Cancer: A Story of Stem Cells and Evolution

Cancer is an acquired genetic disease of clonal origin. Carcinogenesis and its subsequent development follow the principles of evolution, starting with a single cell with stem cell properties and a proliferative advantage, leading to clonal expansion, clonal evolution and subsequent demise by killing the host: “Evolution gone awry”. Evolution can be divided into three essential steps: 1. “Chance” or random movement of molecules allows structures to interact. 2. Molecular affinity, “Necessity” (J. Monod, Chance and Necessity: Essay on the Natural Philosophy of Modern Biology, 1970), leads to a new structure providing novel properties and function. The 3rd step of the evolutionary processes, for which I would propose the term “Synclipse”, occurs, if the new constellation provides a biochemical and biological survival advantage, “survival of the fittest”, in a given environmental context. The initial event, in the context of germ line predisposing mutations/polymorphisms, reflects the cellular reaction to environmental factors: microenvironment, chemicals, radiation, viruses by altering epigenetic gene regulation. These genes of importance for proliferation, apoptosis and differentiation, are thus more prone to mutations, and after further evolution a malignant genotype is acquired. The development of these new molecular structures and functions follow the principles of evolution outlined above. These genetic alterations are the basis for the pathophysiological alterations of the malignant phenotype and are also potential targets for therapeutic strategies. The genetic analysis, whole exon and whole genome sequencing identify the genetic alterations in specific genes that frequently code for proteins targeted by small synthetic molecules. Re-sequencing in different metastasis and during the clinical course has demonstrated the ongoing evolution of cancer cells.