Merkel cell carcinoma (MCC) is the most aggressive skin cancer. Recently, it was demonstrated that human Merkel cell polyomavirus (MCV) is clonally integrated inMerkel cell carcinoma (MCC) is a highly aggressive neuroendocrine skin cancer. Although it is rare, its reported incidence is increasing (19). MCC is associated with UV exposure and affects primarily elderly and immune-suppressed patients (5,11,17,26). The susceptibility of MCC to immune surveillance is similar to that of known virus-induced cancers and suggests that MCC has an infectious trigger (9). Recently, a new human polyomavirus, termed Merkel cell polyomavirus (MCV), was discovered to be clonally integrated into MCC tumor genomes (14). While MCV integration occurs at distinct sites in MCC tumors from different individuals, primary tumors and corresponding metastases have identical integration sites, consistent with the occurrence of MCV infection and integration prior to clonal expansion and metastasis (14,37). A number of studies have confirmed that MCV is present in 69 to 85% of MCC tumors collected from Europe and the United States (4, 15, 21, 41). Surveys of control non-MCC skin, hematolymphoid, and neuroendocrine tumors are generally negative for MCV, although incidental low-level infection can be detected (4,14,22,33,34,39,42,44).All polyomaviruses encode alternatively spliced large T (LT) and small T (sT) antigen transcripts that share exon 1 of the T-antigen (TA) locus. Additional multiply spliced TA transcripts have been described for different polyomaviruses, including the 17kT and 57kT antigens in simian virus 40 (SV40) and MCV, respectively (40,46). Research on viral proteins encoded by the TA locus has been central to uncovering cell signaling networks important in cancer biology (10, 38). The targeting of cellular proteins, such as retinoblastoma protein (Rb), p53, and protein phosphatase 2A (PP2A), by TAs contributes to polyomavirusinduced cell transformation (for reviews, see references 1 and 2). MCV TAs that are expressed in MCC tumors lack a putative p53 binding domain because of tumor-associated T-antigen deletion mutations (37,40). Other conserved tumor suppressor-targeting motifs, including the Rb binding domain (LXCXE motif), the J domain (HPDK) in LT/57kT, and a putative PP2A interaction domain in sT, remain intact (40).Current data point toward MCV as the infectious cause for most Merkel cell cancers: the virus is associated with MCC tumors and, when present, expresses T antigen in tumor cells but not in healthy surrounding tissues (7,20,39). MCV is specific to MCC and is not detected at significant levels in other cancers or in healthy skin examined to date, despite widespread circulation of MCV among human populations (8,23,29,42). Clonal analysis of MCC tumors also supports the correct temporal relationship for causality; i.e., MCV infection occurs prior to MCC tumor development (18). If MCV is a direct cause of MCC tumorigenesis, it is expected that MCC tumors will require MCV protein expression to maintain the tumor ...

MCPyV represents an exciting direction for future studies in two major areas. The first area is functional characterization of the MCPyV and determination if it expresses biologically active viral proteins and whether it is in fact involved in the generation or maintenance of MCC tumors. The second major direction is an epidemiologic characterization of the prevalence of MCPyV in healthy people and in various tumors as this virus may plausibly be associated with other human diseases or malignancies.

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer that frequently harbours Merkel cell polyomavirus (MCV) DNA integrated in the genome of the tumor cells. In our study, we elaborate our recent finding that MCV-positive MCC cell lines require the expression of the viral T antigens (TA). Indeed, in a xeno-transplantation model, we prove that TA expression is essential also in an in vivo situation, as knock down of TA leads to tumor regression. Moreover, rescuing TA short hairpin RNA (shRNA)-treated MCV-positive MCC cells by ectopic expression of shRNA-insensitive TAs clearly demonstrates that the observed effect is caused by TA knockdown. Notably, introduction of a mutation in the LTA protein interfering with LTA binding to the retinoblastoma protein (RB) ablated this rescue. The importance of this interaction was further confirmed as LTA-specific knockdown leads to explicit cell growth inhibition. In summary, the presented data demonstrate that established MCV-positive MCC tumors critically depend on TA expression, in particular the LTA and RB interaction, for sustained tumor growth. Consequently, interference with LTA/RB interaction appears as promising strategy to treat MCC.