On the origin and destination of cancer stem cells: a conceptual evaluation.

Despite remaining uncertainties and ongoing research it is possible to draw up a model for the role of (cancer) stem cells in both the initiation and progression of cancer towards metastasis. The cancer stem cell of origin and the cancer stem cell are, despite phenotypic similarities, genotypically different entities. Given the right circumstances provided by a combination of genomic changes and biochemical and physical interactions with its microenvironment, an epithelial cancer cell may undergo a phenotypic epithelial mesenchymal transition (EMT) towards a cancer stem cell. This transition conveys upon the cell crucial stem cell-like abilities which facilitate migration into the blood circulation as an individual circulating tumor cell, survive there, and subsequently seed into organ tissue where, once more in close interaction with its microenvironment, the process of clonal self renewal may start, leading to a metastatic tumor. Both in the primary tumor as well as in the metastatic tumor, partial differentiation of the cancer stem cell progeny leads to phenotypic heterogeneity. Throughout this complex process of cancer metastasis similarities with the way stem cells function during embryonic development, including the signaling pathways that mediate these functions, are evident. Deeper insight in the EMT process, plasticity of the resulting cancer stem cells, and the role of cancer stem cells in the metastatic process is expected to lead to novel anti-metastatic cancer therapies. Emerging human in vitro cancer models in the form of "organ-on-a-chip" may contribute valuable novel research tools to achieve this aim.