Stem cell biology and the cellular pathways of carcinogenesis.

Tissues in the body are maintained by somatic stem cells. This has been demonstrated both in organs with high cell turnover rate, such as the bone marrow, colon and skin, and in organs with low cell turnover rate, such as the brain. To maintain homeostasis in the body it is important to keep tight control over stem cell fate. Stem cells are under strict control from both intrinsic and extrinsic factors and loss of this control has been postulated to be a key step in the carcinogenic process. There is increasing evidence that cancer initiation results from accumulative oncogenic mutations (intrinsic loss of control) in long-lived stem cells or their immediate progenitor, followed by modification of the surrounding microenvironment (loss of extrinsic control). Decades ago, studies on teratocarcinoma led to the hypothesis that a small subset of self-renewing cancer stem cells with differentiation potential exists within tumors. These studies showed that teratocarcinomas contain undifferentiated embryonic carcinoma cells that are able to give rise to differentiated cells which belong to all three germ layers. More recent studies have confirmed cancer stem cells in such diverse cancers as leukemia, brain and breast cancer. It is, however, unclear whether cancer stem cells originate from resident stem cells or whether they arise as a result of an acquired gain of self-renewal capacity in tissue progenitor cells or even more differentiated cells. The characterization of a cancer stem cell profile within diverse cancer types may open up new avenues for cancer treatment. In this review we discuss the concept of cancer stem cells and focus on examples where these cells have been identified.