Abstract
Merkel cell carcinoma (MCC) is arelatively rare but highly malignant non-melanoma skin cancer of the elderly and immunosuppressed patients. The discovery of the Merkel cell polyomavirus (MCPyV) in 2008 significantly impacted the understanding of the etiopathogenesis of MCC. MCPyV is clonally integrated into the MCC genome and approximately 80% of MCC are MCPyV-positive. Recent results of clinical trials using blockade of the PD-1 immune modulatory pathway are promising for the future treatment of MCC. Despite this major progress of the past few years, the cellular origin of MCC still remains obscure. Based on histomorphology, gene expression profiling, and molecular analyses, we have recently hypothesized that MCC originates from pre‑/pro-Bcells. Here we review putative cells of MCC, including Merkel cells, (epi‑)dermal stem cells, and pro‑/pre-Bcells. In the present work, the focus is on the concept of pre‑/pro-Bcells as the cellular origin of MCC, which might also impact the understanding of other human small cell malignancies of unknown cellular origin, such as small cell carcinomas of the lung and other anatomical locations. In addition, this concept might pave the way for novel treatment options, especially for advanced MCC.
Highlights
Abb. 1 8 Schema zur Prä-/pro-B-Zell-Hypothese als zellulärer Ursprung des Merkelzellkarzinoms (MZK)
Merkel cell polyomavirus (MCPyV) is clonally integrated into the Merkel cell carcinoma (MCC) genome and approximately 80% of MCC are MCPyV-positive
Shuda M, Guastafierro A, Geng X, Shuda Y, Ostrowski SM, Lukianov S et al (2015) Merkel cell polyomavirus small T antigen induces cancer and embryonic Merkel cell proliferation in a transgenic mouse model
Summary
Das Merkelzellkarzinom (MZK) wurde erstmals 1972 von Cyril Toker [1] als trabekuläres Karzinom der Haut beschrieben. Etwa 80 % der MZK sind assoziiert mit dem Merkelzell-Polyomavirus (MCPyV), das 2008 identifiziert wurde [15]. Die übrigen 20 % der MZK sind MCPyV-negativ und zeichnen sich durch charakteristische UV-assoziierte Schäden auf genomischer Ebene aus [16, 17]. Histologisch handelt es sich bei den MZK um eine heterogene Gruppe von 3 sehr unterschiedlichen Typen. Sowohl die Integration der MCPyVDNA als auch der kurz darauf erfolgte Nachweis tumorspezifischer funktioneller Mutationen des „large T antigens“ (LTag), eines viralen Onkogens des MCPyV, legten eine wichtige funktionale Relevanz in der Ätiologie und Pathogenese des MZK nahe [15, 19]. Experimentelle Knock-down-Versuche haben mittlerweile die funktionelle Abhängigkeit der MZK vom LTag gezeigt [24]
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