International Review of Cell and Molecular

Biology
Volume 337, 2018, Pages 135-152

Chapter Five - Apoptosis and Cancer: Force Awakens,

Phantom Menace, or Both?
Kai Cao * †, Stephen W.G. Tait * †

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Abstract

Apoptotic cell death serves as an important tumor suppressor mechanism at multiple

steps during cancer progression. Equally, engagement of apoptosis represents a potent
therapeutic effector mechanism. Nevertheless, the role of apoptosis in cancer may be
more complex than previously thought. Indeed, various studies have found that
apoptosis signaling also has oncogenic potential. In this review, we discuss how
apoptosis can promote cancer and how these effects might be targeted to optimize
apoptosis-inducing anticancer therapy.

Section snippets

Apoptosis vs Cancer—A New Hope

In metazoans, physiological cell death often occurs via apoptosis, which is a highly
conserved and tightly regulated mechanism (Green, 2011). Apoptosis plays important
roles in many processes including embryonic development, normal cell turnover,
neuronal selection, and immune cell homeostasis (reviewed in Fuchs and Steller, 2011;
Kerr et al., 1972; Opferman and Korsmeyer, 2003). Thus, too much or too little apoptosis,
or its occurrence at the wrong time or place, can contribute to diverse…

Unleashing the Force—Apoptotic Signaling Pathways

Apoptosis occurs either through the extrinsic (death receptor) or the intrinsic
(mitochondrial) pathway. The extrinsic pathway is triggered by a family of death
receptors located on the cell membrane, including TNF-R1, FAS (CD95), TRAIL-R1, and
TRAIL-R2 (reviewed in Green and Llambi, 2015). In a simplified model, following
ligand/receptor binding, the caspase protease, caspase-8, is activated through
dimerization. Activated caspase-8 cleaves and activates the executioner caspase-3 and
-7,…

Cancer Strikes Back: Apoptosis as an Oncogenic Driver

Apoptosis clearly has important roles in the elimination of aberrant cells, thereby
preventing tumorigenesis. However, increasing numbers of studies have shown that
apoptosis may also have oncogenic functions (reviewed in Ichim and Tait, 2016; Labi and
Erlacher, 2015). While overlap occurs, in general terms oncogenic effects can either be
cell autonomous or via nonautonomous effects on the surrounding tumor
microenvironment.…

Flying Casual: Nonlethal, Oncogenic Roles for Apoptotic Proteins

Besides regulating apoptosis, nonlethal functions for apoptosis proteins in tumor

progression have been described (Cullen and Martin, 2015). As discussed, certain types
of tumor cells express FAS and TRAIL on their surface. Besides their role in inducing T-
cell death, nonapoptotic functions have also been revealed, for example, their ability to
stimulate production of inflammatory cytokines/chemokines and wound-healing
mediators, including IL-6, GM-CSF, and CXCL1 that are often beneficial for…

Help Me Apoptosis. You Are My Only Hope: Targeting Oncogenic Effects of

Apoptosis in Cancer Therapy

The therapeutic goal of most antitumor strategies be it radiotherapy, chemotherapy, or

immunotherapy is to induce tumor cell death (DeSantis et al., 2014). However, a major
problem in anticancer treatment is therapeutic resistance, in which tumor-promoting
roles of apoptosis may play a role. Therapy-induced apoptotic tumor cells were reported
to promote tumor regrowth through the secretion of signaling molecules dependent on
caspase-3-mediated activation of cytosolic calcium-iPLA2 and…
Outlook

Intuitively, one would expect apoptosis to be an effective mechanism to both prevent

and treat cancer—indeed, this had been borne out by many studies. Nevertheless, as we
have discussed, the role of apoptosis in cancer appears to be more complex such that it
may also have tumor-promoting effects. Going forward, it will be essential to address the
importance of these effects in vivo with respect to their influence on tumor initiation,
progression, and response to treatment. Understanding the…

Acknowledgments
Research in the Tait lab is supported by Cancer Research UK and Breast Cancer Now.
Figures were generated, in part, using images provided by Servier Medical Art
(http://www.servier.co.uk/content/servier-medical-art ↗).…

References (98)

S. von Karstedt
Cancer cell-autonomous TRAIL-R signaling promotes KRAS-driven cancer
progression, invasion, and metastasis
Cancer Cell (2015)

F. Vaillant
Targeting BCL-2 with the BH3 mimetic ABT-199 in estrogen receptor-positive
breast cancer
Cancer Cell (2013)

J. Spychala
Tumor-promoting functions of adenosine
Pharmacol. Ther. (2000)

J.B. Smerage
Monitoring apoptosis and Bcl-2 on circulating tumor cells in patients with
metastatic breast cancer
Mol. Oncol. (2013)

T. Sakurai
Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate
carcinogen-induced compensatory proliferation and liver tumorigenesis
Cancer Cell (2008)

H.D. Ryoo et al.

Apoptotic cells can induce compensatory cell proliferation through the JNK and
the wingless signaling pathways
Dev. Cell (2004)

X. Liu
Caspase-3 promotes genetic instability and carcinogenesis
Mol. Cell (2015)

G. Ichim
Limited mitochondrial permeabilization causes DNA damage and genomic
instability in the absence of cell death
Mol. Cell (2015)

V. Huber
Human colorectal cancer cells induce T-cell death through release of
proapoptotic microvesicles: role in immune escape
Gastroenterology (2005)

T. Hartwig
The TRAIL-induced cancer secretome promotes a tumor-supportive immune
microenvironment via CCR2
Mol. Cell (2017)

View more references

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