| Summary: | 博士 === 中山醫學大學 === 生化暨生物科技研究所 === 95 === With little knowledge about the origin and development of androgen-independent prostate cancer, no effective therapy has been available so far. Recently, a cancer stem/progenitor cell hypothesis has been proposed, in which abnormal prostatic basal cells or their progeny cells are regarded as the cause of malignant androgen- independent tumorigenesis. Hedgehog (Hh) gene is thought to be reactivated during self-renewal and differentiation of adult stem cells, leading to tissue regeneration or cancer stem cells activation. Recent studies have implicated hyperactive Hh signaling in advanced and metastatic prostate cancers, but the molecular mechanism of Hh involved in prostate tumorigenesis remains unclear. In this study, we addressed the effects of Hh overexpression by intraprostate injection of an Hh-expressing vector. The manipulation, with confirmed Hh signaling pathway activation, caused lesions originated from prostatic basal cells showing characteristic PIN or invasive CaP phenotypes. Further analyses demonstrated Hh involvement in heterogeneous basal cell lineage differentiation, AR-negative cancer formation, cancer stem cell activation, cell proliferation, and metastasis. Furthermore, we indicated Hedgehog involvement in forming BCH and its progressing towards CaP in human prostate cancer, presumably by transforming the normal basal stem cells into the cancer stem cells where persistent Hedgehog activation might be mandatory for tumorigenesis. To conclude, a mouse prostate cancer model induced by Hh-overexpression was established and may be used for testing novel therapeutical approaches targeting at Hh signaling pathway.
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