Caspase 3–mediated stimulation of tumor cell repopulation during cancer radiotherapy

• Published in: Nature medicine Vol. 17; no. 7; pp. 860 - 866
• Main Authors: Huang, Qian, Li, Fang, Liu, Xinjian, Li, Wenrong, Shi, Wei, Liu, Fei-Fei, O'Sullivan, Brian, He, Zhimin, Peng, Yuanlin, Tan, Aik-Choon, Zhou, Ling, Shen, Jingping, Han, Gangwen, Wang, Xiao-Jing, Thorburn, Jackie, Thorburn, Andrew, Jimeno, Antonio, Raben, David, Bedford, Joel S, Li, Chuan-Yuan
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2011; Nature Publishing Group
• Subjects: 631/67/1059/485; 631/80/82/23; 631/80/86; 692/699/67; Animals; Apoptosis; Apoptosis - radiation effects; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Caspase 3 - metabolism; Caspase 3 - physiology; Cell Death - physiology; Cell Death - radiation effects; Cell Line, Tumor; Cell Proliferation; Cytotoxicity; Dinoprostone - metabolism; Dinoprostone - physiology; Group VI Phospholipases A2 - metabolism; Health aspects; Humans; Infectious Diseases; Metabolic Diseases; Mice; Molecular Medicine; Mortality; Neoplasms, Experimental - radiotherapy; Neurosciences; Physiological aspects; Prostaglandins E; Radiation therapy; Radiotherapy; Repopulation; Tumors; United States
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/nm.2385

Cytotoxic cancer therapy can induce accelerated growth of surviving cancer cells, a phenomenon known as tumor repopulation. This report uncovers a mechanism by which caspase 3 activation in treated cells promotes growth of surviving cells, mediated by iPLA 2 and PGE 2 . The level of caspase 3 activation in human tumors also correlates with risk of relapse, suggesting that this pathway may be a determinant of therapeutic effects. In cancer treatment, apoptosis is a well-recognized cell death mechanism through which cytotoxic agents kill tumor cells. Here we report that dying tumor cells use the apoptotic process to generate potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy. Furthermore, activated caspase 3, a key executioner in apoptosis, is involved in the growth stimulation. One downstream effector that caspase 3 regulates is prostaglandin E 2 (PGE 2 ), which can potently stimulate growth of surviving tumor cells. Deficiency of caspase 3 either in tumor cells or in tumor stroma caused substantial tumor sensitivity to radiotherapy in xenograft or mouse tumors. In human subjects with cancer, higher amounts of activated caspase 3 in tumor tissues are correlated with markedly increased rate of recurrence and death. We propose the existence of a cell death–induced tumor repopulation pathway in which caspase 3 has a major role.