Current In Vitro and In Vivo Models to Study MCPyV-Associated MCC

Abstract

Merkel cell polyomavirus (MCPyV) is the only human polyomavirus currently known to cause human cancer. MCPyV is believed to be an etiological factor in at least 80% of cases of the rare but aggressive skin malignancy Merkel cell carcinoma (MCC). In these MCPyV+ MCC tumors, clonal integration of the viral genome results in the continued expression of two viral proteins: the viral small T antigen (ST) and a truncated form of the viral large T antigen. The oncogenic potential of MCPyV and the functional properties of the viral T antigens that contribute to neoplasia are becoming increasingly well-characterized with the recent development of model systems that recapitulate the biology of MCPyV+ MCC. In this review, we summarize our understanding of MCPyV and its role in MCC, followed by the current state of both in vitro and in vivo model systems used to study MCPyV and its contribution to carcinogenesis. We also highlight the remaining challenges within the field and the major considerations related to the ongoing development of in vitro and in vivo models of MCPyV+ MCC.

Interplay between the DNA damage response and the life cycle of DNA tumor viruses

“…Merkel cells are not believed to be the primary reservoir for MCPyV. Rather other dermal cells, specifically fibroblasts, may support viral replication to achieve high levels of viral particles and viral shedding [ 83 ].…”

“…The 5.4 kb genome encodes two subsets of viral proteins, early and late, from bi-directional promoters near the origin that are transcribed in opposite directions. The early genes encode the full-length LT, sT, 57kd (57 kT), and alternate LT open reading frame (ALTO) tumor antigens expressed from an alternatively spliced common transcript [ 83 ]. LT has a primary role in promoting viral replication through its origin binding and helicase activity domains and through the recruitment of cellular DNA replication factors, including DDR factors [ 84 ].…”

“…The late region encodes the major capsid protein VP1 and the minor capsid protein VP2. In between the early and late regions is the non-coding region, which contains the origin of replication [ 83 ].…”

A review on the oncogenesis of Merkel cell carcinoma: Several subsets arise from different stages of differentiation of stem cell

“…In 2008, Feng et al reported a breakthrough in understanding MCC biology through their discovery of MCPyV, which was monoclonally integrated into the genome of tumor cells. [ 12 ] MCPyV, a novel human polyomavirus, comprises a closed, circular, double-stranded DNA. Further studies confirmed that MCPyV is a ubiquitous virus that causes asymptomatic infections in the general population and is integrated into approximately 80% of MCCs.…”

Special Issue “New Frontiers in Small DNA Virus Research”

“…Suresh and Menne summarize recent preclinical studies of developing antivirals, immunomodulators, and therapeutic vaccines for chronic hepatitis B, using the Eastern woodchuck with woodchuck hepatitis virus as an HBV laboratory animal model [ 7 ]. Loke et al describe in vitro and in vivo model systems of Merkel cell polyomavirus (MCPyV) currently available for studying MCPyV-associated MCC [ 8 ]. Kines and Schiller provide an in-depth discussion about the role of heparan sulfate proteoglycans (HSPG) in HPV entry into the host cell, particularly focusing on the modification of sulfation patterns on HSPG.…”