Caspase 3-mediated Stimulation of Tumor Cell Repopulation During Cancer Radiotherapy

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2011 Jul 5

PMID 21725296

Citations 424

Authors

Qian Huang

Fang Li

Xinjian Liu

Wenrong Li

Wei Shi

Fei-Fei Liu

Brian OSullivan

Zhimin He

Yuanlin Peng

Aik-Choon Tan

Ling Zhou

Jingping Shen

Gangwen Han

Xiao-Jing Wang

Jackie Thorburn

Andrew Thorburn

Antonio Jimeno

David Raben

Joel S Bedford

Chuan-Yuan Li

Affiliations

Soon will be listed here.

Abstract

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.

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References

Atsumi G, Tajima M, HADANO A, Nakatani Y, Murakami M, Kudo I . Fas-induced arachidonic acid release is mediated by Ca2+-independent phospholipase A2 but not cytosolic phospholipase A2, which undergoes proteolytic inactivation. J Biol Chem. 1998; 273(22):13870-7. DOI: 10.1074/jbc.273.22.13870. View

Li F, He Z, Shen J, Huang Q, Li W, Liu X . Apoptotic caspases regulate induction of iPSCs from human fibroblasts. Cell Stem Cell. 2010; 7(4):508-20. PMC: 2996867. DOI: 10.1016/j.stem.2010.09.003. View

Lauber K, Bohn E, Krober S, Xiao Y, Blumenthal S, Lindemann R . Apoptotic cells induce migration of phagocytes via caspase-3-mediated release of a lipid attraction signal. Cell. 2003; 113(6):717-30. DOI: 10.1016/s0092-8674(03)00422-7. View

Fujita J, Crane A, Souza M, Dejosez M, Kyba M, Flavell R . Caspase activity mediates the differentiation of embryonic stem cells. Cell Stem Cell. 2008; 2(6):595-601. PMC: 2494585. DOI: 10.1016/j.stem.2008.04.001. View

Contag C, Jenkins D, Contag P, Negrin R . Use of reporter genes for optical measurements of neoplastic disease in vivo. Neoplasia. 2000; 2(1-2):41-52. PMC: 1550286. DOI: 10.1038/sj.neo.7900079. View

Lakhani S, Masud A, Kuida K, Porter Jr G, Booth C, Mehal W . Caspases 3 and 7: key mediators of mitochondrial events of apoptosis. Science. 2006; 311(5762):847-51. PMC: 3738210. DOI: 10.1126/science.1115035. View

Chera S, Ghila L, Dobretz K, Wenger Y, Bauer C, Buzgariu W . Apoptotic cells provide an unexpected source of Wnt3 signaling to drive hydra head regeneration. Dev Cell. 2009; 17(2):279-89. DOI: 10.1016/j.devcel.2009.07.014. View

Kuida K, Zheng T, Na S, Kuan C, Yang D, Karasuyama H . Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature. 1996; 384(6607):368-72. DOI: 10.1038/384368a0. View

Stephens T, CURRIE G, Peacock J . Repopulation of gamma-irradiated Lewis lung carcinoma by malignant cells and host macrophage progenitors. Br J Cancer. 1978; 38(5):573-82. PMC: 2009782. DOI: 10.1038/bjc.1978.252. View

10.

Zhao X, Wang D, Zhao Z, Xiao Y, Sengupta S, Xiao Y . Caspase-3-dependent activation of calcium-independent phospholipase A2 enhances cell migration in non-apoptotic ovarian cancer cells. J Biol Chem. 2006; 281(39):29357-68. DOI: 10.1074/jbc.M513105200. View

11.

Hermens A, Barendsen G . Changes of cell proliferation characteristics in a rat rhabdomyosarcoma before and after x-irradiation. Eur J Cancer (1965). 1969; 5(2):173-89. DOI: 10.1016/0014-2964(69)90065-6. View

12.

Kang T, Ben-Moshe T, Varfolomeev E, Pewzner-Jung Y, Yogev N, Jurewicz A . Caspase-8 serves both apoptotic and nonapoptotic roles. J Immunol. 2004; 173(5):2976-84. DOI: 10.4049/jimmunol.173.5.2976. View

13.

Szymczyk K, Freeman T, Adams C, Srinivas V, Steinbeck M . Active caspase-3 is required for osteoclast differentiation. J Cell Physiol. 2006; 209(3):836-44. DOI: 10.1002/jcp.20770. View

14.

Ahn G, Brown J . Matrix metalloproteinase-9 is required for tumor vasculogenesis but not for angiogenesis: role of bone marrow-derived myelomonocytic cells. Cancer Cell. 2008; 13(3):193-205. PMC: 2967441. DOI: 10.1016/j.ccr.2007.11.032. View

15.

Fan Y, Bergmann A . Distinct mechanisms of apoptosis-induced compensatory proliferation in proliferating and differentiating tissues in the Drosophila eye. Dev Cell. 2008; 14(3):399-410. PMC: 2277325. DOI: 10.1016/j.devcel.2008.01.003. View

16.

Garcia-Barros M, Paris F, Cordon-Cardo C, Lyden D, Rafii S, Haimovitz-Friedman A . Tumor response to radiotherapy regulated by endothelial cell apoptosis. Science. 2003; 300(5622):1155-9. DOI: 10.1126/science.1082504. View

17.

Ivshina A, George J, Senko O, Mow B, Putti T, Smeds J . Genetic reclassification of histologic grade delineates new clinical subtypes of breast cancer. Cancer Res. 2006; 66(21):10292-301. DOI: 10.1158/0008-5472.CAN-05-4414. View

18.

Kennedy N, Kataoka T, Tschopp J, Budd R . Caspase activation is required for T cell proliferation. J Exp Med. 1999; 190(12):1891-6. PMC: 2195711. DOI: 10.1084/jem.190.12.1891. View

19.

Li F, Huang Q, Chen J, Peng Y, Roop D, Bedford J . Apoptotic cells activate the "phoenix rising" pathway to promote wound healing and tissue regeneration. Sci Signal. 2010; 3(110):ra13. PMC: 2905599. DOI: 10.1126/scisignal.2000634. View

20.

North T, Goessling W, Walkley C, Lengerke C, Kopani K, Lord A . Prostaglandin E2 regulates vertebrate haematopoietic stem cell homeostasis. Nature. 2007; 447(7147):1007-11. PMC: 2775137. DOI: 10.1038/nature05883. View