This ongoing Program Project Grant was originally initiated in 1985 in order to develop a team approach to clarifying the mechanisms by which common malignancies such as breast cancer and myeloma affect the skeleton and cause disastrous clinical consequences. This area of research has evolved since the original application. Since identification of the major tumor- associated factors in the 1980s, our emphasis has changed so that a major objective now is to understand how these factors interact to cause the characteristic osteolytic and osteoblastic lesions seen in different types of malignancy. Our key accomplishments in the last grant period have been to develop new in vivo models of osteolytic and osteoblastic lesions associated with solid tumors and myeloma bone disease; to show the importance of the bone microenvironment in tumor cell behavior in bone; to demonstrate the anti-tumor effects of bisphosphonates on solid tumors; and to demonstrate in vivo the key roles of TGFbeta and PTH-rP in local osteolysis in breast cancer. We have assembled a team of investigators with skills in bone cell biology, molecular biology, protein chemistry, and bone histomorphometry to use state-of-the-art techniques for examining the mechanisms by which bone cell function is altered in a number of in vivo models of human tumors. In the 12 years our team has had support from this grant, we have presented 150 abstracts and published over 400 manuscripts in the general area supported by this grant, and 138 manuscripts which can be directly ascribed to it since the last competitive renewal in 1994. During the next grant period, we emphasize three features of our experimental approaches. 1) reliance in each project on well-described animal models of bone disease which occur in different common human malignancies; 2) extensive use of the powerful morphologic technique of quantitative bone histomorphometry in these in vivo models; and 3) examination of the role of bone itself in promoting growth of those tumors which have a special predilection for bone sites such as breast cancer and myeloma. Our hope is that as we gain insights into mechanisms by which tumor cells affect bone cell function, we will develop novel approaches for preventing these effects or reversing them once they have become established. These animal models should enable us to gain information on this common complication of many cancers which is not possible to gather in patients with terminal malignancy.
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