Abstract
Cancer mortality is primarily attributed to metastasis and the resulting compromise of organs secondary to the initial tumor site. Metastasis is a multi-step process in which the tumor cells must first acquire a migratory phenotype and invade through the surrounding tissue for spread to distant organs in the body. The ability of malignant cells to migrate and breach surrounding tissue/matrix barriers is among the most daunting challenges to disease management for men in the United States diagnosed with prostate cancer (CaP), especially since, at diagnosis, a high proportion of patients already have occult or clinically-detectable metastasis. The interaction between hepatocyte growth factor (HGF) secreted by the stroma, with its receptor c-Met located in the epithelium, must occur for epithelial CaP cells to become migratory. We studied the effects of grape-derived phytochemical resveratrol on the transition of epithelial tumor cells from sedentary to a mobile, penetrant phenotype. A time lapse microscopy assay was used to monitor the acquisition of the migratory phenotype by resveratrol. The results show that resveratrol inhibits HGF-mediated interaction between the stroma and epithelium and suppresses epithelial CaP cell migration by attenuating the control of epithelial-to-mesenchymal transition (EMT).
Highlights
Metastatic prostate cancer (CaP) is a leading cause of death among men in the United States
LNCaP and PC-3 cells maintained in 10% FBS supplemented RPMI 1640 media were separately treated with 10% and 30% Conditioned Media (CM) obtained from day 2 untreated and 25 μM resveratrol-treated Prostate Stromal Cells (PrSC)
We added CM from control and treated prostate epithelium cell (PrEC) which showed neither stimulatory nor inhibitory effect on growth of LNCaP or PC-3 cells. These studies comparing CM from control and resveratrol-treated PrSC and showing that they exert differential growth modulatory effect on LNCaP and PC-3 cells support the thesis that resveratrol modulates signaling between stromal cells and stage-specific epithelial CaP cells (LNCaP, not PC-3) through paracrine-acting factors secreted into the culture media
Summary
Metastatic prostate cancer (CaP) is a leading cause of death among men in the United States. Metastasis and invasion are tumorigenic features that counter the efficacy of treatment for CaP; metastasis disseminates the tumor to ectopic sites and is a mitigating factor for therapies directed at the primary cancer site. Several steps are involved in the acquisition of metastasis by primary epithelial tumor cells. Interaction of disseminated epithelial tumor cells with endothelial cells in the bone marrow [6] is followed by resumption of proliferation in the distant, new sites as metastatic tumors. These changes as a whole suggest that metastasis is predicated on epithelial tumor cells acquiring motility by EMT that facilitates their exit from the primary site as the initiation of metastasis
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