Special Issue "Infection and Cancer"
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A special issue of Pathogens (ISSN 2076-0817).
Deadline for manuscript submissions: closed (29 June 2012)
Special Issue Editor
Special Issue Information
Dear Colleagues,
It is estimated that infection contributes to the development of around 20% of human cancer – some 2 million cases per year. Understanding the role of infection in cancer continues to provide fundamental insights into the underlying mechanisms responsible for driving the oncogenic process as well as highlighting opportunities for therapeutic and prophylactic intervention. It is just over 100 years since Peyton Rous discovered an infectious agent capable of transmitting sarcoma to chickens. This observation spawned the field of tumour virology resulting in a range of key discoveries including the identification of oncogenes and of viruses associated with human cancer. In the last few years the significance of infection-related cancer has been recognized by the award of the Nobel prize in Physiology or Medicine. In 2005 the Nobel prize was awarded to Barry Marshall and Robin Warren for their discovery of Helicobacter pylori, the bacterium associated with peptic ulcers, gastritis and gastric cancer. And in 2008 Harald zur Hausen was awarded the Nobel prize for his discovery of human papillomaviruses and their association with cervical cancer. Both these seminal observations have not only shed light on different oncogenic mechanisms but led to exciting cancer prevention approaches based on eradicating infection – antibiotics in the case of Helicobacter pylori and vaccination in the case of human papillomavirus. The special issue on ‘Infection and Cancer’ will focus on the current status of our understanding of the role of infectious agents in the etiology of human cancer and on the opportunities for therapeutic and prophylactic intervention. We thus invite submission of research and review manuscripts that cover any aspect of the epidemiology, molecular and cell biology, immunology, diagnosis, treatment and prevention of infection-related cancer. I look forward to your contributions and to a valuable edition that will promote further developments in this exciting field.
Thank you for your collaboration.
Prof. Dr. Lawrence S. Young
Editor-in-Chief
Submission
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. Papers will be published continuously (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.
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Keywords
- cancer
- viruses
- infectious agents
- oncogenes
- tumour viruses
- tumour immunology
- epigenetics
- epidemiology
- vaccination
- therapeutics
Published Papers (7 papers)
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Received: 12 August 2012; in revised form: 25 August 2012 / Accepted: 31 August 2012 / Published: 12 September 2012
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Abstract: As new platforms for high-risk strains of human papillomavirus (HR HPV) testing are introduced into the clinical laboratory, it is important to verify their performance and agreement. In this validation study, post-aliquot cervical cytopathology specimens (n = 226) were used to analyze agreement between the Invader HPV ASR assay (Hologic) and the recently FDA-approved Cobas 4800 high-risk HPV assay (Roche). Residual sample from 92 Invader positive and 134 Invader negative samples were analyzed with the Cobas 4800 test. Discordant results were further analyzed by Linear Array HPV genotype testing (Roche). To assess intra- and inter-run precision, 31 Invader positive samples were run in duplicate on the Cobas 4800 by different operators over multiple days and purchased HR HPV DNA control was run in ten replicates. Cross-contamination during cytology processing was evaluated by spiking 6 Invader negative samples with different volumes of Acrometrix HPV High Risk Positive Control and analyzed on the Cobas with 4 negative samples in between. There was significant discordance between the assays (p < 0.001; exact McNemar X2 test), with overall agreement of 82%. Of the 92 Invader positive samples, 58 (63%) were positive with the Cobas assay, while 34 (37%) were negative. Of the 134 Invader negative samples, 6 (4%) were positive with the Cobas while 128 (96%) were negative. The observed discordance may be attributed to the previously described false positive rate of the Invader ASR assay. The Cobas 4800 high-risk HPV assay is a viable new tool for use in the clinical setting to identify high-risk HPV.
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Received: 2 August 2012; in revised form: 21 August 2012 / Accepted: 4 September 2012 / Published: 17 September 2012
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Abstract: EBNA1, a nuclear protein expressed in all EBV-associated neoplasms is indispensable for the maintenance of the viral episomes in latently infected cells. EBNA1 may induce genetic alterations by upregulating cellular recombinases, production of reactive oxygen species (ROS) and affecting p53 levels and function. All these changes may contribute to tumorigenesis. In this overview we focus, however, on the epigenetic alterations elicited by EBNA1 by drawing a parallel between EBNA1 and the FoxA family of pioneer transcription factors. Both EBNA1 and FoxA induce local DNA demethylation, nucleosome destabilization and bind to mitotic chromosomes. Local DNA demethylation and nucleosome rearrangement mark active promoters and enhancers. In addition, EBNA1 and FoxA, when associated with mitotic chromatin may “bookmark” active genes and ensure their reactivation in postmitotic cells (epigenetic memory). We speculate that DNA looping induced by EBNA1-EBNA1 interactions may reorganize the cellular genome. Such chromatin loops, sustained in mitotic chromatin similarly to the long-distance interactions mediated by the insulator protein CTCF, may also mediate the epigenetic inheritance of gene expression patterns. We suggest that EBNA1 has the potential to induce patho-epigenetic alterations contributing to tumorigenesis.
