Dysregulation of Apoptosis - Genentech BioOncology

Apoptosis (programmed cell death) is a key process in cancer development and progression.^1,2 The ability of cancer cells to avoid apoptosis and continue to proliferate is one of the fundamental hallmarks of cancer and is a major target of cancer therapy development.² Developing novel molecules that promote apoptosis by targeting both the intrinsic and extrinsic apoptotic pathways advances our understanding of the mechanisms behind tumor cell proliferation, which may also lead to the development of effective cancer therapies.

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Apoptosis is triggered through 2 main signaling pathways^1,3,4:

• The extrinsic pathway, which is activated in response to multiple external pro-apoptotic signals, including endogenous Apo2L/TRAIL and other pro-apoptotic receptor agonists (PARAs)
• The intrinsic pathway, which is activated by cellular developmental cues or as a result of severe cellular stress (eg, DNA damage)

Dysregulation of apoptosis

All cells have a finite life span, and cell death occurs mainly as a result of passive necrotic processes or due to an active process of programmed cell death, or apoptosis.^5,6 Apoptosis plays an important role in both human embryonic development and adult tissue homeostasis.⁶ Apoptosis is the most common mechanism by which the body eliminates damaged or unneeded cells without local inflammation from leakage of cell contents.^5,7

In normal cells, apoptosis is initiated in response to certain developmental cues, such as a decrease in the local concentration of a particular tissue morphogen or growth factor. Other stimuli include severe stress or damage to vital cellular components, which can be caused by ionizing radiation, heat shock, toxins, cell detachment from surrounding tissue, bacterial or viral infection, and/or oncogenic signaling.^1,8

References:

1.

Ashkenazi A. Targeting death and decoy receptors of the tumour-necrosis factor superfamily. Nat Rev Cancer. 2002;2:420-430.

2.

Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100:57-70.

3.

Jin Z, El-Deiry WS. Overview of cell death signaling pathways. Cancer Biol Ther. 2005;4:139-163.

4.

Ghobrial IM, Witzig TE, Adjei AA. Targeting apoptosis pathways in cancer therapy. CA Cancer J Clin. 2005;55:178-194.

5.

Bree RT, Stenson-Cox C, Grealy M, Byrnes L, Gorman AM, Samali A. Cellular longevity: role of apoptosis and replicative senescence. Biogerontology. 2002;3:195-206.

6.

Fulda S, Debatin KM. Apoptosis signaling in tumor therapy. Ann N Y Acad Sci. 2004;1028:150-156.

7.

Fadeel B, Orrenius S. Apoptosis: a basic biological phenomenon with wide-ranging implications in human disease. J Intern Med. 2005;258:479-517.

8.

Ashkenazi A. Directing cancer cells to self-destruct with pro-apoptotic receptor agonists. Nat Rev Drug Discov. 2008;7:1001-1012.