MCV and Merkel cell carcinoma: a molecular success story

Abstract

Merkel cell polyomavirus (MCV), discovered in 2008, is clonally integrated in ~80% Merkel cell carcinoma (MCC). MCV is a common skin flora and initiates cancer in susceptible hosts only after it acquires a precise set of mutations that render it replication incompetent. Both MCV large and small T proteins promote cancer cell survival and proliferation. Large T targets pocket proteins regulating cell cycle transit while small T activates cap-dependent translation critical for cancer cell growth. These findings already have led to new diagnostics and clinical trials to target MCV-induced survivin and to promote antitumor immunity. In four years, the cause, diagnosis and therapy for an intractable cancer has been changed due to the molecular discovery of MCV.

Figure 1. Merkel cell polyomavirus virions

Top panel shows typical Merkel cell polyomavirus particles produced by transfection of whole genome in 293 cells. In comparison, lower panel reveals assembled MCV virus-like particles (VLP), generated by expression of VP1 and VP2 genes alone, that can be used in serologic assays (Modfied from Feng et al., PLoS one, 2011).

Figure 2. MCV T antigen locus

Three MCV T antigen isoforms are generated by alternative splicing of the T antigen gene: Large T (LT), small T (sT) and 57kT (amino acid positions, shown). Exon1 is common to all three T antigen proteins. Major conserved MCV T antigen motifs (top, base pair positions, shown) are in color (CR1, conserved region 1; DnaJ, Hsp70-binding conserved region; RB, retinoblastoma-binding; PP2A, protein phosphatase 2A-binding; NLS, nuclear localization signal; OBD, origin-binding domain). LT and 57kT encode a MCV-unique region (MUR) that includes the Vam6p/Vps39-binding motif. Tumor specific mutations (red arrow) occur C-terminal to the RB-binding domain and disrupt the helicase activity of LT but do not eliminate tumor suppressor binding domains. Locations for mutations for two MCV tumor strains (MCV350 and MCV339) are shown.

Figure 3. Merkel cell polyomavirus large T (left) and small T (right) antigen expression in MCC tumors

MCV large T antigen usually shows distinct nuclear expression in MCC cells (dependent on an intact nuclear localization signal that can be deleted in some tumors), while MCV small T antigen displays both nuclear and cytoplasmic staining patterns. Only tumor cells show strong positivity with antibody staining, and not the surrounding non-tumor tissues.

Figure 4. Survivin inhibition improves survival of mice bearing human MCC xenografts

Survival curves are shown for mice with MCC xenografts and treated with YM155 (red line), bortezomib (blue line) or saline (green line) for three weeks. MCV positive MKL-1 cells were injected into immune deficient mice and the three-week treatment was given once tumors became palpable. Only 26–33% of bortezomib/saline-treated mice survived three weeks after appearance of tumors while 100% of YM155-treated mice survived the treatment period. Tumors resumed growth once YM155 was discontinued indicating a cytostatic rather than cytocidal effect for YM155 with short-term treatment. (Modified from Arora et al., STM, 2012)