Abstract
Merkel cell carcinoma (MCC) is an aggressive skin cancer with a high propensity for recurrence and metastasis. Merkel cell polyomavirus (MCPyV) is recognised as the causative factor in the majority of MCC cases. The MCPyV small tumour antigen (ST) is considered to be the main viral transforming factor, however potential mechanisms linking ST expression to the highly metastatic nature of MCC are yet to be fully elucidated. Metastasis is a complex process, with several discrete steps required for the formation of secondary tumour sites. One essential trait that underpins the ability of cancer cells to metastasise is how they interact with adjoining tumour cells and the surrounding extracellular matrix. Here we demonstrate that MCPyV ST expression disrupts the integrity of cell-cell junctions, thereby enhancing cell dissociation and implicate the cellular sheddases, A disintegrin and metalloproteinase (ADAM) 10 and 17 proteins in this process. Inhibition of ADAM 10 and 17 activity reduced MCPyV ST-induced cell dissociation and motility, attributing their function as critical to the MCPyV-induced metastatic processes. Consistent with these data, we confirm that ADAM 10 and 17 are upregulated in MCPyV-positive primary MCC tumours. These novel findings implicate cellular sheddases as key host cell factors contributing to virus-mediated cellular transformation and metastasis. Notably, ADAM protein expression may be a novel biomarker of MCC prognosis and given the current interest in cellular sheddase inhibitors for cancer therapeutics, it highlights ADAM 10 and 17 activity as a novel opportunity for targeted interventions for disseminated MCC.
Highlights
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine cancer of the skin [1]
Recent quantitative proteomic studies suggest Merkel cell polyomavirus (MCPyV) small tumour antigen (ST) expression can promote cell motility and migration [30,31,32] by inducing differential expression of cellular proteins involved in microtubule [30] and actin-associated cytoskeletal organization and dynamics [31], leading to microtubule destabilization and filopodium formation. These results suggest that MCPyV may be associated with the highly metastatic nature of MCC, and is supported by studies showing that engraftment of MCC cell lines into SCID mice results in circulating tumour cells and metastasis formation [33]
MCPyV ST expression induces cell dissociation by disrupting cell junctions Cell-cell adhesion and cell interaction to the extracellular matrix is required for tissue integrity [54]
Summary
Merkel cell carcinoma (MCC) is a highly aggressive neuroendocrine cancer of the skin [1]. UV light appears to be an important factor in MCC, with a positive correlation between geographic UVB radiation indices and age-adjusted MCC amongst Caucasians [1, 3]. The predominance of MCC in elderly persons highlights immunosuppression as an important risk factor, supported by disproportionally higher rates of MCC in patients on long-term iatrogenic immunosuppression, in addition to patients with lymphoproliferative disorders and HIV/AIDs [2]. Due to its aggressive nature MCC carries a high risk of local, regional and distant recurrence [4]. The 5-year survival rates range from 60– 87% for local disease to 11–20% for metastatic disease [5,6,7]
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