Extrinsic cell death pathway plasticity: a driver of clonal evolution in cancer?

Human cancers are known to adhere to basic evolutionary principles. During their journey from early transformation to metastatic disease, cancer cell populations have proven to be remarkably adaptive to different forms of intra- and extracellular selective pressure, including nutrient scarcity, oxidative stress, and anti-cancer immunity. Adaption may be achieved via the expansion of clones bearing driver mutations that optimize cellular fitness in response to the specific selective scenario, e.g., mutations facilitating evasion of cell death, immune evasion or increased proliferation despite growth suppression, all of which constitute well-established hallmarks of cancer. While great progress concerning the prevention, diagnosis and treatment of clinically apparent disease has been made over the last 50 years, the mechanisms underlying cellular adaption under selective pressure via the immune system during early carcinogenesis and its influence on cancer cell fate or disease severity remain to be clarified. For instance, evasion of cell death is generally accepted as a hallmark of cancer, yet recent decades have revealed that the extrinsic cell death machinery triggered by immune effector cells is composed of an astonishingly complex network of interacting-and sometimes compensating-modes of cell death, whose role in selective processes during early carcinogenesis remains obscure. Based upon recent advances in cell death research, here we propose a concept of cell death pathway plasticity in time shaping cancer evolution prior to treatment in an effort to offer new perspectives on how cancer cell fate may be determined by cell death pathway plasticity during early carcinogenesis.