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Received: 14 August 2012; in revised form: 28 August 2012 / Accepted: 4 September 2012 / Published: 19 September 2012
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Abstract: Although there is increasing evidence that aberrant expression of those enzymes which control protein arginine methylation contribute to carcinogenesis, their de-regulation by oncogenic viruses in primary cells has yet to be reported. We first show that the protein arginine methyltransferases, CARM1, PRMT1 and PRMT5 are strongly expressed in Hodgkin Reed-Sternberg (HRS) cells, and up-regulated in Hodgkin's lymphoma (HL) cell lines. Given that Epstein-Barr virus (EBV) can be detected in approximately 50% of primary HL, we next examined how EBV infection of germinal centre (GC) B cells, the presumptive precursors of HRS cells, modulated the expression of these proteins. EBV infection of GC B cells was followed by the up-regulation of CARM1, PRMT1 and PRMT5, and by the down-regulation of the arginine deiminase, PADI4. Latent membrane protein 1 (LMP1), the major EBV transforming gene was shown to induce PRMT1 in GC B cells and in a stably transfected B cell line. The recent development of compounds which inhibit PRMT-mediated reactions provides a compelling case for continuing to dissect the contribution of virus induced changes in these proteins to lymphomagenesis.
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Nicolas Gillet, Fabian Vandermeers, Alix de Brogniez, Arnaud Florins, Annamaria Nigro, Carole François, Amel-Baya Bouzar, Olivier Verlaeten, Eric Stern, Didier M. Lambert, Johan Wouters and Luc Willems
Received: 5 September 2012; in revised form: 24 September 2012 / Accepted: 2 October 2012 / Published: 8 October 2012
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Abstract: We previously proved that a histone deacetylase inhibitor (valproate, VPA) decreases the number of leukemic cells in bovine leukemia virus (BLV)-infected sheep. Here, we characterize the mechanisms initiated upon interruption of treatment. We observed that VPA treatment is followed by a decrease of the B cell counts and proviral loads (copies per blood volume). However, all sheep eventually relapsed after different periods of time and became refractory to further VPA treatment. Sheep remained persistently infected with BLV. B lymphocytes isolated throughout treatment and relapse were responsive to VPA-induced apoptosis in cell culture. B cell proliferation is only marginally affected by VPA ex vivo. Interestingly, in four out of five sheep, ex vivo viral expression was nearly undetectable at the time of relapse. In two sheep, a new tumoral clone arose, most likely revealing a selection process exerted by VPA in vivo. We conclude that the interruption of VPA treatment leads to the resurgence of the leukemia in BLV-infected sheep and hypothesize that resistance to further treatment might be due to the failure of viral expression induction. The development of more potent HDAC inhibitors and/or the combination with other compounds can overcome chemoresistance. These observations in the BLV model may be important for therapies against the related Human T-lymphotropic virus type 1.
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Received: 15 August 2012; in revised form: 19 September 2012 / Accepted: 24 September 2012 / Published: 8 October 2012
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Abstract: B-lymphocyte-induced maturation protein 1 (BLIMP1) exists as two major isoforms, α and β, which arise from alternate promoters. Inactivation of the full length BLIMP1α isoform is thought to contribute to B cell lymphomagenesis by blocking post-germinal centre (GC) B cell differentiation. In contrast, the shorter β isoform is functionally impaired and over-expressed in several haematological malignancies, including diffuse large B cell lymphomas (DLBCL). We have studied the influence on BLIMP1β expression of the Epstein-Barr virus (EBV), a human herpesvirus that is implicated in the pathogenesis of several GC-derived lymphomas, including a subset of DLBCL and Hodgkin’s lymphoma (HL). We show that BLIMP1β expression is increased following the EBV infection of normal human tonsillar GC B cells. We also show that this change in expression is accompanied by hypomethylation of the BLIMP1β-specific promoter. Furthermore, we confirmed previous reports that the BLIMP1β promoter is hypomethylated in DLBCL cell lines and show for the first time that BLIMP1β is hypomethylated in the Hodgkin/Reed-Sternberg (HRS) cells of HL. Our results provide evidence in support of a role for BLIMP1β in the pathogenesis of EBV-associated B cell lymphomas.
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Received: 2 September 2012; in revised form: 11 October 2012 / Accepted: 13 October 2012 / Published: 22 October 2012
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Abstract: As obligate intracellular pathogens, viruses depend on the host cell machinery to complete their life cycle. Kaposi’s sarcoma-associated herpesvirus (KSHV) is an oncogenic virus causally linked to the development of Kaposi’s sarcoma and several other lymphoproliferative malignancies. KSHV entry into cells is tightly regulated by diverse viral and cellular factors. In particular, KSHV actively engages cellular integrins and ubiquitination pathways for successful infection. Emerging evidence suggests that KSHV hijacks both actin and microtubule cytoskeletons at different phases during entry into cells. Here, we review recent findings on the early events during primary infection of KSHV and its closely related primate homolog rhesus rhadinovirus with highlights on the regulation of cellular cytoskeletons and signaling pathways that are important for this phase of virus life cycle.
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Received: 10 October 2012; in revised form: 16 October 2012 / Accepted: 30 October 2012 / Published: 8 November 2012
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Abstract: Some key questions in Epstein-Barr virus (EBV) biology center on whether naturally occurring sequence differences in the virus affect infection or EBV associated diseases. Understanding the pattern of EBV sequence variation is also important for possible development of EBV vaccines. At present EBV isolates worldwide can be grouped into Type 1 and Type 2, a classification based on the EBNA2 gene sequence. Type 1 EBV is the most prevalent worldwide but Type 2 is common in parts of Africa. Type 1 transforms human B cells into lymphoblastoid cell lines much more efficiently than Type 2 EBV. Molecular mechanisms that may account for this difference in cell transformation are now becoming clearer. Advances in sequencing technology will greatly increase the amount of whole EBV genome data for EBV isolated from different parts of the world. Study of regional variation of EBV strains independent of the Type 1/Type 2 classification and systematic investigation of the relationship between viral strains, infection and disease will become possible. The recent discovery that specific mutation of the EBV EBNA3B gene may be linked to development of diffuse large B cell lymphoma illustrates the importance that mutations in the virus genome may have in infection and human disease.
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Last update: 3 January 2013
