of the biopsy lesions, the green fluorescence, and original fluorescence of the real-time fluorescence development of the biopsy lesions. (E) The histopathologic biopsy results (hematoxylin and eosin, original magnification 100×) confirmed the bone lesion as a non-Hodgkin’s lymphoma. (F–I) Medical imaging before biopsy for the diagnosis of soft tissue tumors (yellow arrow). (J) The pathological results (non-Hodgkin’s lymphoma) after surgical resection of the humeral tumor were consistent with the pathological results of the biopsy (hematoxylin and eosin, original magnification 40×). Full article ">Figure 4
A 35-year-old male suspected to have malignant tumors of the right pelvis and surrounding soft tissue. (A–D) Medical imaging before biopsy for the diagnosis of pelvic malignant tumors (yellow arrow). (E) Under the guidance of CT, the biopsy needle was implanted into the lesion (red arrow). (F–H) Naked-eye view of biopsy lesions and real-time fluorescence imaging of lesion specimens (no fluorescence imaging). (I) Pathological results of the first biopsy (necrotic lesions, inflammatory tissues). (J) The position and direction of the puncture channel were immediately adjusted, the supplementary biopsy was performed (under the guidance of CT), and then real-time fluorescence imaging was performed again after the lesions were obtained (red arrow). (K–M) The naked-eye view of the biopsy lesions, the green fluorescence, and original fluorescence of the real-time fluorescence development of the supplementary biopsy lesions. (N) The histopathologic biopsy results (hematoxylin and eosin, original magnification 100×) confirmed the bone lesion as a fibrosarcoma. Full article ">Figure 5
(A) Under the guidance of CT, the biopsy needle was implanted into the lesion (red arrow). (B–D) The naked-eye view of the biopsy lesions and real-time fluorescence imaging of the lesion specimens (no fluorescence imaging). (E) Pathological results of the first biopsy (necrotic tissue). (F) The direction and position of the needle track were adjusted immediately, and the focus was obtained again. After the end of the biopsy, the specimen was developed with real-time fluorescence. In the picture, the biopsy needle was implanted into the lesion (red arrow). (G–I) The naked-eye view of the biopsy lesions, the green fluorescence, and original fluorescence of the real-time fluorescence development of the supplementary biopsy lesions. (J) The pathological results of the supplementary biopsy (osteosarcoma). (K–M) Imaging data before biopsy (yellow arrow). (N) The pathological results (osteosarcoma) after surgical resection of the humeral tumor were consistent with the pathological results of the biopsy. Full article ">

16 pages, 4233 KiB

Open AccessArticle

Pterostilbene and Probiotic Complex in Chemoprevention of Putative Precursor Lesions for Colorectal Cancer in an Experimental Model of Intestinal Carcinogenesis with 1,2-Dimethylhydrazine

by Márcio Alencar Barreira, Márcio Wilker Soares Campelo, Conceição da Silva Martins Rebouças, Antoniella Souza Gomes Duarte, Maria Lucianny Lima Barbosa, Said Gonçalves da Cruz Fonseca, Raphaela Ribeiro Queiroz, Érica Uchoa Holanda, Ana Beatriz Aragão de Vasconcelos, Vitória Jannyne Guimarães de Sousa Araújo, Gabriel Maia Diniz, Reinaldo Barreto Oriá and Paulo Roberto Leitão de Vasconcelos

Cancers 2023, 15(8), 2401; https://doi.org/10.3390/cancers15082401 - 21 Apr 2023

Cited by 1 | Viewed by 1789

Abstract

Dietary supplementation with pterostilbene (PS) and/or a probiotic (PRO) may ameliorate the intestinal microbiota in disease conditions. This study aims to evaluate PS and PRO for the chemoprevention of putative precursor lesions for colorectal cancer (CRC) in an experimental model of intestinal carcinogenesis [...] Read more.

Dietary supplementation with pterostilbene (PS) and/or a probiotic (PRO) may ameliorate the intestinal microbiota in disease conditions. This study aims to evaluate PS and PRO for the chemoprevention of putative precursor lesions for colorectal cancer (CRC) in an experimental model of intestinal carcinogenesis with 1,2-dimethylhydrazine (1,2-DMH). Sixty male Wistar rats were equally divided into five groups: Sham, 1,2-DMH, 1,2-DMH + PS, 1,2-DMH + PRO, and 1,2-DMH + PS + PRO. PRO (5 × 10⁷/mL) was offered in water, and PS (300 ppm) was provided in the diet ad libitum. 1,2-DMH (20 mg/kg/week) was administered for 15 consecutive weeks. In the 25th week, proctocolectomy was conducted. PRO alone and PRO combined with PS were the best intervention strategies to improve experimental 1,2-DMH-induced CRC regarding several parameters of carcinogenesis. Our findings may contribute to the development of novel preventive strategies for CRC and may help to identify novel modulators of colon carcinogenesis. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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Experiment design. Full article ">Figure 2
Histopathology of the experimental groups. Photos 2 (A–E) and 2 (K–O) were under 20× objective magnification (scale bar 100 μm) and the longitudinal section. Photos 2 (F–J) and 2 (P–T) were under 40× objective magnification (scale bar 50 μm) and the cross-section. Black arrow—the presence of an aggregate of ACF with more intense staining due to nuclear enlargement and mucin depletion. Full article ">Figure 3
Analysis of oxidative damage by measuring MDA and GSH levels in the distal colon segment. (A) MDA and GSH (B) levels in the distal colon segment. The values are presented as the mean ± SEM. # p < 0.05 vs. Sham and * p < 0.05 vs. 1,2-DMH group. For statistical analysis, the one-way ANOVA test was used followed by Tukey’s post-test. Full article ">Figure 4
Immunoexpression of iNOS, NF-kB, TNF-α, and IL1β proteins in the distal colon segment. (A) Representative histology of iNOS, NF-kB, TNF-α, and IL1β immunolabeling in the experimental groups. The graphs (B–E) represent the mean ± SEM of the percentage of the immunopositive area for iNOS, NF-kB, TNF-α, and IL1β in relation to the total area. # p < 0.05 vs. Sham and * p < 0.05, ** p < 0.01, *** p < 0.001 vs. 1,2-DMH group. (B,D) The data were analyzed using the Kruskal–Wallis test followed by the Dunn’s post-test. (C,E) The data were analyzed by the one-way ANOVA test followed by Tukey’s post-test. Full article ">Figure 5
Immunoexpression of Ki67, P53, β-catenin, and Wnt-3a proteins in the distal colon. (A) Representative histology of Ki67, P53, β-catenin, and Wnt-3a protein immunolabeling in the experimental groups. The graphs (B–E) represent the mean ± SEM of the percentage of the immunopositive area for Ki67, P53, β-catenin, and Wnt-3a in relation to the total area. # p < 0.05 vs. Sham and * p < 0.05, ** p < 0.01, *** p < 0.001 vs. 1,2-DMH group. (B,C) The data were analyzed using the Kruskal–Wallis test followed by the Dunn’s post-test. (D,E) The data were analyzed by the one-way ANOVA test followed by the Tukey’s post-test. Full article ">Figure 6
The outcome of PRO and/or PS supplementation in an experimental model of CRC development with 1,2-DMH. 1,2-DMH increased histopathological scores, OS (elevated MDA and reduced GSH), and selected inflammatory and tumorigenesis markers (Ki67, β-catenin, Wnt3a, p53, NF-kB, iNOS, IL1-β, and TNF- α). 1,2-DMH + PRO and 1,2-DMH + PS + PRO reduced histopathological scores, and selected inflammatory and tumorigenesis markers (Ki67, β-catenin, Wnt3a, p53, NF-kB, iNOS, IL1-β, and TNF- α) and improved OS (MDA). 1,2-DMH + PS + PRO also increased intestinal GSH levels. 1,2-DMH + PS reduced p53, Ki67, IL1-β and TNF-α tissue expression, but without improving OS and histopathological scores. ↑, increased; ↓, decreased. Full article ">

14 pages, 302 KiB

Open AccessReview

The Role of AI in Breast Cancer Lymph Node Classification: A Comprehensive Review

by Josip Vrdoljak, Ante Krešo, Marko Kumrić, Dinko Martinović, Ivan Cvitković, Marko Grahovac, Josip Vickov, Josipa Bukić and Joško Božic

Cancers 2023, 15(8), 2400; https://doi.org/10.3390/cancers15082400 - 21 Apr 2023

Cited by 8 | Viewed by 2548

Abstract

Breast cancer is a significant health issue affecting women worldwide, and accurately detecting lymph node metastasis is critical in determining treatment and prognosis. While traditional diagnostic methods have limitations and complications, artificial intelligence (AI) techniques such as machine learning (ML) and deep learning [...] Read more.

Breast cancer is a significant health issue affecting women worldwide, and accurately detecting lymph node metastasis is critical in determining treatment and prognosis. While traditional diagnostic methods have limitations and complications, artificial intelligence (AI) techniques such as machine learning (ML) and deep learning (DL) offer promising solutions for improving and supplementing diagnostic procedures. Current research has explored state-of-the-art DL models for breast cancer lymph node classification from radiological images, achieving high performances (AUC: 0.71–0.99). AI models trained on clinicopathological features also show promise in predicting metastasis status (AUC: 0.74–0.77), whereas multimodal (radiomics + clinicopathological features) models combine the best from both approaches and also achieve good results (AUC: 0.82–0.94). Once properly validated, such models could greatly improve cancer care, especially in areas with limited medical resources. This comprehensive review aims to compile knowledge about state-of-the-art AI models used for breast cancer lymph node metastasis detection, discusses proper validation techniques and potential pitfalls and limitations, and presents future directions and best practices to achieve high usability in real-world clinical settings. Full article

(This article belongs to the Section Cancer Informatics and Big Data)

13 pages, 610 KiB

Open AccessReview

Optimizing Treatment Options for Newly Diagnosed Acute Myeloid Leukemia in Older Patients with Comorbidities

by Gaku Oshikawa and Koji Sasaki

Cancers 2023, 15(8), 2399; https://doi.org/10.3390/cancers15082399 - 21 Apr 2023

Cited by 1 | Viewed by 2257

Abstract

Traditionally, the goal of AML therapy has been to induce remission through intensive chemotherapy, maintain long-term remission using consolidation therapy, and achieve higher rates of a cure by allogeneic transplantation in patients with a poor prognosis. However, for the elderly patients and those [...] Read more.

