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Cancers
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The Role of Viruses in the Development of Cancer
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The Role of Viruses in the Development of Cancer

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Infectious Agents and Cancer".

Deadline for manuscript submissions: 31 March 2025 | Viewed by 620

Special Issue Editor

Prof. Dr. George Eric Blair

E-Mail Website
Guest Editor
School of Molecular and Cellular Biology, University of Leeds, Leeds, UK
Interests: DNA viruses; HPV; adenovirus; viral vectors; cancer virotherapy

Special Issue Information

Dear Colleagues,

We are pleased to invite you to contribute a paper for this Special Issue on “The Role of Viruses in the Development of Cancer”. Viruses have been studied as etiological agents in the development of animal and human cancers for more than a century. This work has aided the identification of oncogenes and tumour suppressor genes as well as highlighting viruses that play a crucial role in the development of human cancers, for example, the role of high-risk human papillomaviruses (HPVs) in ano-genital and oral cancers, and of the human retrovirus T-lymphotropic virus 1 (HTLV 1) in adult T-cell leukaemia (ATL). The field continues to be buoyant, with new tumour viruses such as the DNA viruses, Merkel Cell Polyomavirus (MCPyV) and Kaposi’s sarcoma herpesvirus (KSHV or HHV8) being discovered using DNA sequence and genomic analysis within the past two decades. While effective prophylactic vaccines have been developed against HPVs and Hepatitis B (HBV), there is still a requirement for novel therapeutic approaches to human cancers that are driven by tumour virus infection. 

Original research articles and reviews are welcome in this Special Issue. Research areas may include (but are not limited to) fundamental studies on the molecular mechanisms of cell transformation and oncogenesis by DNA and RNA tumour viruses; the immune response to tumour viruses; the immune evasion of cancers driven by tumour viruses; prophylactic and therapeutic vaccines against tumour viruses and the cancers that they cause; emerging tumour viruses; and global perspectives on tumour viruses and cancers.

We look forward to receiving your contributions.

Prof. Dr. George Eric Blair
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • DNA and RNA tumour viruses
  • HPV
  • EBV
  • KSHV
  • HCV
  • HBV
  • HTLV1
  • McPyV

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Further information on MDPI's Special Issue polices can be found here.

Published Papers (1 paper)

