Role of Fluid Induced Shear Stresses in Inducing Bone Metastasis in Prostate Cancer

The World Cancer Research Fund International reports that prostate cancer is the second most commonly occurring cancer in men. In addition, 1,414,259 new cases of prostate cancer were reported in 2020. The World Health Organization, reports 375,304 deaths in 2020 due to prostate cancer. The majority of deaths due to prostate cancer result from the cancer relocating to a distant location in the body through the process of metastasis. The bone is a common niche of relocation of prostate cancer metastasis. Prostate cancer that has metastasized to bone is incurable. We have developed a novel nanoclay-based tissue-engineered polymeric scaffold in order to mimic the bone metastasis site through sequentially seeding with hMSCs and cancer cells. The role of blood flow in cellular processes is well known through the effect of shear forces exerted by the fluid. It is also known that the fluid flow provides unique biochemical cues for metastasis. We have designed and fabricated a bioreactor that enables physiologically relevant interstitial fluid-flow for prostate cancer bone metastasis. We have also conducted computational fluid dynamics studies to establish that a fluid flow of 0.05 ml/min recapitulates the physiological condition. We did extensive gene expression and protein evaluation studies on the cellular materials grown with and without the effect of fluid flow. We observe that the interstitial fluid-flow does not alter the CXCR4 level, an important regulator of metastasis and invasiveness of cancer. On the other hand, a large impact of bone proximity on the CXCR4 levels. The bone proximity upregulates CXCR4 levels enabling increased MMP-9 levels. We also investigated the levels of integrins which are important cellular adhesion proteins and found that avb3 integrins and MMP-9 levels are upregulated by fluid-flow causing increased migration under fluid-flow. Hence our studies indicate that avb3 integrins act as potential mechanosensory agents transducing mechanical signals via avb3-MMP 9 signaling to promote flow induced motility of prostate cancer cells. Overall, these experiments describe the significant role of interstitial fluid-flow in prostate cancer metastasis.