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Spread of cancers to bone
Summary
We aim to identify why some cancers, particularly those of the breast, have a predilection to bone, and determine mechanisms to limit tumour growth in bone.
Description
Breast and other tumours, including kidney and lung cancers may metastasise to bone where they establish and grow, typically resulting in local bone breakdown - termed an osteolytic metastasis.
Prostate cancers also spread to bone, but result not in destruction but in massive bone formation - an osteoblastic metastasis.
Both types of metastasis are associated with considerable pain and, in the case of osteolytic metastases, fractures result from the weakened bone structure.
We have examined how breast cancers result in osteolytic metastases and determined that this is in part due to parathyroid hormone-related protein (PTHrP) production by the tumour, which stimulates the local normal bone cells to form osteoclast cells.
As a result of new osteoclast formation, bone is removed, releasing some hormones that are normally stored within the bone. This includes the hormone TGF-β, which powerfully stimulates the tumor cells to produce more PTHrP, and this sets up a vicious cycle of more bone destruction leading to more PTHrP, and so on.
The interaction of these cell types with the bone matrix facilitates the establishment of a vicious cycle for bone destruction.
We have identified a number of agents that block the progression of this cycle, and these are being evaluated in model systems.
Our aims are to:
understand the biology of PTHrP and its actions upon breast cancer cells;
understand the intra-nuclear actions of PTHrP;
identify breast cancer products that can contribute to the bone invasive ability of tumours;
determine whether the bone microenvironment causes a change in breast cancer cells;
determine the action of breast cancer-derived factors upon osteoblasts and osteoclasts.
Funding
National Health and Medical Research Council
Selected Publications
Fisher, J.L., Thomas-Mudge, R.J., Elliott, J., Hards, D.K., Sims, N.A., Slavin, J., Martin, T.J. and Gillespie, M.T. (2006). Osteoprotegerin over-expression by breast cancer cells enhances orthotopic and osseous tumor growth, and contrasts with that delivered therapeutically. Cancer Research. 66, 3620-3628. Reported in The BreastCancer.Net News.
Price, J.T., Quinn, J.M.W., Sims, N.A., Moore, J., Waldeck, K., Docherty, S.E., Myers, D., Nakamura, A., Waltham, M.C., Gillespie, M.T. and Thompson, E.W. (2005). The HSP90 inhibitor, 17-AAG, enhances osteoclast formation and potentiates bone metastasis of a human breast cancer cell line. Cancer Research. 65, 4929-4938.
Jans, D.A., Thomas, R.J. and Gillespie, M.T. (2003). Parathyroid hormone-related protein (PTHrP): a nucleocytoplasmic shuttling protein with distinct paracrine and intracrine roles. In "Vitamins and Hormones", Edited by Gerald Litwack. Elsevier Science, pp. 345-384
Conlan, L.A., Martin, T.J. and Gillespie, M.T. (2002). The C-terminus of parathyroid hormone-related protein (PTHrP) interacts with b-arrestin 1B. FEBS Letters. 527, 71-75.
Guise, T.A., Yin, J.J., Thomas, R.J., Dallas, M., Cui, Y. and Gillespie, M.T. (2002). Parathyroid hormone-related protein (PTHrP)-(1-139) isoform is efficiently secreted in vitro and enhances breast cancer metastasis to bone in vivo. Bone. 30, 670-676.
Thomas, R.J., Guise, T.A., Yin, J.J., Elliott, J., Horwood, N.J., Martin, T.J., and Gillespie, M.T. (1999). Breast cancer cells interact with osteoblasts to support osteoclast formation. Endocrinology. 140, 4451-4458