Abstract
Prostate cancer bone metastasis is the leading cause of cancer-related mortality in men in the United States, causing severe damage to skeletal tissue. The treatment of advanced-stage prostate cancer is always challenging due to limited drug treatment options, resulting in low survival rates. There is a scarcity of knowledge regarding the mechanisms associated with the effects of biomechanical cues by the interstitial fluid flow on prostate cancer cell growth and migration. We have designed a novel bioreactor system to demonstrate the impact of interstitial fluid flow on the migration of prostate cancer cells to the bone during extravasation. First, we demonstrated that a high flow rate induces apoptosis in PC3 cells via TGF-β1 mediated signaling; thus, physiological flow rate conditions are optimum for cell growth. Next, to understand the role of interstitial fluid flow in prostate cancer migration, we evaluated the migration rate of cells under static and dynamic conditions in the presence or absence of bone. We report that CXCR4 levels were not significantly changed under static and dynamic conditions, indicating that CXCR4 activation in PC3 cells is not influenced by flow conditions but by the bone, where CXCR4 levels were upregulated. The bone-upregulated CXCR4 levels led to increased MMP-9 levels resulting in a high migration rate in the presence of bone. In addition, upregulated levels ofαvβ3integrins under fluid flow conditions contributed to an overall increase in the migration rate of PC3 cells. Overall, this study demonstrates the potential role of interstitial fluid flow in prostate cancer invasion. Understanding the critical role of interstitial fluid flow in promoting prostate cancer cell progression will enhance current therapies for advanced-stage prostate cancer and provide improved treatment options for patients.