Traditionally, the goal of AML therapy has been to induce remission through intensive chemotherapy, maintain long-term remission using consolidation therapy, and achieve higher rates of a cure by allogeneic transplantation in patients with a poor prognosis. However, for the elderly patients and those with comorbidities, the toxicity often surpasses the therapeutic benefits of intensive chemotherapy. Consequently, low-intensity therapies, such as the combination of a hypomethylating agent with venetoclax, have emerged as promising treatment options for elderly patients. Given the rise of low-intensity therapies as the leading treatment option for the elderly, it is increasingly important to consider patients’ age and comorbidities when selecting a treatment option. The recently proposed comorbidity-based risk stratification for AML allows prognosis stratification not only in patients undergoing intensive chemotherapy, but also in those receiving low-intensity chemotherapy. Optimizing treatment intensity based on such risk stratification is anticipated to balance treatment efficacy and safety, and will ultimately improve the life expectancy for patients with AML. Full article

(This article belongs to the Special Issue Actionable Vulnerabilities in Hematological Malignancies)

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12 pages, 1452 KiB

Open AccessArticle

Protective Effects of Influenza Vaccine against Colorectal Cancer in Populations with Chronic Kidney Disease: A Nationwide Population-Based Cohort Study

by Chun-Chao Chen, Wen-Rui Hao, Hong-Jye Hong, Kuan-Jie Lin, Chun-Chih Chiu, Tsung-Yeh Yang, Yu-Ann Fang, William Jian, Ming-Yao Chen, Min-Huei Hsu, Shih-Chun Lu, Yu-Hsin Lai, Tsung-Lin Yang and Ju-Chi Liu

Cancers 2023, 15(8), 2398; https://doi.org/10.3390/cancers15082398 - 21 Apr 2023

Viewed by 2065

Abstract

Chronic kidney disease (CKD) is associated with malignancy, including colorectal cancer, via the potential mechanism of chronic inflammation status. This study aimed to determine whether influenza vaccines can reduce the risk of colorectal cancer in patients with CKD. Our cohort study enrolled 12,985 [...] Read more.

Chronic kidney disease (CKD) is associated with malignancy, including colorectal cancer, via the potential mechanism of chronic inflammation status. This study aimed to determine whether influenza vaccines can reduce the risk of colorectal cancer in patients with CKD. Our cohort study enrolled 12,985 patients older than 55 years with a diagnosis of CKD in Taiwan from the National Health Insurance Research Database at any time from 1 January 2001 to 31 December 2012. Patients enrolled in the study were divided into a vaccinated and an unvaccinated group. In this study, 7490 and 5495 patients were unvaccinated and vaccinated, respectively. A propensity score was utilized to reduce bias and adjust the results. Cox proportional hazards regression was used to estimate the correlation between the influenza vaccine and colorectal cancer in patients with CKD. The results showed that the influenza vaccine exerted a protective effect against colorectal cancer in populations with CKD. The incidence rate of colon cancer in the vaccinated group was significantly lower than in the unvaccinated group, with an adjusted hazard rate (HR) of 0.38 (95% CI: 0.30–0.48, p < 0.05). After the propensity score was adjusted for Charlson comorbidity index, age, sex, dyslipidemia, hypertension, diabetes, monthly income, and level of urbanization, the dose-dependent effect was found, and it revealed adjusted HRs of 0.74 (95% CI: 0.54–1.00, p < 0.05), 0.41 (95% CI: 0.30–0.57, p < 0.001), 0.16 (95% CI: 0.11–0.25, p < 0.001) for one, two to three, and four or more vaccinations, respectively. In summary, the influenza vaccine was found to be associated with a reduced risk of colorectal cancer in CKD patients. This study highlights the potential chemopreventive effect of influenza vaccination among patients with CKD. Future studies are required to determine whether the aforementioned relationship is a causal one. Full article

(This article belongs to the Section Cancer Epidemiology and Prevention)

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14 pages, 3585 KiB

Open AccessArticle

Partial Hepatic Vein Occlusion and Venous Congestion in Liver Exploration Using a Hyperspectral Camera: A Proposal for Monitoring Intraoperative Liver Perfusion

by Simone Famularo, Elisa Bannone, Toby Collins, Elisa Reitano, Nariaki Okamoto, Kohei Mishima, Pietro Riva, Yu-Chieh Tsai, Richard Nkusi, Alexandre Hostettler, Jacques Marescaux, Eric Felli and Michele Diana

Cancers 2023, 15(8), 2397; https://doi.org/10.3390/cancers15082397 - 21 Apr 2023

Viewed by 1879

Abstract

Introduction. The changes occurring in the liver in cases of outflow deprivation have rarely been investigated, and no measurements of this phenomenon are available. This investigation explored outflow occlusion in a pig model using a hyperspectral camera. Methods. Six pigs were enrolled. The [...] Read more.

Introduction. The changes occurring in the liver in cases of outflow deprivation have rarely been investigated, and no measurements of this phenomenon are available. This investigation explored outflow occlusion in a pig model using a hyperspectral camera. Methods. Six pigs were enrolled. The right hepatic vein was clamped for 30 min. The oxygen saturation (StO₂%), deoxygenated hemoglobin level (de-Hb), near-infrared perfusion (NIR), and total hemoglobin index (THI) were investigated at different time points in four perfused lobes using a hyperspectral camera measuring light absorbance between 500 nm and 995 nm. Differences among lobes at different time points were estimated by mixed-effect linear regression. Results. StO₂% decreased over time in the right lateral lobe (RLL, totally occluded) when compared to the left lateral (LLL, outflow preserved) and the right medial (RML, partially occluded) lobes (p < 0.05). De-Hb significantly increased after clamping in RLL when compared to RML and LLL (p < 0.05). RML was further analyzed considering the right portion (totally occluded) and the left portion of the lobe (with an autonomous draining vein). StO₂% decreased and de-Hb increased more smoothly when compared to the totally occluded RLL (p < 0.05). Conclusions. The variations of StO₂% and deoxy-Hb could be considered good markers of venous liver congestion. Full article

(This article belongs to the Special Issue Innovative Approaches to the Liver Tumors: Molecular, Imaging, Surgical and Artificial Intelligence Applications in Clinical Practice)

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18 pages, 6709 KiB

Open AccessArticle

Cross-Dataset Single-Cell Analysis Identifies Temporal Alterations in Cell Populations of Primary Pancreatic Tumor and Liver Metastasis

by Daowei Yang, Rohan Moniruzzaman, Hua Wang, Huamin Wang and Yang Chen

Cancers 2023, 15(8), 2396; https://doi.org/10.3390/cancers15082396 - 21 Apr 2023

Cited by 5 | Viewed by 3684

Abstract

Pancreatic ductal adenocarcinoma (PDAC) has a unique tumor microenvironment composed of various cell populations such as cancer cells, cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells. Recently, single-cell RNA-sequencing analysis (scRNA-seq) has systemically revealed the genomic profiles of these cell populations in PDAC. [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) has a unique tumor microenvironment composed of various cell populations such as cancer cells, cancer-associated fibroblasts (CAFs), immune cells, and endothelial cells. Recently, single-cell RNA-sequencing analysis (scRNA-seq) has systemically revealed the genomic profiles of these cell populations in PDAC. However, the direct comparison of cell population composition and genomic profile between primary tumors (at both early- and late-stage) and metastatic tumors of PDAC is still lacking. In this study, we combined and analyzed recent scRNA-seq datasets of transgenic KPC mouse models with autochthonous PDAC and matched liver metastasis, revealing the unique tumor ecosystem and cell composition of liver metastasis in contrast to primary PDAC. Metastatic PDAC tumors harbor distinct cancer cell subpopulations from primary tumors. Several unique markers, including HMGA1, were identified for metastasis-enriched cancer cell subpopulations. Furthermore, metastatic tumors reveal significantly enriched granulocytic myeloid-derived suppressor cells (G-MDSCs), mature neutrophils, and granulocyte-myeloid progenitors (GMPs). A common GMP population across primary tumors, liver metastases, and healthy bone marrow was identified as the putative cell origin of tumor-associated neutrophils/granulocytes. Full article

(This article belongs to the Special Issue Neoadjuvant Therapies in Pancreatic Cancer)

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11 pages, 575 KiB

Open AccessArticle

Lung Adenocarcinoma Diagnosed at a Younger Age Is Associated with Advanced Stage, Female Sex, and Ever-Smoker Status, in Patients Treated with Lung Resection

by Tommaso A. Dragani, Thomas Muley, Marc A. Schneider, Sonja Kobinger, Martin Eichhorn, Hauke Winter, Hans Hoffmann, Mark Kriegsmann, Sara Noci, Matteo Incarbone, Davide Tosi, Sara Franzi and Francesca Colombo

Cancers 2023, 15(8), 2395; https://doi.org/10.3390/cancers15082395 - 21 Apr 2023

Cited by 1 | Viewed by 1422

Abstract

To date, the factors which affect the age at diagnosis of lung adenocarcinoma are not fully understood. In our study, we examined the relationships of age at diagnosis with smoking, pathological stage, sex, and year of diagnosis in a discovery (n = 1694) [...] Read more.

