Date of Award
Doctor of Philosophy (PhD)
F. William Orr
Bone is a common site of metastatic involvement. The mechanisms by which bone metastasis occurs are partially elucidated. Interactions between tumor cells and the bone microenvironment are being scrutinized, since their unravelling could lead to novel therapeutic approaches targeting bone metabolism additionally to tumor cells. This thesis summarizes experimental efforts addressing the role of metastatic cells in directly causing local osteolysis. Traditionally it has been thought that tumor cells, once in the bone, can only cause bone degradation by paracrine activation of osteoclasts. This work demonstrates that cancer cells are capable of degrading bone matrix and that their matrix metalloproteinases are partially responsible for this effect. The evidence reviewed here provides in vivo observations suggesting that this may occur during late "osteoclast-independent" phases of experimental bone metastasis by murine B16/F1 melanoma cells. In vitro documentation of bone and bone-related matrix degradation was obtained using these metastatic murine cells. A similar approach with human cell lines obtained from bone metastases demonstrated that these cell lines produce osteolysis in vitro. Since type I collagen is predominant in bone matrix, the potential involvement of tumor-derived matrix metalloproteinases was addressed. These studies showed that, in addition to murine B16/F1 melanoma cells, human prostate PC-3 adenocarcinoma, SK-N-SH neuroblastoma and Hs696 adenocarcinoma cells all produce these enzymes. Neutralizing their activity abrogated matrix degradation by melanoma cells. Induction of enzyme activity correlated with increase in the degradative ability of these cells. Additionally, B16/F1 and PC-3 cells degraded type I collagen, further implicating collagenases as mediators of these effects. These findings are of potential clinical use since they put forward the possibility of using inhibitors of matrix metalloproteinases, already in clinical trials for other neoplastic conditions, in addition to the currently used antineoplastic and antiosteoclastic approaches, for the prevention and treatment of bone metastases.
Sanchez-Sweatman, Otto H., "Mechanisms of local osteolysis in bone metastasis: Direct role of cancer cells and their matrix metalloproteinases" (1997). Open Access Dissertations and Theses. Paper 3367.