Elsevier

Cancer Treatment Reviews

Volume 34, Issue 8, December 2008, Pages 737-749
Cancer Treatment Reviews

Laboratory–Clinical Interface
Apoptosis and non-apoptotic deaths in cancer development and treatment response

https://doi.org/10.1016/j.ctrv.2008.07.001Get rights and content

Summary

Resistance to apoptosis is closely linked to tumorigenesis, as it enables malignant cells to expand even in a stressful environment. Cells resistant to apoptosis are also assumed to be resistant to anti-cancer therapies. Apoptosis has therefore taken a central position in cell death research. However, its contribution to treatment success is highly debated for solid tumors. It becomes more and more clear that cells can also die by non-apoptotic mechanisms, such as autophagy, mitotic catastrophe and necrosis. In this review, we summarize the current knowledge regarding the molecular pathways that underlie these apoptotic and non-apoptotic death pathways, and discuss the clinical data that have now accumulated to evaluate their roles in tumor development and cancer treatment.

Introduction

The process by which a normal cell develops into a malignant cell with the capacity to form a tumor requires several cellular alterations. Evasion of apoptotic cell death is one of the proposed alterations.1 Importantly, evasion of apoptosis is also recognized to result in resistance to anti-cancer therapies.2 Much research has therefore focused on finding ways to circumvent this resistance to apoptosis in order to improve the treatment of cancer patients. However, the contribution of apoptosis resistance to treatment success remains a matter of debate, especially in solid tumors.3 Increasing attention is being directed towards other types of cell death, such as mitotic catastrophe, autophagy and necrosis. These alternative types of cell death may compensate for the resistance to apoptosis. Understanding the regulation of apoptosis and non-apoptotic death pathways will help us to better evaluate their impact on tumor development and treatment response in vivo. Moreover, detailed knowledge regarding the molecular events that contribute to treatment success will facilitate a more rational approach of anti-cancer treatments.

Section snippets

Apoptosis pathway

The term Apoptosis (Greek: apo – from, ptosis – falling) is based on the morphological characteristics of the dying cells, which include cellular shrinkage, membrane blebbing and eventually fragmentation into membrane bound apoptotic bodies.4 During apoptosis, the cell membrane loses its asymmetry, and phosphatidylserine (PS) becomes exposed on the cell surface (illustrated in Fig. 1). This PS exposure functions as ‘eat me’ signal for macrophages, which can mediate the effective clearance of

Apoptosis as prognostic marker

Many different anti-apoptotic modifications are found in human tumors, and resistance to apoptosis most likely is required for tumor cells to survive. This resistance could therefore be associated with a poor prognosis for cancer patients. In order to evaluate its prognostic value, several studies have scored the expression of a single apoptosis-associated protein, such as p53, Bcl-2 and/or Bax, and have correlated their expression with prognosis. As reviewed by Brown and Wilson,115 studies on

Concluding remarks

Almost all human tumors have acquired anti-apoptotic modifications. Therefore, it is tempting to conclude that an intact apoptotic pathway is likely tumor suppressive and that inhibition of apoptosis is necessary for tumor development. In line with this assumption, researchers have speculated that defective apoptotic pathways result in therapy resistance, since many cancer therapies induce apoptosis in tumor cells.

In the case of solid tumors, this inferral may not hold very well. The large

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