To date, the factors which affect the age at diagnosis of lung adenocarcinoma are not fully understood. In our study, we examined the relationships of age at diagnosis with smoking, pathological stage, sex, and year of diagnosis in a discovery (n = 1694) and validation (n = 1384) series of lung adenocarcinoma patients who had undergone pulmonary resection at hospitals in the Milan area and at Thoraxklinik (Heidelberg), respectively. In the discovery series, younger age at diagnosis was associated with ever-smoker status (OR = 1.5, p = 0.0035) and advanced stage (taking stage I as reference: stage III OR = 1.4, p = 0.0067; stage IV OR = 1.7, p = 0.0080), whereas older age at diagnosis was associated with male sex (OR = 0.57, p < 0.001). Analysis in the validation series confirmed the ever versus never smokers’ association (OR = 2.9, p < 0.001), the association with highest stages (stage III versus stage I OR = 1.4, p = 0.0066; stage IV versus stage I OR = 2.0, p = 0.0022), and the male versus female sex association (OR = 0.78, p = 0.032). These data suggest the role of smoking in affecting the natural history of the disease. Moreover, aggressive tumours seem to have shorter latency from initiation to clinical detection. Finally, younger age at diagnosis is associated with the female sex, suggesting that hormonal status of young women confers risk to develop lung adenocarcinoma. Overall, this study provided novel findings on the mechanisms underlying age at diagnosis of lung adenocarcinoma. Full article

(This article belongs to the Special Issue World Lung Cancer Awareness Month)

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10 pages, 671 KiB

Open AccessArticle

Characterization of Tumor and Immune Tumor Microenvironment of Primary Tumors and Metastatic Sites in Advanced Renal Cell Carcinoma Patients Based on Response to Nivolumab Immunotherapy: Preliminary Results from the Meet-URO 18 Study

by Sara Elena Rebuzzi, Matteo Brunelli, Francesca Galuppini, Valerio Gaetano Vellone, Alessio Signori, Fabio Catalano, Alessandra Damassi, Gabriele Gaggero, Pasquale Rescigno, Marco Maruzzo, Sara Merler, Francesca Vignani, Alessia Cavo, Umberto Basso, Michele Milella, Olimpia Panepinto, Manlio Mencoboni, Marta Sbaraglia, Angelo Paolo Dei Tos, Veronica Murianni, Malvina Cremante, Miguel Angel Llaja Obispo, Michele Maffezzoli, Giuseppe Luigi Banna, Sebastiano Buti and Giuseppe Fornarini Show full author list Hide full author list

Cancers 2023, 15(8), 2394; https://doi.org/10.3390/cancers15082394 - 21 Apr 2023

Cited by 3 | Viewed by 1919

Abstract

Background: Prognostic and predictive factors for patients with metastatic renal cell carcinoma (mRCC) treated with immunotherapy are highly warranted, and the immune tumor microenvironment (I-TME) is under investigation. Methods: The Meet-URO 18 was a multicentric retrospective study assessing the I-TME in mRCC patients [...] Read more.

Background: Prognostic and predictive factors for patients with metastatic renal cell carcinoma (mRCC) treated with immunotherapy are highly warranted, and the immune tumor microenvironment (I-TME) is under investigation. Methods: The Meet-URO 18 was a multicentric retrospective study assessing the I-TME in mRCC patients treated with ≥2nd-line nivolumab, dichotomized into responders and non-responders according to progression-free survival (≥12 months and ≤3 months, respectively). The primary objective was to identify differential immunohistochemical (IHC) patterns between the two groups. Lymphocyte infiltration and the expressions of different proteins on tumor cells (CD56, CD15, CD68, and ph-mTOR) were analyzed. The expression of PD-L1 was also assessed. Results: A total of 116 tumor tissue samples from 84 patients (59% were primary tumors and 41% were metastases) were evaluated. Samples from responders (N = 55) were significantly associated with lower expression of CD4+ T lymphocytes and higher levels of ph-mTOR and CD56+ compared with samples from non-responders (N = 61). Responders also showed a higher CD3+ expression (p = 0.059) and CD8+/CD4+ ratio (p = 0.084). Non-responders were significantly associated with a higher percentage of clear cell histology and grading. Conclusions: Differential IHC patterns between the tumors in patients who were responders and non-responders to nivolumab were identified. Further investigation with genomic analyses is planned. Full article

(This article belongs to the Special Issue Updates in Novel Markers on Tumors of the Urological Tract: From Diagnosis and Prognosis to Therapy and Clinical Efficacy)

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25 pages, 410 KiB

Open AccessReview

Triple-Negative Breast Cancer: Basic Biology and Immuno-Oncolytic Viruses

by Michael L. Monaco, Omer A. Idris and Karim Essani

Cancers 2023, 15(8), 2393; https://doi.org/10.3390/cancers15082393 - 21 Apr 2023

Cited by 5 | Viewed by 3588

Abstract

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. TNBC diagnoses account for approximately one-fifth of all breast cancer cases globally. The lack of receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER-2, CD340) results in a lack [...] Read more.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer. TNBC diagnoses account for approximately one-fifth of all breast cancer cases globally. The lack of receptors for estrogen, progesterone, and human epidermal growth factor 2 (HER-2, CD340) results in a lack of available molecular-based therapeutics. This increases the difficulty of treatment and leaves more traditional as well as toxic therapies as the only available standards of care in many cases. Recurrence is an additional serious problem, contributing substantially to its higher mortality rate as compared to other breast cancers. Tumor heterogeneity also poses a large obstacle to treatment approaches. No driver of tumor development has been identified for TNBC, and large variations in mutational burden between tumors have been described previously. Here, we describe the biology of six different subtypes of TNBC, based on differential gene expression. Subtype differences can have a large impact on metastatic potential and resistance to treatment. Emerging antibody-based therapeutics, such as immune checkpoint inhibitors, have available targets for small subsets of TNBC patients, leading to partial responses and relatively low overall efficacy. Immuno-oncolytic viruses (OVs) have recently become significant in the pursuit of effective treatments for TNBC. OVs generally share the ability to ignore the heterogeneous nature of TNBC cells and allow infection throughout a treated tumor. Recent genetic engineering has allowed for the enhancement of efficacy against certain tumor types while avoiding the most common side effects in non-cancerous tissues. In this review, TNBC is described in order to address the challenges it presents to potential treatments. The OVs currently described preclinically and in various stages of clinical trials are also summarized, as are their strategies to enhance therapeutic potential. Full article

(This article belongs to the Special Issue Systems Biology of Tumor Immune Microenvironment and Immuno-Oncology)

10 pages, 1346 KiB

Open AccessArticle

Analysis of Local Recurrence Risk in Ductal Carcinoma In Situ and External Validation of the Memorial Sloan Kettering Cancer Center Nomogram

by Gabriela Oses, Eduard Mension, Claudia Pumarola, Helena Castillo, León Francesc, Inés Torras, Isaac Cebrecos, Xavier Caparrós, Sergi Ganau, Belén Ubeda, Xavier Bargallo, Blanca González, Esther Sanfeliu, Sergi Vidal-Sicart, Reinaldo Moreno, Montserrat Muñoz, Gorane Santamaría and Meritxell Mollà

Cancers 2023, 15(8), 2392; https://doi.org/10.3390/cancers15082392 - 21 Apr 2023

Cited by 3 | Viewed by 2507

Abstract

Background: Adjuvant radiotherapy and hormonotherapy after breast-conserving surgery (BCS) in ductal carcinoma in situ (DCIS) have been shown to reduce the risk of local recurrence. To predict the risk of ipsilateral breast tumor relapse (IBTR) after BCS, the Memorial Sloan Kettering Cancer Center [...] Read more.

Background: Adjuvant radiotherapy and hormonotherapy after breast-conserving surgery (BCS) in ductal carcinoma in situ (DCIS) have been shown to reduce the risk of local recurrence. To predict the risk of ipsilateral breast tumor relapse (IBTR) after BCS, the Memorial Sloan Kettering Cancer Center (MSKCC) developed a nomogram to analyze local recurrence (LR) risk in our cohort and to assess its external validation. Methods: A historical cohort study using data from 296 patients treated for DCIS at the Hospital Clínic of Barcelona was carried out. Patients who had had a mastectomy were excluded from the analysis. Results: The mean age was 58 years (42–75), and the median follow-up time was 10.64 years. The overall local relapse rate was 13.04% (27 patients) during the study period. Actuarial 5- and 10-year IBTR rates were 5.8 and 12.9%, respectively. The external validation of the MSKCC nomogram was performed using a multivariate logistic regression analysis on a total of 207 patients, which did not reach statistical significance in the studied population for predicting LR (p = 0.10). The expression of estrogen receptors was significantly associated with a decreased risk of LR (OR: 0.25; p = 0.004). Conclusions: In our series, the LR rate was 13.4%, which was in accordance with the published series. The MSKCC nomogram did not accurately predict the IBTR in this Spanish cohort of patients treated for DCIS (p = 0.10). Full article

(This article belongs to the Special Issue Medical Complications and Supportive Care in Patients with Cancer)

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11 pages, 288 KiB

Open AccessArticle

Robotic versus Video-Assisted Thoracic Surgery for Lung Cancer: Short-Term Outcomes of a Propensity Matched Analysis

by Savvas Lampridis, Alessandro Maraschi, Corinne Le Reun, Tom Routledge and Andrea Billè

Cancers 2023, 15(8), 2391; https://doi.org/10.3390/cancers15082391 - 21 Apr 2023

Cited by 5 | Viewed by 1971

Abstract

Robot-assisted thoracic surgery (RATS) has gained popularity for the treatment of lung cancer, but its quality outcome measures are still being evaluated. The purpose of this study was to compare the perioperative outcomes of lung cancer resection using RATS versus video-assisted thoracic surgery [...] Read more.

