Anastasis and Other Apoptosis-Related Prosurvival Pathways Call for a Paradigm Shift in Oncology: Significance of Deintensification in Treating Solid Tumors.

What is apoptosis? The Nomenclature Committee on Cell Death and numerous other pioneering cancer/p53 biologists use the terms "apoptosis" and "cell death" interchangeably, disregard the mind-numbing complexity and heterogeneity that exists within a tumor (intratumor heterogeneity), disregard the contribution of polyploid giant cancer cells (PGCCs; the root causes of therapy resistance and relapse) to this heterogeneity, and then propose novel apoptosis-stimulating anticancer strategies. This is shocking for the following three reasons. First, clinical studies reported since the 1990s have revealed that increased apoptosis in solid tumors is associated with increased tumor diversity and poor prognosis. Second, we have known for years that dying (apoptotic) cancer cells release a panel of secretions (e.g., via phoenix rising and other pathways) that promote metastatic outgrowth. Third, over a decade ago, it was demonstrated that cancer cells can recover from late stages of apoptosis (after the formation of apoptotic bodies) via the homeostatic process of anastasis, resulting in the emergence of aggressive variants. The cell surface expression of CD24 has recently been reported to be preferentially enriched in recovered (anastatic) cancer cells that exhibit tumorigenic properties. These and related discoveries outlined herein call for a paradigm shift in oncology to focus on strategies that minimize the occurrence of treacherous apoptosis and other tumor-repopulating events (e.g., therapy-induced cancer cell dormancy and reactivation). They also raise an intriguing question: is deregulated anastasis (rather than evasion of apoptosis) a hallmark of cancer?