A Role for TRPV6 Ion Channels in Prostate Cancer Bone Metastases
Open Access
- Author:
- McCarthy, Sarah Anne
- Graduate Program:
- Anatomy
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 06, 2012
- Committee Members:
- Ronald R Gomes Jr, Dissertation Advisor/Co-Advisor
Henry Joseph Donahue, Committee Member
Patricia Mc Laughlin, Committee Member
Andrea Manni, Committee Member
Andrea Marie Mastro, Committee Member - Keywords:
- Prostate cancer
TRPV6
parathyroid hormone
osteoblastic
calcium
bone metastases
invasion
adhesion - Abstract:
- There are currently no effective therapeutic treatments to prevent prostate cancer (PCa) bone metastases. Identifying mechanisms that facilitate favorable PCa cell to bone interactions will aid in the development of therapies to prevent bone metastases. The objective of this study was to identify a role for calcium and Transient Receptor Potential Vanilloid 6 (TRPV6) ion channels in the metastatic potential and early colonization of osteoblastic PCa cells to murine bone. We proposed that transient increases in serum calcium, following parathyroid hormone (PTH) 1-34 administration, confers a metastatic advantage to PCa cells in circulation, signaled partially via TRPV6 ion channels. To identify the effect of transient elevations in calcium on osteoblastic PCa cell metastatic potential, we employed heterotypic cell adhesion, transwell migration, and invasion assays. Observations from cell adhesion assays suggested that osteoblastic PCa cells increased adhesion to human bone marrow endothelial (hbmE) cells pre-treated with extracellular calcium. Studies suggested that increased extracellular calcium enhanced E-Selectin, VCAM-1 and ICAM-1 cell surface abundance on hbmE cells and that these molecules were partially responsible for increased heterotypic cell adhesion. Increased extracellular calcium also enhanced migration of osteoblastic PCa cell lines, in vitro. To identify the requirement for TRPV6 expression in osteoblastic PCa cell metastatic potential, we reduced TRPV6 expression in osteoblastic PCa cell lines. PCa cells with reduced levels of TRPV6 expression demonstrated slower proliferation rates and an impaired ability to adhere to and invade hbmE cells. Lastly, to identify a role for TRPV6 expression in early PCa cell colonization of murine bone, SCID/Beige mice were administered PTH 1-34 or vehicle, intermittently, then inoculated with PCa cells engineered to express reduced levels of TRPV6. Eight weeks post PCa cell inoculation, PCa cells were identified in long bones of 100% of animals administered PTH 1-34, relative to 20% of animals treated with vehicle. In contrast, PCa cells were identified in only 20% of the long bones of animals administered PTH 1-34, and then inoculated with PCa cells with reduced TRPV6 expression. Our observations support our hypothesis and suggest that calcium and TRPV6 may have a role in facilitating favorable PCa cell to bone interactions.