Robot-assisted thoracic surgery (RATS) has gained popularity for the treatment of lung cancer, but its quality outcome measures are still being evaluated. The purpose of this study was to compare the perioperative outcomes of lung cancer resection using RATS versus video-assisted thoracic surgery (VATS). To achieve this aim, we conducted a retrospective analysis of consecutive patients who underwent lung cancer surgery between July 2015 and December 2020. A propensity-matched analysis was performed based on patients’ performance status, forced expiratory volume in 1 s% of predicted, diffusing capacity of the lungs for carbon monoxide% of predicted, and surgical procedure (lobectomy or segmentectomy). Following propensity matching, a total of 613 patients were included in the analysis, of which 328 underwent RATS, and 285 underwent VATS, with satisfactory performance indicators. The results of the analysis indicated that RATS had a significantly longer operating time than VATS (132.4 ± 37.3 versus 122.4 ± 27.7 min; mean difference of 10 min 95% CI [confidence interval], 4.2 to 15.9 min; p = 0.001). On the other hand, VATS had a significantly higher estimated blood loss compared to RATS (169.7 ± 237.2 versus 82.2 ± 195.4 mL; mean difference of 87.5 mL; 95% CI, 48.1 to 126.8 mL; p < 0.001). However, there were no significant differences between the groups in terms of the duration of chest tubes, length of hospital stay, low- and high-grade complications, as well as readmissions and mortality within 30 days after surgery. Moreover, the number of dissected lymph-node stations was significantly higher with VATS than RATS (5.9 ± 1.5 versus 4.8 ± 2.2; mean difference of 1.2; 95% CI, 0.8 to 1.5; p = 0.001). Nonetheless, the percentage of patients who were upstaged after histopathological analysis of the resected lymph nodes was similar between the two groups. In conclusion, RATS and VATS yielded comparable results for most of the short-term outcomes assessed. Further research is needed to validate the implementation of RATS and identify its potential benefits over VATS. Full article

(This article belongs to the Special Issue Novel Strategy and Technologies in Local and Locoregional Treatment for Lung Cancer)

35 pages, 1850 KiB

Open AccessReview

Reviewing the Prospective Pharmacological Potential of Isothiocyanates in Fight against Female-Specific Cancers

by Shoaib Shoaib, Farheen Badrealam Khan, Meshari A. Alsharif, M. Shaheer Malik, Saleh A. Ahmed, Yahya F. Jamous, Shahab Uddin, Ching Siang Tan, Chrismawan Ardianto, Saba Tufail, Long Chiau Ming, Nabiha Yusuf and Najmul Islam

Cancers 2023, 15(8), 2390; https://doi.org/10.3390/cancers15082390 - 20 Apr 2023

Cited by 5 | Viewed by 3330

Abstract

Gynecological cancers are the most commonly diagnosed malignancies in females worldwide. Despite the advancement of diagnostic tools as well as the availability of various therapeutic interventions, the incidence and mortality of female-specific cancers is still a life-threatening issue, prevailing as one of the [...] Read more.

Gynecological cancers are the most commonly diagnosed malignancies in females worldwide. Despite the advancement of diagnostic tools as well as the availability of various therapeutic interventions, the incidence and mortality of female-specific cancers is still a life-threatening issue, prevailing as one of the major health problems worldwide. Lately, alternative medicines have garnered immense attention as a therapeutic intervention against various types of cancers, seemingly because of their safety profiles and enhanced effectiveness. Isothiocyanates (ITCs), specifically sulforaphane, benzyl isothiocyanate, and phenethyl isothiocyanate, have shown an intriguing potential to actively contribute to cancer cell growth inhibition, apoptosis induction, epigenetic alterations, and modulation of autophagy and cancer stem cells in female-specific cancers. Additionally, it has been shown that ITCs plausibly enhance the chemo-sensitization of many chemotherapeutic drugs. To this end, evidence has shown enhanced efficacy in combinatorial regimens with conventional chemotherapeutic drugs and/or other phytochemicals. Reckoning with these, herein, we discuss the advances in the knowledge regarding the aspects highlighting the molecular intricacies of ITCs in female-specific cancers. In addition, we have also argued regarding the potential of ITCs either as solitary treatment or in a combinatorial therapeutic regimen for the prevention and/or treatment of female-specific cancers. Hopefully, this review will open new horizons for consideration of ITCs in therapeutic interventions that would undoubtedly improve the prognosis of the female-specific cancer clientele. Considering all these, it is reasonable to state that a better understanding of these molecular intricacies will plausibly provide a facile opportunity for treating these female-specific cancers. Full article

(This article belongs to the Special Issue Advances in Anticancer Drugs and Pharmacotherapy of Cancer)

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18 pages, 1913 KiB

Open AccessReview

Inflammation-Driven Colorectal Cancer Associated with Colitis: From Pathogenesis to Changing Therapy

by Olga Maria Nardone, Irene Zammarchi, Giovanni Santacroce, Subrata Ghosh and Marietta Iacucci

Cancers 2023, 15(8), 2389; https://doi.org/10.3390/cancers15082389 - 20 Apr 2023

Cited by 22 | Viewed by 5379

Abstract

Patients affected by inflammatory bowel disease (IBD) have a two-fold higher risk of developing colorectal cancer (CRC) than the general population. IBD-related CRC follows a different genetic and molecular pathogenic pathway than sporadic CRC and can be considered a complication of chronic intestinal [...] Read more.

Patients affected by inflammatory bowel disease (IBD) have a two-fold higher risk of developing colorectal cancer (CRC) than the general population. IBD-related CRC follows a different genetic and molecular pathogenic pathway than sporadic CRC and can be considered a complication of chronic intestinal inflammation. Since inflammation is recognised as an independent risk factor for neoplastic progression, clinicians strive to modulate and control disease, often using potent therapy agents to achieve mucosal healing and decrease the risk of colorectal cancer in IBD patients. Improved therapeutic control of inflammation, combined with endoscopic advances and early detection of pre-cancerous lesions through surveillance programs, explains the lower incidence rate of IBD-related CRC. In addition, current research is increasingly focused on translating emerging and advanced knowledge in microbiome and metagenomics into personalised, early, and non-invasive CRC screening tools that guide organ-sparing therapy in IBD patients. This review aims to summarise the existing literature on IBD-associated CRC, focusing on new insights into the alteration of the intestinal barrier and the interactions with the gut microbiome as the initial promoter. In addition, the role of OMIC techniques for precision medicine and the impact of the available IBD therapeutic armamentarium on the evolution to CRC will be discussed. Full article

(This article belongs to the Special Issue Chronic Intestinal Inflammation and Cancers)

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Pathogenic pathway of sporadic colorectal cancer and IBD-related colorectal cancer. The figure shows the different molecular pathways related to sporadic and IBD-related colorectal cancer (CRC). The sporadic CRC prevails in the adenoma-to-carcinoma sequence, while the inflammation–dysplasia–carcinoma cascade characterises the colitis related-CRC. In addition, the main gene mutations determining the progression of the two tumour phenotypes are reported with emphasis on the earliest mutations in the two processes. Namely, these entail APC loss of function, the WNT-beta catenin pathway activation for sporadic CRC (see zoom circle at left), and p53 mutations with consequent impacts on cell cycle, DNA repair, and cell viability for IBD-related CRC (see zoom circle at right). Finally, high-definition white light endoscopic images and virtual chromoendoscopic images (obtained through the Narrow Band Imaging technology) are provided for each phenotype of tumours. Created with “Biorender.com”. Abbreviations: CRC, colorectal cancer; IBD, inflammatory bowel disease. Full article ">Figure 2
Multi—OMICs and its impact on inflammatory bowel disease and colorectal cancer. This figure schematically represents the main OMIC techniques available to date: genomics—the study of the genetic or epigenetic sequence information; transcriptomics—the evaluation of RNA transcripts; proteomics—the investigation of the structure and function of proteins; metabolomics—the identification and quantification of metabolites; metaomics—the application of the previously described techniques to the gut microbiome. The multiple and integrated application of these techniques, so-called multi-OMICs, will offer a great chance to fill knowledge gaps in inflammatory bowel disease (IBD) and colorectal cancer (CRC). In more detail, the application of multi-OMICs will provide (as specified in figure squares) the discovery of novel biological mechanisms below IBD and CRC pathogenesis, the detection of new clinically relevant biomarkers, the definition of integrated signatures able to stratify patients, and the enhancement of physician ability to establish disease prediction, establish a prognosis, and treat patients appropriately. Created with “Biorender.com”. Abbreviations: CRC, colorectal cancer; IBD, inflammatory bowel disease. Full article ">Figure 3
Intestinal inflammation and evolution to cancer in IBD. The impairment of the mucus layer and epithelial barrier, associated with dysbiosis, determines the inflammatory response, leading to IBD disease development and possible cancer evolution. Bile acids and small-chain fatty acids participate in initiating this process. In the lamina propria, dendritic cells and macrophages, after their interaction with intestinal microbes, determine the activation of innate immune cells through the release of numerous cytokines (neutrophils, eosinophils, etc.) and trigger the adaptative (Th1 and Th17) immune cells differentiation in mesenteric lymph nodes. Activated T cells, through a vascular homing mediated by the alfa4-beta7–MAdCAM-1 pathway, reach the intestinal lamina propria and spread the inflammatory process. The persistence of inflammation can lead to carcinogenesis and metastasis. Proteins involved in maintaining gut barrier function, such as intestinal fatty acid binding protein and tight junction proteins (shown in the dotted-line circle box in the upper left corner of the figure), have been proposed as potential biomarkers for cancer detection. Created with “Biorender.com”. Abbreviations: E. coli, Escherichia coli; ETBF, Enterotoxigenic Bacteroides fragilis; iFABP, intestinal fatty acid binding protein; IFN, interferon; IL, interleukin; JAM, junctional adhesion molecule; MAdCAM, mucosal vascular addressin cell adhesion molecule; pks+, polyketide synthase productor; SCFA, small chain fatty acid; TNF, tumour necrosis factor. Full article ">

13 pages, 481 KiB

Open AccessReview

A Historical Overview on the Role of Hepatitis B and C Viruses as Aetiological Factors for Hepatocellular Carcinoma

by Tommaso Stroffolini and Giacomo Stroffolini

Cancers 2023, 15(8), 2388; https://doi.org/10.3390/cancers15082388 - 20 Apr 2023

Cited by 13 | Viewed by 3083

Abstract

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the leading cause of hepatocellular carcinoma (HCC) worldwide. Currently, HBV-related HCC predominates in Sub-Saharan Africa and South-East-Asia, while HCV-related HCC predominates in northern Africa and in the western world. Liver cirrhosis is the [...] Read more.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the leading cause of hepatocellular carcinoma (HCC) worldwide. Currently, HBV-related HCC predominates in Sub-Saharan Africa and South-East-Asia, while HCV-related HCC predominates in northern Africa and in the western world. Liver cirrhosis is the underlying condition in most HBV cases and in nearly all HCV cases. Several cofactors, viral and non-viral, play a role in the progression toward HCC: dual HBV/HCV infection, HDV, HIV, alcohol intake, smoking, diabetes mellitus, obesity, and NAFLD/NASH. HBV vaccine is effective in preventing both infection and HCC; antiviral drugs may suppress HBV replication and eradicate HCV infection, halting progression to HCC. Inequalities exist between high- and low-income countries with respect to vaccine availability and access to antivirals. These factors represent barriers to the control of HCC incidence. Lack of an effective vaccine against HCV is also a serious barrier to HCV elimination and HCC prevention. The most crucial steps and knowledge that have arisen over time on the association between the two major hepatotropic viruses and HCC are discussed in this historical review. Full article

(This article belongs to the Special Issue Viruses in Cancer Etiology)

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15 pages, 10500 KiB

Open AccessArticle

Biomarkers of Tumor Heterogeneity in Glioblastoma Multiforme Cohort of TCGA

by Garrett Winkelmaier, Brandon Koch, Skylar Bogardus, Alexander D. Borowsky and Bahram Parvin

Cancers 2023, 15(8), 2387; https://doi.org/10.3390/cancers15082387 - 20 Apr 2023

Cited by 1 | Viewed by 2389

Abstract

Tumor Whole Slide Images (WSI) are often heterogeneous, which hinders the discovery of biomarkers in the presence of confounding clinical factors. In this study, we present a pipeline for identifying biomarkers from the Glioblastoma Multiforme (GBM) cohort of WSIs from TCGA archive. The [...] Read more.