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Research

19 pages, 11686 KiB  
Article
Cross-Talk Between Tumor Cells and Stellate Cells Promotes Oncolytic VSV Activity in Intrahepatic Cholangiocarcinoma
by Victoria Neumeyer, Purva Chavan, Katja Steiger, Oliver Ebert and Jennifer Altomonte
Cancers 2025, 17(3), 514; https://doi.org/10.3390/cancers17030514 - 4 Feb 2025
Viewed by 301
Abstract
As the mechanisms underlying tumorigenesis become better understood, the dynamic roles of cellular components of the tumor microenvironment, and their cross-talk with tumor cells, have come to light as key drivers of disease progression and have emerged as important targets of new cancer [...] Read more.
As the mechanisms underlying tumorigenesis become better understood, the dynamic roles of cellular components of the tumor microenvironment, and their cross-talk with tumor cells, have come to light as key drivers of disease progression and have emerged as important targets of new cancer therapies. In the field of oncolytic virus (OV) therapy, stromal cells have been considered as potential barriers to viral spread, thus limiting virus replication and therapeutic outcome. However, new evidence indicates that intratumoral fibroblasts could support virus replication. We have demonstrated in a rat model of stromal-rich intrahepatic cholangiocarcinoma (CCA) that vesicular stomatitis virus (VSV) can be localized within intratumoral hepatic stellate cells (HSCs), in addition to tumor cells, when the virus was applied via hepatic arterial infusion. Furthermore, VSV was shown to efficiently kill CCA cells and activated HSCs, and co-culture of CCA and HSCs increased viral titers. Interestingly, this effect is also observed when each cell type is cultured alone in a conditioned medium of the other cell type, indicating that secreted cell factors are at least partially responsible for this phenomenon. Partial reduction in sensitivity to type I interferons was observed in co-culture systems, providing a possible mechanism for the increased viral titers. Together, the results indicate that targeting activated HSCs with VSV could provide an additional mechanism of OV therapy, which, until now has not been considered. Furthermore, these findings suggest that VSV is a potentially powerful therapeutic agent for stromal-rich tumors, such as CCA and pancreatic cancer, both of which are very difficult to treat with conventional therapy and have a very poor prognosis. Full article
(This article belongs to the Special Issue The Role of Viruses in the Development of Cancer)
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Graphical abstract
Full article ">Figure 1
<p>Crosstalk between CCA cells and HSCs leads to differential gene expression and HSC activation. (<b>A</b>) Human CCA cell lines, RBE and HuCCT1, and primary human hepatic stellate cells (HSCs) were either cultured alone or as co-culture at a ratio of 1:1. Expression of TGF-β, αSMA, and TIMP-1 were analyzed by quantitative real-time RT-PCR and normalized to GAPDH. Mean values from three independent experiments are shown, and error bars indicate SEM. Statistical significance was determined by Student’s <span class="html-italic">t</span>-test (* <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001). (<b>B</b>) Primary human HSCs were cultured in their own medium or medium conditioned by RBE or HuCCT1 cells for 48 h. Immunofluorescence staining for αSMA (red) and nuclei (DAPI, blue) was performed. Pictures were taken with a fluorescence microscope at a magnification of 200×.</p> Full article ">Figure 2
<p>Human CCA cells are susceptible to VSV-GFP expression. Virus replication was monitored after infection of (<b>A</b>) HuCCT1 and (<b>D</b>) RBE cells at MOI 10 and 0.01 at several time points (0, 6, 12, 24, and 48 h post-infection). Viral titers were determined by TCID<sub>50</sub> assay. Cell viability of (<b>B</b>) HuCCT1 was measured by MTS assay at 24, 48, and 72 h post-infection and (<b>E</b>) RBE cells at 24 and 48 h. Representative pictures of uninfected and VSV-GFP-infected (<b>C</b>) HuCCT1 and (<b>F</b>) RBE cells at 48 h post-infection are shown in bright fields (top) and fluorescence for GFP visualization (bottom). The scale bar indicates 100 µm. Mean values from three independent experiments are shown, and error bars indicate SEM.</p> Full article ">Figure 3
<p>Crosstalk between CCA cells and HSCs enhances viral replication and cytotoxicity. (<b>A</b>) Viral titers were determined 24 h post-infection by TCID<sub>50</sub> assay after co-culture of HuCCT1 and RBE cells with HSCs at a ratio of 1:1. (<b>B</b>) Cytotoxicity was measured by LDH release upon infection of HuCCT1 and RBE cells with VSV-GFP at MOI 0.01 for 24 h in co-culture with LX2 cells. Values were normalized to a maximum release control. TCID<sub>50</sub> assay of HuCCT1 and RBE cells cultured in (<b>C</b>) primary HSC or (<b>D</b>) LX2 conditioned media were measured at 48 h post-infection. (<b>E</b>) Cytotoxicity was measured as a function of LDH release from infected HuCCT1 and RBE cells cultured in own or LX2-conditioned medium at 48 h post-infection at MOI 0.01. Values were normalized to a maximum release control. (<b>F</b>) Representative images of HuCCT1 cells infected with VSV-GFP at MOI 0.01 48 h post-infection. The scale bar indicates 100 µm. (<b>G</b>) Viral titers measured by TCID<sub>50</sub> assay from VSV-GFP-infected primary HSCs and LX2 cells 48 h post-infection. (<b>H</b>) Cytotoxicity was measured by LDH release assay upon infection of LX2 cells with VSV-GFP after 48 h. Values were normalized to a maximum release control. (<b>I</b>) Representative photomicrographs of LX2 cells infected in own, HuCCT1, or RBE conditioned media with VSV-GFP at MOI 0.01 at 48 h post-infection are shown. The scale bar indicates 100 µm. Mean values from three independent experiments are shown, and error bars indicate SEM. Statistical significance was determined by Student’s <span class="html-italic">t</span>-test (* <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, *** <span class="html-italic">p</span> &lt; 0.001).</p> Full article ">Figure 4
<p>Crosstalk between CCA cells and HSCs dampens IFN signaling and response pathways. (<b>A</b>) IFNβ and (<b>B</b>) Interferon-stimulated response element (ISRE) promoter activation were measured in HuCCT1, RBE, and primary human stellate cells (HSCs) after overnight infection with VSV or VSV(MΔ51) or stimulation with poly I:C or universal type-I IFN, respectively, using luciferase reporter plasmids and the Dual-Luciferase Reporter assay. Values were normalized to control the luciferase signal and are shown as fold-induction compared to uninfected controls. (<b>C</b>) HuCCT1, RBE, and HSC cells were treated with type-I IFN overnight prior to infection with VSV at MOI 1. Viral titers were measured 18 h post-infection using TCID<sub>50</sub> assay. Mean values from three independent experiments are shown, and error bars indicate SEM. Statistical significance was determined by Student’s <span class="html-italic">t</span>-test (* <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01).</p> Full article ">Figure 5
<p>VSV replicates in tumor cells and HSCs in a rat model of CCA. Intrahepatic CCA was induced in male rats by long-term treatment with thioacetamide. Representative photomicrographs of (<b>A</b>) hematoxylin-eosin for histology analysis and (<b>B</b>) Elastica van Gieson staining for collagen (stained pink) of intrahepatic CCA sampled 24 h after treatment with PBS by hepatic arterial infusion. The scale bar indicates 100 µm. (<b>C</b>) Virus titers were measured by TCID<sub>50</sub> assay from lysates of the tumor and healthy liver tissue was isolated and snap-frozen 24 h after treatment. Mean values from four individual animals are shown; error bars indicate SEM. (<b>D</b>) Representative images of immunohistochemical staining of intrahepatic CCA tumors stained for VSV-M (red) or (<b>E</b>) immunofluorescent staining of α-SMA (green) and VSV-M (red) 1 day after treatment with PBS or VSV.</p> Full article ">Figure 6
<p>VSV reduces fibrosis in a rat model of CCA. CCA tumors were induced in rats by long-term thioacetamide treatment in drinking water, and animals were treated with PBS or VSV by intrahepatic arterial infusion. Expression of (<b>A</b>) α-SMA, (<b>B</b>) TGF-β, and (<b>C</b>) collagen was analyzed by RT-qPCR 1-day post-treatment. mRNA levels were normalized to GAPDH and are depicted as fold-change compared to PBS-treated controls. (<b>D</b>) Intratumoral fibrotic content was quantified by analysis of pink-stained collagen fibers from the Elastica van Gieson staining of VSV- or PBS-treated CCA tumors. Mean values from four animals and representative photomicrographs are shown; error bars indicate SEM. Statistical significance was determined by Student’s <span class="html-italic">t</span>-test (* <span class="html-italic">p</span> &lt; 0.05, *** <span class="html-italic">p</span> &lt; 0.001).</p> Full article ">
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