Stress-induced Premature Promotes Prostate Cancer Growth and Metastasis through Alteration of Microenvironment
Annual summary rept. 1 May 2009-31 Dec 2012
TEXAS UNIV SOUTHWESTERN MEDICAL SCHOOL AT DALLAS
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Prostate Cancer is the leading cancer diagnosed and the second leading cause of cancer death of men in the United States. The incidence of prostate cancer is closely associated with aging. Recent evidences suggested that the causes of cancer development are not limited to mutations within cancer cells, but also involve in alterations of cancer microenvironment. Senescent cells are irreversibly growth arrested, but remain metabolically active. Senescent cells, especially senescent fibroblasts in the stroma may provide a beneficial environment for tumor growth through secretion of certain factors. In our studies, we found that expression of insulin-like growth factor 1 IGF-1 and secretory clusterin sCLU are increased in senescent fibroblasts, and increasing of sCLU expression in senescent fibroblasts is mediated through IGF-1 signaling pathway and regulated by ATM. Both IGF-1 and sCLU are known tumor promoting factors, and are closely associated with progression of various cancers. Increased IGF-1 signaling is reported to be a poor prognostic factor of breast cancer and overexpression of sCLU protects cells from various stressors induced apoptosis. Thus, we hypothesize that accumulation of senescent fibroblasts would lead to alterations in the microenvironment that could promote cancer growth and progression through secretion of IGF-1 and sCLU. To test this hypothesis, we established an in vivo co-culture mouse model by co-injection of cancer cells with young or senescent normal fibroblasts into mice prostate.
- Medicine and Medical Research