Tumor Whole Slide Images (WSI) are often heterogeneous, which hinders the discovery of biomarkers in the presence of confounding clinical factors. In this study, we present a pipeline for identifying biomarkers from the Glioblastoma Multiforme (GBM) cohort of WSIs from TCGA archive. The GBM cohort endures many technical artifacts while the discovery of GBM biomarkers is challenged because “age” is the single most confounding factor for predicting outcomes. The proposed approach relies on interpretable features (e.g., nuclear morphometric indices), effective similarity metrics for heterogeneity analysis, and robust statistics for identifying biomarkers. The pipeline first removes artifacts (e.g., pen marks) and partitions each WSI into patches for nuclear segmentation via an extended U-Net for subsequent quantitative representation. Given the variations in fixation and staining that can artificially modulate hematoxylin optical density (HOD), we extended Navab’s Lab method to normalize images and reduce the impact of batch effects. The heterogeneity of each WSI is then represented either as probability density functions (PDF) per patient or as the composition of a dictionary predicted from the entire cohort of WSIs. For PDF- or dictionary-based methods, morphometric subtypes are constructed based on distances computed from optimal transport and linkage analysis or consensus clustering with Euclidean distances, respectively. For each inferred subtype, Kaplan–Meier and/or the Cox regression model are used to regress the survival time. Since age is the single most important confounder for predicting survival in GBM and there is an observed violation of the proportionality assumption in the Cox model, we use both age and age-squared coupled with the Likelihood ratio test and forest plots for evaluating competing statistics. Next, the PDF- and dictionary-based methods are combined to identify biomarkers that are predictive of survival. The combined model has the advantage of integrating global (e.g., cohort scale) and local (e.g., patient scale) attributes of morphometric heterogeneity, coupled with robust statistics, to reveal stable biomarkers. The results indicate that, after normalization of the GBM cohort, mean HOD, eccentricity, and cellularity are predictive of survival. Finally, we also stratified the GBM cohort as a function of EGFR expression and published genomic subtypes to reveal genomic-dependent morphometric biomarkers. Full article

(This article belongs to the Special Issue Application of Multi-Omics Analysis in Cancer Diagnosis, Treatment and Prognosis)

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16 pages, 709 KiB

Open AccessSystematic Review

Plasma Device Functions and Tissue Effects in the Female Pelvis—A Systematic Review

by Nick J. van de Berg, Gatske M. Nieuwenhuyzen-de Boer, Xu Shan Gao, L. Lucia Rijstenberg and Heleen J. van Beekhuizen

Cancers 2023, 15(8), 2386; https://doi.org/10.3390/cancers15082386 - 20 Apr 2023

Viewed by 2007

Abstract

Medical use of (non-)thermal plasmas is an emerging field in gynaecology. However, data on plasma energy dispersion remain limited. This systematic review presents an overview of plasma devices, fields of effective application, and impact of use factors and device settings on tissues in [...] Read more.

Medical use of (non-)thermal plasmas is an emerging field in gynaecology. However, data on plasma energy dispersion remain limited. This systematic review presents an overview of plasma devices, fields of effective application, and impact of use factors and device settings on tissues in the female pelvis, including the uterus, ovaries, cervix, vagina, vulva, colon, omentum, mesenterium, and peritoneum. A search of the literature was performed on 4 January 2023 in the Medline Ovid, Embase, Cochrane, Web of Science, and Google Scholar databases. Devices were classified as plasma-assisted electrosurgery (ES) using electrothermal energy, neutral argon plasma (NAP) using kinetic particle energy, or cold atmospheric plasma (CAP) using non-thermal biochemical reactions. In total, 8958 articles were identified, of which 310 were scanned, and 14 were included due to containing quantitative data on depths or volumes of tissues reached. Plasma-assisted ES devices produce a thermal effects depth of <2.4 mm. In turn, NAP effects remained superficial, <1.0 mm. So far, the depth and uniformity of CAP effects are insufficiently understood. These data are crucial to achieve complete treatment, reduce recurrence, and limit damage to healthy tissues (e.g., prevent perforations or preserve parenchyma). Upcoming and potentially high-gain applications are discussed, and deficits in current evidence are identified. Full article

(This article belongs to the Special Issue Gynecologic Oncology: Prevention, Screening and Treatment Innovations)

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29 pages, 1599 KiB

Open AccessReview

The Ubiquitin–Proteasome System in Tumor Metabolism

by Jie Wang, Yuandi Xiang, Mengqi Fan, Shizhen Fang and Qingquan Hua

Cancers 2023, 15(8), 2385; https://doi.org/10.3390/cancers15082385 - 20 Apr 2023

Cited by 7 | Viewed by 3472

Abstract

Metabolic reprogramming, which is considered a hallmark of cancer, can maintain the homeostasis of the tumor environment and promote the proliferation, survival, and metastasis of cancer cells. For instance, increased glucose uptake and high glucose consumption, known as the “Warburg effect,” play an [...] Read more.

Metabolic reprogramming, which is considered a hallmark of cancer, can maintain the homeostasis of the tumor environment and promote the proliferation, survival, and metastasis of cancer cells. For instance, increased glucose uptake and high glucose consumption, known as the “Warburg effect,” play an essential part in tumor metabolic reprogramming. In addition, fatty acids are harnessed to satisfy the increased requirement for the phospholipid components of biological membranes and energy. Moreover, the anabolism/catabolism of amino acids, such as glutamine, cystine, and serine, provides nitrogen donors for biosynthesis processes, development of the tumor inflammatory environment, and signal transduction. The ubiquitin–proteasome system (UPS) has been widely reported to be involved in various cellular biological activities. A potential role of UPS in the metabolic regulation of tumor cells has also been reported, but the specific regulatory mechanism has not been elucidated. Here, we review the role of ubiquitination and deubiquitination modification on major metabolic enzymes and important signaling pathways in tumor metabolism to inspire new strategies for the clinical treatment of cancer. Full article

(This article belongs to the Special Issue Cancer Metabolomic Analysis)

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The process of the ubiquitin–proteasome system. Ubiquitination conjugation is initiated by activating enzyme E1, with ATP-dependent hydrolysis. Then, ubiquitin is transferred to E2, and E3 ligase cooperates with the E2 ligase ubiquitin complex onto the target substrates; the ubiquitins can covalently attach to each other by forming various linear or branched ubiquitin chains on the target substrates, forming mono-ubiquitination, multi-ubiquitination, and poly-ubiquitination ways of modification on substrates. Among them, the mono-ubiquitinated proteins cannot be degraded by proteasomes, and the substrates with at least four ubiquitins attached can be degraded by proteasomes. Then, the labelled substrates are recognized by the 26S proteasome and degraded. Deubiquitination enzymes (DUBs) can deconjugate ubiquitin from substrates to stabilize the protein levels of substrates and keep the balance of the ubiquitin pool in the human body. Ub, ubiquitin; DUB: deubiquitination enzymes. Full article ">Figure 2
The ubiquitination and deubiquitination of the essential enzymes in tumor glucose metabolism and fatty acid metabolism. Glucose metabolism can produce large amounts of raw materials for the synthesis of many biological macromolecules for tumor cells, and fatty acid metabolism contributes to the tumor cell membrane and transmission of secondary messengers. The ligands bind to cell surface receptors and initiate signal transduction cascades; essential enzymes of these two kinds of metabolism reprograming are highlighted in red, pyruvate is a bridge between them, and the ubiquitination enzyme (red) and DUB (blue) control the balance of key enzymes that regulate tumor cell proliferation and chemotherapy resistance as described in the text. Transcription factors mTOR, KRAS, HIF, and c-Myc regulate the tumor glucose and fatty acid metabolism. HK2, Hexokinase 2; PFK2, Phosphofructokinase 2; PKM2, Pyruvate kinase M2; Glucose-6-P, Glucose-6-phosphate; Fructose-6-P, fructose-6-phosphate; Fructose-1,6-2P,fructose-1,6-bisphosphate; 3PG, 3-phosphoglycerate; PKM2, Pyruvate kinase M2; PEP, phosphoenolpyruvate; LDH, lactate dehydrogenase; NADH, Nicotinamide Adenine Dinucleotide; Ribose-5-P, ribose-5-phosphate; ACC1, Acetyl-coenzyme A carboxylase 1; FASN, Fatty acid synthase; ACLY, ATP citrate lyase; PPARγ, Peroxisome proliferator-activated receptor gamma; α-KG, ketoglutarate; IDH2, isocitrate dehydrogenase2; Ac-CoA, acetyl-coenzyme A; TCA cycle, Tricarboxylic acid cycle. Full article ">Figure 3
The ubiquitination and deubiquitination of the essential enzymes in tumor amino acid metabolism. “Glutamine addition” in tumor cells provides carbon and nitrogen to replenish the tricarboxylic acid cycle (TCA) and maintain mitochondrial ATP production. The essential enzymes of amino acid metabolism reprogramming are highlighted in blue. The ubiquitin enzymes (red) and DUBs (blue) negatively or positively regulate the activity of the key enzymes; among them, PHGDH, ASCT2, SLC7A11, and ASS1 were the frequently UPS-modified enzymes, and the glycolysis intermediate 3-PG can be used to the synthesis of serine. Transcription factors mTOR, KRAS, HIF, c-Myc, and YAP/TAZ regulate the tumor amino acid metabolism. GLS, glutaminase; GLUD, glutamate dehydrogenase; α-KG: α-ketoglutarate; 3-PG, 3-phosphoglycerate; OAA, oxaloacetate; GOT2; Glutamic-oxaloacetic transaminase 2; PHGDH,3-phosphoglycerate dehydrogenase; PSPH, phosphoserine phosphatase; ASS1, argininosuccinate synthase1; GSH, glutathione; GSSG, glutathione disulfide; ROS, reactive oxygen species; SAM, S-adenosylmethionine. Full article ">

