Changing mutational and adaptive landscapes and the genesis of cancer.

By the time the process of oncogenesis has produced an advanced cancer, tumor cells have undergone extensive evolution. The cellular phenotypes resulting from this evolution have been well studied, and include accelerated growth rates, apoptosis resistance, immortality, invasiveness, and immune evasion. Yet with all of our current knowledge of tumor biology, the details of early oncogenesis have been difficult to observe and understand. Where different oncogenic mutations may work together to enhance the survival of a tumor cell, in isolation they are often pro-apoptotic, pro-differentiative or pro-senescent, and therefore often, somewhat paradoxically, disadvantageous to a cell. It is also becoming clear that somatic mutations, including those in known oncogenic drivers, are common in tissues starting at a young age. These observations raise the question: how do we largely avoid cancer for most of our lives? Here we propose that evolutionary forces can help explain this paradox. As humans and other organisms age or experience external insults such as radiation or smoking, the structure and function of tissues progressively degrade, resulting in altered stem cell niche microenvironments. As tissue integrity declines, it becomes less capable of supporting and maintaining resident stem cells. These stem cells then find themselves in a microenvironment to which they are poorly adapted, providing a competitive advantage to those cells that can restore their functionality and fitness through mutations or epigenetic changes. The resulting oncogenic clonal expansions then increase the odds of further cancer progression. Understanding how the causes of cancer, such as aging or smoking, affect tissue microenvironments to control the impact of mutations on somatic cell fitness can help reconcile the discrepancy between marked mutation accumulation starting early in life and the somatic evolution that leads to cancer at advanced ages or following carcinogenic insults. This article is part of a Special Issue entitled: Evolutionary principles - heterogeneity in cancer?, edited by Dr. Robert A. Gatenby.