Hijacking homeostasis: Regulation of the tumor microenvironment by apoptosis

Cancers are genetically driven, rogue tissues which generate dysfunctional, obdurate organs by hijacking normal, homeostatic programs. Apoptosis is an evolutionarily conserved regulated cell death program and a profoundly important homeostatic mechanism that is common (alongside tumor cell proliferation) in actively growing cancers, as well as in tumors responding to cytotoxic anti-cancer therapies. Although well known for its cell-autonomous tumor-suppressive qualities, apoptosis harbors pro-oncogenic properties which are deployed through non-cell-autonomous mechanisms and which generally remain poorly defined. Here, the roles of apoptosis in tumor biology are reviewed, with particular focus on the secreted and fragmentation products of apoptotic tumor cells and their effects on tumor-associated macrophages, key supportive cells in the aberrant homeostasis of the tumor microenvironment. Historical aspects of cell loss in tumor growth kinetics are considered and the impact (and potential impact) on tumor growth of apoptotic-cell clearance (efferocytosis) as well as released soluble and extracellular vesicle-associated factors are discussed from the perspectives of inflammation, tissue repair, and regeneration programs. An "apoptosis-centric" view is proposed in which dying tumor cells provide an important platform for intricate intercellular communication networks in growing cancers. The perspective has implications for future research and for improving cancer diagnosis and therapy.