28 pages, 486 KiB

Open AccessReview

Locoregional Therapy for Intrahepatic Cholangiocarcinoma

by Mackenzie Owen, Mina S. Makary and Eliza W. Beal

Cancers 2023, 15(8), 2384; https://doi.org/10.3390/cancers15082384 - 20 Apr 2023

Cited by 15 | Viewed by 2511

Abstract

Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis, and surgical resection (SR) offers the only potential for cure. Unfortunately, only a small proportion of patients are eligible for resection due to locally advanced or metastatic disease. Locoregional therapies (LRT) are often used in unresectable [...] Read more.

Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis, and surgical resection (SR) offers the only potential for cure. Unfortunately, only a small proportion of patients are eligible for resection due to locally advanced or metastatic disease. Locoregional therapies (LRT) are often used in unresectable liver-only or liver-dominant ICC. This review explores the role of these therapies in the treatment of ICC, including radiofrequency ablation (RFA), microwave ablation (MWA), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), external beam radiotherapy (EBRT), stereotactic body radiotherapy (SBRT), hepatic arterial infusion (HAI) of chemotherapy, irreversible electroporation (IE), and brachytherapy. A search of the current literature was performed to examine types of LRT currently used in the treatment of ICC. We examined patient selection, technique, and outcomes of each type. Overall, LRTs are well-tolerated in the treatment of ICC and are effective in improving overall survival (OS) in this patient population. Further studies are needed to reduce bias from heterogenous patient populations and small sample sizes, as well as to determine whether certain LRTs are superior to others and to examine optimal treatment selection. Full article

(This article belongs to the Special Issue New Insights in Biliary Tract Cancers Therapy)

27 pages, 1326 KiB

Open AccessReview

Immunotherapy for Peritoneal Carcinomatosis: Challenges and Prospective Outcomes

by Mefotse Saha Cyrelle Ornella, Narayanasamy Badrinath, Kyeong-Ae Kim, Jung Hee Kim, Euna Cho, Tae-Ho Hwang and Jae-Joon Kim

Cancers 2023, 15(8), 2383; https://doi.org/10.3390/cancers15082383 - 20 Apr 2023

Cited by 9 | Viewed by 6960

Abstract

Peritoneal metastasis, also known as peritoneal carcinomatosis (PC), is a refractory cancer that is typically resistant to conventional therapies. The typical treatment for PC is a combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Recently, research in this area has seen [...] Read more.

Peritoneal metastasis, also known as peritoneal carcinomatosis (PC), is a refractory cancer that is typically resistant to conventional therapies. The typical treatment for PC is a combination of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Recently, research in this area has seen significant advances, particularly in immunotherapy as an alternative therapy for PC, which is very encouraging. Catumaxomab is a trifunctional antibody intraperitoneal (IP) immunotherapy authorized in Europe that can be used to diminish malignant ascites by targeting EpCAM. Intraperitoneal (IP) immunotherapy breaks immunological tolerance to treat peritoneal illness. Increasing T-cell responses and vaccination against tumor-associated antigens are two methods of treatment. CAR-T cells, vaccine-based therapeutics, dendritic cells (DCs) in combination with pro-inflammatory cytokines and NKs, adoptive cell transfer, and immune checkpoint inhibitors are promising treatments for PC. Carcinoembryonic antigen-expressing tumors are suppressed by IP administration of CAR-T cells. This reaction was strengthened by anti-PD-L1 or anti-Gr1. When paired with CD137 co-stimulatory signaling, CAR-T cells for folate receptor cancers made it easier for T-cell tumors to find their way to and stay alive in the body. Full article

(This article belongs to the Section Cancer Immunology and Immunotherapy)

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14 pages, 1030 KiB

Open AccessArticle

First- versus Third-Generation EGFR Tyrosine Kinase Inhibitors in EGFR-Mutated Non-Small Cell Lung Cancer Patients with Brain Metastases

by Vineeth Tatineni, Patrick J. O’Shea, Ahmad Ozair, Atulya A. Khosla, Shreya Saxena, Yasmeen Rauf, Xuefei Jia, Erin S. Murphy, Samuel T. Chao, John H. Suh, David M. Peereboom and Manmeet S. Ahluwalia

Cancers 2023, 15(8), 2382; https://doi.org/10.3390/cancers15082382 - 20 Apr 2023

Cited by 6 | Viewed by 2626

Abstract

Introduction: Up to 50% of non-small cell lung cancer (NSCLC) harbor EGFR alterations, the most common etiology behind brain metastases (BMs). First-generation EGFR-directed tyrosine kinase inhibitors (EGFR-TKI) are limited by blood-brain barrier penetration and T790M tumor mutations, wherein third-generation EGFR-TKIs, like Osimertinib, have [...] Read more.

Introduction: Up to 50% of non-small cell lung cancer (NSCLC) harbor EGFR alterations, the most common etiology behind brain metastases (BMs). First-generation EGFR-directed tyrosine kinase inhibitors (EGFR-TKI) are limited by blood-brain barrier penetration and T790M tumor mutations, wherein third-generation EGFR-TKIs, like Osimertinib, have shown greater activity. However, their efficacy has not been well-studied in later therapy lines in NSCLC patients with BMs (NSCLC-BM). We sought to compare outcomes of NSCLC-BM treated with either first- or third-generation EGFR-TKIs in first-line and 2nd-to-5th-line settings. Methods: A retrospective review of NSCLC-BM patients diagnosed during 2010–2019 at Cleveland Clinic, Ohio, US, a quaternary-care center, was performed and reported following ‘strengthening the reporting of observational studies in epidemiology’ (STROBE) guidelines. Data regarding socio-demographic, histopathological, molecular characteristics, and clinical outcomes were collected. Primary outcomes were median overall survival (mOS) and progression-free survival (mPFS). Multivariable Cox proportional hazards modeling and propensity score matching were utilized to adjust for confounders. Results: 239 NSCLC-BM patients with EGFR alterations were identified, of which 107 received EGFR-TKIs after diagnosis of BMs. 77.6% (83/107) received it as first-line treatment, and 30.8% (33/107) received it in later (2nd–5th) lines of therapy, with nine patients receiving it in both settings. 64 of 107 patients received first-generation (erlotinib/gefitinib) TKIs, with 53 receiving them in the first line setting and 13 receiving it in the 2nd–5th lines of therapy. 50 patients received Osimertinib as third-generation EGFR-TKI, 30 in first-line, and 20 in the 2nd–5th lines of therapy. Univariable analysis in first-line therapy demonstrated mOS of first- and third-generation EGFR-TKIs as 18.2 and 19.4 months, respectively (p = 0.57), while unadjusted mPFS of first- and third-generation EGFR-TKIs was 9.3 and 13.8 months, respectively (p = 0.14). In 2nd–5th line therapy, for first- and third-generation EGFR-TKIs, mOS was 17.3 and 11.9 months, (p = 0.19), while mPFS was 10.4 and 6.08 months, respectively (p = 0.41). After adjusting for age, performance status, presence of extracranial metastases, whole-brain radiotherapy, and presence of leptomeningeal metastases, hazard ratio (HR) for OS was 1.25 (95% CI 0.63–2.49, p = 0.52) for first-line therapy. Adjusted HR for mOS in 2nd-to-5th line therapy was 1.60 (95% CI 0.55–4.69, p = 0.39). Conclusions: No difference in survival was detected between first- and third-generation EGFR-TKIs in either first or 2nd-to-5th lines of therapy. Larger prospective studies are warranted reporting intracranial lesion size, EGFR alteration and expression levels in primary tumor and brain metastases, and response rates. Full article

(This article belongs to the Special Issue Updates on Molecular Targeted Therapies for CNS Tumors)

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13 pages, 1069 KiB

Open AccessReview

Non-Invasive Imaging Modalities in Intravesical Murine Models of Bladder Cancer

by Sydney Relouw, George J. Dugbartey and Alp Sener

Cancers 2023, 15(8), 2381; https://doi.org/10.3390/cancers15082381 - 20 Apr 2023

Cited by 2 | Viewed by 1757

Abstract

Bladder cancer (BCa) is the sixth most prevalent cancer in men and seventeenth most prevalent cancer in women worldwide. Current treatment paradigms have limited therapeutic impact, suggesting an urgent need for the investigation of novel therapies. To best emulate the progression of human [...] Read more.

