Merkel cell carcinoma (MCC), a highly aggressive skin tumour with increasing incidence, is associated with the newly discovered Merkel cell polyomavirus (MCPyV). Studies on MCC and MCPyV as well as other risk factors have significantly increased our knowledge of MCC pathogenesis, but the cells of origin, which could be important targets in future therapies, are still unknown. Merkel cells (MCs), the neuroendocrine cells of the skin, were believed to be at the origin of MCC due to their phenotypic similarities. However, for several reasons, for example, heterogeneous differentiation of MCCs and postmitotic character of MCs, it is not very likely that MCC develops from differentiated MCs. Skin stem cells, probably from the epidermal lineage, are more likely to be cells of origin in MCC. Future studies will have to address these questions more directly in order to identify the physiological cells which are transformed to MCC cells.
Merkel cell carcinoma (MCC) is a highly aggressive skin malignancy mainly affecting elderly and immunosuppressed people [
Cells of origin in cancer have been defined as cells which “acquire the first genetic hit or hits that culminate in the initiation of cancer” [
The second group of cells of origin in cancer are committed progenitor cells [
Third, even differentiated cells could give rise to cancer, as any cell which is able to proliferate could become a cell of origin in cancer, provided it acquires mutations which restore the ability to self-renew and prevent differentiation to a postmitotic state [
Before turning to the origin of MCC, it is important to keep in mind that the terms “cell-of-origin in cancer” and “cancer stem cell” are different [
Early histological and ultrastructural analyses of the so-called “trabecular carcinoma of the skin” [
Scheme of potential cells of origin of Merkel cell carcinoma (MCC), shown from an ontogenetic perspective. All arrows with a
Although at first glance, these observations strongly support the hypothesis that MCC emerges from transformed MCs, there are quite a few data which question this view. First, MCs and MCC differ in some aspects of their immunophenotype. For instance, the neural cell adhesion molecule L1 (CD171), a relative of NCAM, is produced by MCC cells, but not by MCs [
Second, in a study on fetal and human skin, no proliferative Merkel cells could be detected, strongly suggesting that human Merkel cells are postmitotic [
Third, differences in tissue localization argue against MCs as cells-of-origin for MCC. Whereas the majority of MCs is located in the basal layer of the epidermis [
Finally, the observed heterogeneity in MCC rather favors less differentiated cells as cells of origin [
As mentioned before, in mice, MCs arise from stem/progenitor cells of the epidermal lineage [
Based on their histomorphological pattern as well as results of immunohistochemical stainings, dermal neuroendocrine cells have been suggested as a potential source for MCC [
In addition to the neural crest-derived stem cells mentioned before, a further stem cell population has been isolated from murine and human dermis and termed skin-derived precursors (SKPs) [
If the MCPyV plays an important role in MCC genesis, as suggested by several recent studies (reviewed in [
Despite intense research on MCC during the last years, the cells of origin of this cutaneous malignancy remain elusive. Merkel cells (MCs), originally the favourite candidate for such a role, appear less likely to give rise to MCC now, mainly because of MCC heterogeneity and the postmitotic character of MCs. Stem cells located in the skin, most probably of the epidermal lineage, appear to be more probable cells of origin for MCC. However, as experimental evidence for a stem cell origin is missing, too, more direct approaches to tackle the “origin-of-MCC-question” are needed. These could include genetic lineage tracing or reprogramming of MCC cells.
The authors thank Ewa Wladykowski for expert technical assistance.