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Cancer-Associated Bone Disease; Role of Obesity and Adipokines

Final Report Summary - CABROA (Cancer-Associated Bone Disease; Role of Obesity and Adipokines)

The overall goal of CABROA was to identify the role of adiposity and adipokines in the pathogenesis of the skeletal metastases associated with myeloma. We have made significant progress in determining the effect of obesity on cancer-induced bone disease, by combining in vivo models of cancer-induced bone disease with diet-induced obesity. Work published in Leukemia has identified that diet-induced obesity creates a permissive environment for the development of a myeloma-like condition, associated with tumour burden within bone and bone loss. This is not associated with changes in adiponectin, or Dkk1, however is linked to changes in IGF-1. In contrast, a genetic obesity model was not permissive for myeloma development. Our results have also begun to dissect the mechanisms responsible. We have also utilised genetic models of adiposity to begin to elucidate the effect of bone marrow adiposity in cancer-induced bone disease. Finally, we have undertaken array analysis to study the expression profile of adipokines and adiposity-related factors in patients with prostate cancer and/or myeloma and in panels of cell lines. This array analysis has identified a number of novel adipokines that are dysregulated in cancer-induced bone disease, and these are currently under further investigation both in vitro and in vivo. We have identified a novel factor that is up-regulated in prostate cancer bone metastasis, and are currently working to elucidate the precise function and mechanism of action of this factor to promote bone disease. Our work has also lead us to investigate the effect of the anti-diabetic agent metformin in cancer-induced bone disease. Metformin has a number of effects, including regulation of adipokines and adipocytes, and our studies demonstrate a protective effect of metformin on cancer-induced bone disease. This work is currently in preparation for submission.
In addition to publication in peer-reviewed journals, work directly funded from this research has been presented at a number of national and international meetings, including the World Cancer Research Fund conference, the Bone Research Society Annual Meetings, which is the largest national society in Europe devoted to bone research and the International Conferences on Cancer-Induced Bone Disease, which is the only society dedicated to skeletal metastases. Work directly relating to this funding is under preparation for submission of two manuscripts. Regarding re-integration of the fellow, Dr. Edwards has successfully established an independent research group at the University of Oxford, and has successfully obtained further funding for her research. Taken together this demonstrates the success of and interest in this research.