The Role of Cellular Differentiation and Cell Fate in Malignant Melanoma

1.1 Defining differentiation and cell fate in cancer In the setting of embryonic development, terms such as “cell fate“ and “cellular differentiation“ are relatively easy to grasp, since they refer to a straightforward linear model whereby progenitor cells give rise sequentially to various distinct and identifiable lineages, eventually resulting in a terminally differentiated cell that has until recently been thought to possess very little cellular plasticity or multipotent capacity. The sequences of events that regulate this process are extremely well conserved within a species, and even across species in many instances. In the setting of cancer, cell fate and cellular differentiation are often used descriptively to convey an observed phenotype rather than a defined and well-understood molecular process. How accurate is it to refer to “differentiation“ in cancer when the so-called end-point for this process results in cellular heterogeneity that is antithetical to the regulated and predictable differentiated cells that result from embryonic development? What does it mean to refer to “cell fate“ during the inherently dysregulated series of events involved in oncogenesis, which may not result in a distinct endpoint even across cells within the same tumor? Our review uses these terms in reference to the dynamic processes that constantly shape the function and properties of melanoma cells, which coincidentally utilize many of the same pathways involved in the regulated process of differentiation and determination of cell fate during embryonic development. While the label of being a differentiated cell may imply a terminal nature that might be viewed as less tumorigenic or lethal in the setting of cancer, this concept requires further experimental confirmation. Undoubtedly, these terms will become more refined as our understanding of the molecular events underlying melanoma progression comes into clearer focus. For now, they are the best terms available to describe some of the events and processes that help determine the behavior and response of tumor cells, and we use them with the full knowledge that years from now, advances in our understanding of cancer could render these terms woefully inadequate, or worse yet inaccurate.