Effect of Physical Forces on the Metastatic Bone Microenvironment
Final annual summary rept. 1 Sep 2012-31 Aug 2014
MICHIGAN UNIV ANN ARBOR
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The overall goal of this project is to determine if prostate cancer PCa bone metastases increase intramedullary pressure ImP. The central hypothesis to be tested is that tumors promote increased pressure thereby creating a more pro-tumorigenic environment. We have tested this hypothesis in vivo observing that tumors with an osteoblastic component do indeed lead to increased ImP. We have then utilized the pathologic pressures determined in vivo to perform in vitro experiments on PCa and bone cell lines. In vitro experiments have shown that increased pressure leads to altered PCa proliferation. Osteocytes, physiologic monitors of pressure in bone that regulate bone homeostasis, were observed to increase proliferation in the presence of pressure. The role of osteocytes in bone metastases has not yet been explored. Conditioned media isolated from osteocytes promotes an aggressive tumor phenotype by inducing PCa proliferation, migration, and invasion. We have identified increased expression of CCL5RANTES and MMPs in OCy due to application of hydrostatic pressure. Inhibition of CCL5 and MMPs mitigates the pro-tumorigenic effects of OCy on PCa. These results provide evidence that tumor induced pressure leads to a pro-tumorigenic environment and is the center of ongoing studies.
- Medicine and Medical Research