Apoptosis as the Primary Elimination Mechanism for Cancer Cells: Mechanisms, Evidence, and Therapeutic Implications

Abstract

Apoptosis constitutes the principal mechanism controlling the elimination of cancer cells. Apoptosis arises as a fundamental capability of multicellular organisms regulating cell number and maintaining homeostasis. It is the best-studied form of programmed cell death and broadly participates in multiple physiological processes embryogenesis, tissue remodeling, and immune cell maturation, among others. According to accumulated evidence, apoptosis acts as a potent tumor-suppressor mechanism curtailing cancer cell expansion. Cancer cells are subjected to multiple biological insults continuously exerted by their micro- and macro-environment and, when left unresolved, such detrimental events drive cells toward a neoplastic transformation. Cancer cells often acquire opposing alterations that foster adaptation to these events, evade replication barriers, and expand into tumors. Recent studies have argued that when cancer clones develop resistance, pro-apoptotic signals become a prominent component of antagonistic programs, reinforcing the notion that a majority of cancer clones are still susceptible to apoptotic removal during tumor establishment.

At least three forms of terminal cancer-cell elimination have been identified: apoptosis, senescence, and necrosis. Apoptosis distinctively leads to the generation of an immunogenic signal that facilitates the elimination of cancer-cell clones even from resistant tumors. Available genetic, molecular, and pharmacological evidence supports the notion that apoptosis operates as a major mode for the elimination of cancer cells during malignant transformation. Importantly, a wide variety of therapeutic modalities induce death predominantly through apoptosis. Because apoptosis appears to still remain a critical backup option during cancer prevention, continued further investigation into the mechanisms of apoptosis and the establishment of new therapeutics for its induction holds considerable promise for improving cancer treatment.

A multitude of stresses imparted by tumor microenvironments destabilizes normal tissues and triggers apoptosis. Treatments that cause further stresses, including DNA lesions, directly promote massive apoptosis, underscoring the still-latent vulnerability of cancer cells. Collectively, compounds that elicit extensive, unmanageable apoptosis in cancer cells, either through direct activation or relay of biochemical signals, can become new agents or be combined with existing ones for more effective therapy