Bladder cancer (BCa) is the sixth most prevalent cancer in men and seventeenth most prevalent cancer in women worldwide. Current treatment paradigms have limited therapeutic impact, suggesting an urgent need for the investigation of novel therapies. To best emulate the progression of human BCa, a pre-clinical intravesical murine model is required in conjunction with existing non-invasive imaging modalities to detect and evaluate cancer progression. Non-invasive imaging modalities reduce the number of required experimental models while allowing for longitudinal studies of novel therapies to investigate long-term efficacy. In this review, we discuss the individual and multi-modal use of non-invasive imaging modalities; bioluminescence imaging (BLI), micro-ultrasound imaging (MUI), magnetic resonance imaging (MRI), and positron emission tomography (PET) in BCa evaluation. We also provide an update on the potential and the future directions of imaging modalities in relation to intravesical murine models of BCa. Full article

(This article belongs to the Special Issue Multidisciplinary Approaches in Bladder Cancer)

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Figure 1
Bioluminescence imaging (BLI) method in an intravesical murine model of BCa, where a BCa cell line is transfected with a luciferase vector that is subsequently inoculated into the bladder wall of the murine model. The D-luciferin substrate is administered via intravascular or intraperitoneal injection 10–18 min prior to visualization to stimulate the reporter system. Visualization occurs using an in vivo imaging system that detects the emission of green light when luciferase converts D-luciferin to oxyluciferin. Figure prepared with BioRender (<a href="http://biorender.com" target="_blank">biorender.com</a>, accessed on 1 February 2023). Full article ">Figure 2
Micro-ultrasound imaging (MUI) method in an intravesical model of BCa where the abdomen is shaved, depilatory cream is applied to remove fine hairs, and high viscosity ultrasound gel is utilized during imaging to enhance the image resolution. Subsequent studies administered microbubbles via intravenous injection prior to imaging for visualization and quantification of the superficial tumor vasculature. Figure prepared with BioRender (<a href="http://biorender.com" target="_blank">biorender.com</a>, accessed on 1 February 2023). Full article ">Figure 3
Positron emission tomography (PET) method in an intravesical murine model of BCa in which EGFR-expressing BCa cells are inoculated into the mouse bladder wall. Antibodies are conjugated and radiolabeled producing [89Zr] Zr DFO-panitumumab, which was administered intravenously, and mice were imaged 72 h later. Figure prepared with BioRender (<a href="http://biorender.com" target="_blank">biorender.com</a>, accessed on 1 February 2023). Full article ">

14 pages, 1235 KiB

Open AccessArticle

Cyclooxygenase and Lipoxygenase Gene Expression in the Inflammogenesis of Colorectal Cancer: Correlated Expression of EGFR, JAK STAT and Src Genes, and a Natural Antisense Transcript, RP11-C67.2.2

by Brian M. Kennedy and Randall E. Harris

Cancers 2023, 15(8), 2380; https://doi.org/10.3390/cancers15082380 - 20 Apr 2023

Cited by 4 | Viewed by 2057

Abstract

We examined the expression of major inflammatory genes, cyclooxygenase-1, 2 (COX1, COX2), arachidonate-5-lipoxygenase (ALOX5), and arachidonate-5-lipoxygenase activating protein (ALOX5AP) among 469 tumor specimens of colorectal cancer in The Cancer Genome Atlas (TCGA). Among 411 specimens without mutations in mismatch repair (MMR) genes, the [...] Read more.

We examined the expression of major inflammatory genes, cyclooxygenase-1, 2 (COX1, COX2), arachidonate-5-lipoxygenase (ALOX5), and arachidonate-5-lipoxygenase activating protein (ALOX5AP) among 469 tumor specimens of colorectal cancer in The Cancer Genome Atlas (TCGA). Among 411 specimens without mutations in mismatch repair (MMR) genes, the mean expression of each of the inflammatory genes ranked above the 80th percentile, and the overall mean cyclooxygenase expression (COX1+COX2) ranked in the upper 99th percentile of all genes. Similar levels were observed for 58 cases with MMR mutations. Pearson correlation coefficients exceeding r = 0.70 were observed between COX and LOX mRNA levels with genes of major cell-signaling pathways involved in tumorigenesis (Src, JAK STAT, MAPK, PI3K). We observed a novel association (r = 0.78) between ALOX5 expression and a natural antisense transcript (NAT), RP11-67C2.2, a long non-coding mRNA gene, 462 base pairs in length that is located within the terminal intron of the ALOX5 gene on chromosome 10q11.21. Tumor-promoting genes highly correlated with the expression of COX1, COX2, ALOX5 and ALOX5AP are known to increase mitogenesis, mutagenesis, angiogenesis, cell survival, immunosuppression and metastasis in the inflammogenesis of colorectal cancer. These genes and the novel NAT, RP1167C2.2 are potential molecular targets for chemoprevention and therapy of colorectal cancer. Full article

(This article belongs to the Special Issue Cyclooxygenase (COX) and Lipoxygenase (LOX) in the Inflammogenesis of Cancer)

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Violin density plots of the genetic expression of COX1, COX2, ALOX5 and ALOX5AP in invasive colorectal cancer. Means and standard deviations are indicated by horizontal bars and box plots, respectively. Prostaglandin Synthetase-1, PTSG1 (Cyclooxygenase-1, COX1). Prostaglandin Synthetase-2, PTSG2 (Cyclooxygenase-2, COX2). Arachidonate 5-Lipoxygenase (ALOX5). Arachidonate 5-Lipoxygenase Activating Protein (ALOX5AP). RP11-67C2.2: Novel Natural Antisense Transcript Gene, RP11-67C2.2 nested within the terminal region of the ALOX5 gene on chromosome 10q11.21. Full article ">Figure 2
Violin density plots of the expression of inflammation-correlated genes of the Src and JAK STAT signaling pathways. (a) Src Genes; (b) JAK STAT Genes. Full article ">Figure 3
Violin density plots of the expression of EGFR and other inflammation-correlated tumor response genes. Full article ">Figure 4
Inflammogenesis model of colorectal carcinogenesis. Genes and pathways in the model. Arachidonic Acid biosynthesis: Phospholipase A2: PLA2, Acyl-CoA synthetase: ACSLl; Prostaglandin biosynthesis: Cyclooxygenase-1, 2 (COX1, COX2), Leukotriene biosynthesis: ALOX5 arachidonate 5-lipoxygenase, RP 11 67C2.2 long noncoding natural antisense transcript of ALOX5, ALOX5AP (FLAP) arachidonate 5-lipoxygenase activating protein; Prostaglandin E receptors: PTGER1, PTGER2, PTGER3, PTGER4, PTGFR; Leukotriene receptors: LTB4R, CysLTR1, CysLTR2; Colony Stimulating Factor receptors: CSFR1, CSFR2B, CSFR3; Transforming Growth Factor: TGF; Janus Kinase Transduction and Transcription cell signaling: JAK STAT; Receptor Tyrosine Kinase: RTK; Epidermal Growth Factor Receptor: EGFR; Mitogen Activated Protein Kinase cell signaling: MAPK; Phosphoinositide 3 Kinase cell signaling: PI3K; Src Tyrosine Kinase cell signaling: Src; TEK Receptor Tyrosine Kinase: TEK; Oncostatin Tyrosine Kinase Membrane Receptor: OSMR; Interleukin 6: IL6; Interleukin 1B: IL1B; CXC Motif Chemokine Ligands 5 and 8: CXCL5, CXCL8; ATPase Phospholipid Transporting 8B2: ATP8B2; Disheveled Activator of Morphogenesis 1: DAAM1; Signaling Lymphocytic Activation Molecule Family 8: SLAMF8; Serglycin: SRGN; Bruton’s Tyrosine Kinase: BTK; Feline Gardner–Rasheed proto-oncogene: FGR; Hematopoietic Cytokinase: HCK; Lysosomal Activating Transmembrane Protein-5: LAPTM5; Carcinoembryonic antigen-related cell adhesion molecules: CEACAM 1, 5, 6; Mismatch Repair Genes: PMS2, MLH 1, 5, 6; Suppressor of Cytokine Signaling: SOCS3; Alpha 2 Macroglobulin (Protease Inhibitor): A2M; Death Associated Protein Kinase: DAPK1; Ras Associated Family: RAASF8. Full article ">

14 pages, 4238 KiB

Open AccessArticle

Non-Inflamed Tumor Microenvironment and Methylation/Downregulation of Antigen-Presenting Machineries in Cholangiocarcinoma

by Naoshi Nishida, Tomoko Aoki, Masahiro Morita, Hirokazu Chishina, Masahiro Takita, Hiroshi Ida, Satoru Hagiwara, Yasunori Minami, Kazuomi Ueshima and Masatoshi Kudo

Cancers 2023, 15(8), 2379; https://doi.org/10.3390/cancers15082379 - 20 Apr 2023

Cited by 8 | Viewed by 1839

Abstract

Cholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. The genetic/epigenetic status [...] Read more.

Cholangiocarcinoma (CCA) is a refractory cancer; a majority of CCAs represents a non-inflamed tumor phenotype that should be resistant to treatment, including immune checkpoint inhibitors (ICIs). In this study, we aimed to understand the molecular characteristics associated with non-inflamed CCAs. The genetic/epigenetic status of 36 CCAs was obtained from the Cancer Genome Atlas (PanCancerAtlas). CCAs were classified based on immune class using hierarchical clustering analysis of gene expressions related to tumor-infiltrating lymphocytes. The associations between immune class and genetic/epigenetic events were analyzed. We found that the tumors with alterations in FGFR2 and IDH1/2 had a “non-inflamed” tumor phenotype. A significant association was observed between the non-inflamed group and the downregulation of genes involved in antigen presentation (p = 0.0015). The expression of antigen-presenting machineries was inversely correlated with their DNA methylation levels, where 33.3% of tumors had an upregulation/low-methylation pattern, and 66.7% of tumors had a downregulation/high-methylation pattern. All tumors in the “inflamed” group exhibited an upregulation/low-methylation pattern. In contrast, 24 of 30 tumors in the non-inflamed group represent the downregulation/high-methylation pattern (p = 0.0005). Methylation with downregulation of antigen-presenting machineries is associated with the “non-inflamed” tumor phenotype of CCAs. This evidence provides important insights for developing new strategies for treating CCA. Full article

(This article belongs to the Collection Primary Liver Cancer)

