The Apoptosis Paradox in Cancer

Abstract

Cancer growth represents a dysregulated imbalance between cell gain and cell loss, where the rate of proliferating mutant tumour cells exceeds the rate of those that die. Apoptosis, the most renowned form of programmed cell death, operates as a key physiological mechanism that limits cell population expansion, either to maintain tissue homeostasis or to remove potentially harmful cells, such as those that have sustained DNA damage. Paradoxically, high-grade cancers are generally associated with high constitutive levels of apoptosis. In cancer, cell-autonomous apoptosis constitutes a common tumour suppressor mechanism, a property which is exploited in cancer therapy. By contrast, limited apoptosis in the tumour-cell population also has the potential to promote cell survival and resistance to therapy by conditioning the tumour microenvironment (TME)-including phagocytes and viable tumour cells-and engendering pro-oncogenic effects. Notably, the constitutive apoptosis-mediated activation of cells of the innate immune system can help orchestrate a pro-oncogenic TME and may also effect evasion of cancer treatment. Here, we present an overview of the implications of cell death programmes in tumour biology, with particular focus on apoptosis as a process with "double-edged" consequences: on the one hand, being tumour suppressive through deletion of malignant or pre-malignant cells, while, on the other, being tumour progressive through stimulation of reparatory and regenerative responses in the TME.

Keywords: apoptosis; cancer; cancer therapy; cell death; extracellular vesicle; immune system; macrophage; regeneration; repair; tumour.

Figure 1

The ‘apoptosis paradox’ in malignant disease (A): Apoptosis as a cell-autonomous process is tumour-suppressive (top, blue arrow). Protection from apoptosis (e.g., by anti-apoptotic BCL-2 family members) permits survival of mutant cells and outgrowth of premalignant or malignant populations. Fractional apoptosis within these populations, dependent upon the relative levels of proliferating and dying cells, yields different growth rates. Therapeutic efficacy is achieved when cell death exceeds cell birth (remission, bottom right). (B): The best-known functional programmes of phagocytes (especially macrophages) engaging in efferocytosis. All have pro-oncogenic features. Note that immune responses (shown here as suppressed) may also be stimulated by apoptotic cells in certain contexts.

Figure 2

Pro-oncogenic effects of apoptosis and the concept of the Onco-Regenerative Niche (ORN). Apoptotic tumour cells have broad effects on the tumour population as a whole and provide the driving force in a conceptual sub-sector of the tumour micro-environment, which we have termed the ORN. Solid blue arrows and associated molecules highlight proven pathways that we and others have elucidated in recent years. Green lines indicate putative pathways in the ORN that we have identified through in situ transcriptomics of TAMs. Grey arrows indicate potential functional pathways of Apo-EVs. See text for further details.