Do nonmelanoma skin cancers develop from extra-cutaneous stem cells?

A hypothesis is presented that nonmelanoma skin cancers can develop from extra-cutaneous stem cells, and not exclusively from skin keratinocytes. This idea is supported by recent findings regarding the initiation of cancers in the digestive tract, and by a cancer stem cell model of a neoplasia. It is known that multipotent adult progenitor cells can trans-differentiate into very diverse cellular lineages and can be recruited to areas of profound tissue injury. In these settings, they might also initiate malignant transformation. Some epidemiological data and recent findings regarding mechanisms of wound healing indicate that skin cancers could also originate from bone marrow-derived or other extra-cutaneous stem cells in addition to local stem cells. It can therefore be speculated that the biology of keratinocyte stem cells derived from these sources differs from that of local epidermal stem cells, and consequently, these cells might be poorly controlled within their niches. Furthermore, in chronically inflamed skin, or in an immunodeficient patient, malignant transformation of extra-cutaneous stem cells is more likely to occur. There is one well-documented case of basal cell cancer which has arisen from donor cells in a kidney transplant recipient, but it remains unclear if this cancer developed directly from a donor-derived cell, or via fusion of such cells with premalignant keratinocytes. Hopefully, combining animal models of skin cancer initiation with experiments exploring the role of bone marrow-derived cells in skin healing will bring to light the exact mechanism of carcinogenesis of nonmelanoma skin cancers. (C) 2008 Wiley-Liss, Inc.