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Figure 1
Hierarchical clustering analysis using z-scores of mRNA levels related to tumor-infiltrated lymphocytes. The color map (red-gray-blue): red, degree of increased mRNA expression; blue, degree of decreased mRNA expression. For clustering analysis, z-scores of mRNA levels of the following genes were used: CD2, CD3D, CD8A, CD8B, CD48, CD52, and CD53 as T-cell surface markers; FYB1, IFNG, LAPTM5, LCP2, PTPRC, and SLA as T-cell signaling and activation-related markers; CCL5, CXCL9, CXCL10, CXCL11, and CXCR4 as lymphocyte chemotactic markers; GZMA, GZMB, GZMK, GZMH, and GZMM as T-cell-related cytolytic factors; CTLA4, LAG3, TIGIT, CD274, PDCD1, and HAVCR4 as immune checkpoint molecules. Among the 36 cases, 6 (17%) formed a cluster and were considered to belong to the inflamed class because of the high expression of genes related to tumor-infiltrated lymphocytes. The remaining 30 cases were classified as non-inflamed. Of these, seventeen formed a cluster with low expression of these markers and were defined as non-inflamed A; thirteen cases with a mild expression of markers were defined as non-inflamed B. Full article ">Figure 2
Correlation between methylation level and expression of the genes involved in antigen-presenting machineries. Negative correlations are observed between expression and methylation levels in HLA-B, HLA-C, HLA-E, B2M, TAP1, and CIITA. Pearson’s correlation coefficients are shown for each correlation. Full article ">Figure 3
Hierarchical clustering analysis using z-scores of mRNA expression and methylation levels of antigen-presenting machineries. The color map (red-gray-blue): red, degree of increased mRNA expression or methylation density; blue, degree of decreased mRNA expression or methylation density. CCAs in the cluster with high expression (red rectangle) and low methylation levels (blue rectangle) were considered upregulation/low-methylation pattern, and those with low expression (blue rectangle) and high methylation levels (red rectangle) were determined as downregulation/high-methylation pattern, respectively. Tumors classified as inflamed group, which are indicated in <a href="#cancers-15-02379-f001" class="html-fig">Figure 1</a>, are shown with red squares. Similarly, tumors harboring FGFR2 alterations and mutations in IDH1/2 are shown as black squares. All six tumors considered to have an inflamed tumor phenotype showed upregulation and low-methylation pattern in the genes involved in antigen presentation, whereas 24 of 30 tumors with a non-inflamed tumor phenotype showed downregulation with high-methylation pattern (p = 0.0005). All seven tumors carrying mutations in the IDH genes and six of the seven tumors carrying FGFR2 alterations were classified into the downregulation/high-methylation pattern group (p = 0.0704 and 0.3839 for mutations in the IDH genes and alterations in the FGFR2 genes, respectively). Full article ">Figure 4
Comparisons of mRNA expression and DNA methylation level between inflamed and non-inflamed cholangiocarcinoma. mRNA expressions of the genes involved in antigen presentation are significantly higher in inflamed group than in non-inflamed group for all comparisons (a). Similarly, their DNA methylation levels are significantly lower in inflamed group than in non-inflamed group for all comparisons (b). Red boxes and whisker plots denote 75% and 95% distribution, respectively, and the red lines in the boxes show the median values. p values by non-parametric Wilcoxon rank-sum test are shown. Full article ">Figure 4 Cont.
Comparisons of mRNA expression and DNA methylation level between inflamed and non-inflamed cholangiocarcinoma. mRNA expressions of the genes involved in antigen presentation are significantly higher in inflamed group than in non-inflamed group for all comparisons (a). Similarly, their DNA methylation levels are significantly lower in inflamed group than in non-inflamed group for all comparisons (b). Red boxes and whisker plots denote 75% and 95% distribution, respectively, and the red lines in the boxes show the median values. p values by non-parametric Wilcoxon rank-sum test are shown. Full article ">Figure 5
Schematic representation of the role of methylation and downregulation of genes involved in antigen presentation. In cholangiocarcinomas (CCAs), the phenotype of “inflamed” and “non-inflamed” classes, determined by the transcriptome of tumor-infiltrated lymphocytes, is strongly associated with the methylation and downregulation of genes related to antigen-presenting machinery. Consequently, lack of antigen-presenting machinery for the presentation of tumor-specific neoantigen result in the failure of attracting cytotoxic T lymphocytes (CTLs) into tumor. Some driver mutations unique to CCAs, such as mutations in the IDH1/2 genes and alterations in the FGFR2 gene, may be associated with these methylation and downregulation events. Full article ">

21 pages, 15648 KiB

Open AccessArticle

Ursolic Acid Alleviates Cancer Cachexia and Prevents Muscle Wasting via Activating SIRT1

by Weili Tao, Ze Ouyang, Zhiqi Liao, Lu Li, Yujie Zhang, Jiali Gao, Li Ma and Shiying Yu

Cancers 2023, 15(8), 2378; https://doi.org/10.3390/cancers15082378 - 20 Apr 2023

Cited by 9 | Viewed by 3142

Abstract

Skeletal muscle wasting is the most remarkable phenotypic feature of cancer cachexia that increases the risk of morbidity and mortality. However, there are currently no effective drugs against cancer cachexia. Ursolic acid (UA) is a lipophilic pentacyclic triterpene that has been reported to [...] Read more.

Skeletal muscle wasting is the most remarkable phenotypic feature of cancer cachexia that increases the risk of morbidity and mortality. However, there are currently no effective drugs against cancer cachexia. Ursolic acid (UA) is a lipophilic pentacyclic triterpene that has been reported to alleviate muscle atrophy and reduce muscle decomposition in some disease models. This study aimed to explore the role and mechanisms of UA treatment in cancer cachexia. We found that UA attenuated Lewis lung carcinoma (LLC)-conditioned medium-induced C2C12 myotube atrophy and muscle wasting of LLC tumor-bearing mice. Moreover, UA dose-dependently activated SIRT1 and downregulated MuRF1 and Atrogin-1. Molecular docking results revealed a good binding effect on UA and SIRT1 protein. UA rescued vital features wasting without impacting tumor growth, suppressed the elevated spleen weight, and downregulated serum concentrations of inflammatory cytokines in vivo. The above phenomena can be attenuated by Ex-527, an inhibitor of SIRT1. Furthermore, UA remained protective against cancer cachexia in the advanced stage of tumor growth. The results revealed that UA exerts an anti-cachexia effect via activating SIRT1, thereby downregulating the phosphorylation levels of NF-κB and STAT3. UA might be a potential drug against cancer cachexia. Full article

(This article belongs to the Special Issue Advances in Cancer Cachexia)

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11 pages, 245 KiB

Open AccessReview

Role for Neoadjuvant Systemic Therapy for Potentially Resectable Pancreatic Cancer

by Brandon G. Smaglo

Cancers 2023, 15(8), 2377; https://doi.org/10.3390/cancers15082377 - 19 Apr 2023

Cited by 6 | Viewed by 1760

Abstract

Despite aggressive adjuvant management, a high percentage of patients who undergo appropriate surgical resection for pancreatic cancer will see their cancer recur and thus will not be cured. An important paradigm shift to achieve better outcomes has been therapy sequence, with neoadjuvant chemotherapy [...] Read more.

Despite aggressive adjuvant management, a high percentage of patients who undergo appropriate surgical resection for pancreatic cancer will see their cancer recur and thus will not be cured. An important paradigm shift to achieve better outcomes has been therapy sequence, with neoadjuvant chemotherapy preceding surgery. Patients with a borderline resectable cancer, or patients with a resectable cancer but who have other high-risk features, are ideal candidates to consider for neoadjuvant chemotherapy. Among the high-risk features, a baseline elevated CA 19-9 concentration can be particularly useful, as its response trend during neoadjuvant chemotherapy can offer important insights into the prognosis after surgery. When selecting a neoadjuvant chemotherapy regimen, response data available for the use of FOLFIRINOX and gemcitabine and nabpaclitaxel in the metastatic setting support their use in this space. FOLFIRINOX is perhaps the preferred regimen, given its proven adjuvant benefit and possibly its superior tumor response rate; still, patient tolerance and thus ability to complete recommended treatment must be carefully considered. This review presents the evidence supporting neoadjuvant chemotherapy for resectable pancreatic cancer, the factors to consider when making such a recommendation, the selection of specific regimens, and our institutional approach using these tools. Full article

(This article belongs to the Special Issue Neoadjuvant Therapies in Pancreatic Cancer)

15 pages, 1118 KiB

Open AccessReview

Targeting Angiogenesis in the Era of Biliary Tract Cancer Immunotherapy: Biological Rationale, Clinical Implications, and Future Research Avenues

by Annalisa Schirizzi, Giampiero De Leonardis, Vincenza Lorusso, Rossella Donghia, Alessandro Rizzo, Simona Vallarelli, Carmela Ostuni, Laura Troiani, Ivan Roberto Lolli, Gianluigi Giannelli, Angela Dalia Ricci, Rosalba D’Alessandro and Claudio Lotesoriere

Cancers 2023, 15(8), 2376; https://doi.org/10.3390/cancers15082376 - 19 Apr 2023

Cited by 5 | Viewed by 2202

Abstract

Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role [...] Read more.

Although biliary tract cancers are traditionally considered rare in Western countries, their incidence and mortality rates are rising worldwide. A better knowledge of the genomic landscape of these tumor types has broadened the number of molecular targeted therapies, including angiogenesis inhibitors. The role of immune checkpoint inhibitors (ICIs) could potentially change the first-line therapeutic approach, but monotherapy with ICIs has shown disappointing results in CCA. Several clinical trials are evaluating combination strategies that include immunotherapy together with other anticancer agents with a synergistic activity. The tumor microenvironment (TME) composition plays a pivotal role in the prognosis of BTC patients. The accumulation of immunosuppressive cell types, such as tumor-associated macrophages (TAMs) and regulatory T-cells, together with the poor infiltration of cytotoxic CD8+ T-cells, is known to predispose to a poor prognosis owing to the establishment of resistance mechanisms. Likewise, angiogenesis is recognized as a major player in modulating the TME in an immunosuppressive manner. This is the mechanistic rationale for combination treatment schemes blocking both immunity and angiogenesis. In this scenario, this review aims to provide an overview of the most recent completed or ongoing clinical trials combining immunotherapy and angiogenesis inhibitors with/without a chemotherapy backbone. Full article

(This article belongs to the Special Issue Drug Resistance in Gastrointestinal Cancer)

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