Effect of Physical Forces on the Metastatic Bone Microenvironment
Abstract
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 CCL5/RANTES 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2014
- Accession Number
- ADA614541
Entities
People
- Joseph L. Sottnik
Organizations
- University of Michigan