?3 integrins (?v?3 and ?IIb?3) play critical roles in tumor metastasis by mediating bone resorption, platelet aggregation, and neo-angiogenesis. The long-term goal of this project is to define the mechanisms by which ?3 integrins expressed on non-tumor cells contribute to bone metastasis and tumor growth in the bone micro-environment. In the first funding period of this R01, we found that the global ?3 knockout mouse was protected from tumor-associated bone loss and bone metastasis. Bone marrow transplantation experiments demonstrated that hematopoeitic cells were responsible for metastasis protection, suggesting a role for platelet or osteoclast ?3 integrins. ?3 integrins are also expressed on non-hematopoeitic cells like endothelial cells, which can influence tumor biology. We have generated mice with germline-targeted ?3 integrin gene flanked by loxP sites and deleted the gene in platelets and osteoclast precursors, using Cre transgenic mice. ?3 integrin function is modulated by P2Y12, an ADP receptor, and the target of the anti- platelet drug, clopidogrel (Plavix). ?3 integrin ligand binding can also be enhanced by association with CD47, also known as integrin-associated protein. We have data showing that P2Y12 regulates integrin activation and receptor conformation and that P2Y12-/- mice have osteoclast and platelet function defects as seen in the ?3-/- mice. We have found that CD47-/- have defects in osteoclast function. Based on data that the global ?3 knockout mouse has decreased bone metastases, but increased tumor associated angiogenesis, and that ?3 integrin modulating proteins P2Y12 and CD47 play critical roles in osteoclast and platelet function, we hypothesize that 1) ?3 integrin expression on different tissues and ?3 integrin regulation by 2) P2Y12 and 3) Integrin associated protein/CD47 will regulate tumor metastasis to bone. Thus, our Specific Aims are: 1. Define role of ?3 on platelets, osteoclasts/myeloid cells and endothelium during metastasis to bone and tumor growth in the bone micro-environment. 2. Define the role of P2Y12, an upstream activator of ?3 integrin, on platelets and osteoclasts during skeletal metastasis and tumor osteolysis. 3. Evaluate the role of integrin associated protein (CD47) during skeletal metastasis and tumor osteolysis. Mice harboring tissue-specific deletions of integrin ?3, and global deletion of CD47 and P2Y12, will be useful tools in assessing the individual roles of ?3 integrins in tumor cell homing to and growth in bone and may uncover novel molecular targets to more effectively treat skeletal metastasis and pathologic bone loss.
?3 integrins (?v?3 and ?IIb?3) play critical roles in tumor invasion and metastasis by mediating bone resorption, platelet aggregation, and neo-angiogenesis. The long-term goal of this project is to define the mechanisms by which ?3 integrins expressed on non-tumor cells contribute to metastasis and tumor growth in the bone environment. Mice harboring tissue-specific deletions of integrin ?3, and integrin modulating molecules, CD47 and P2Y12, will be used to assess the individual roles of ?3 integrins in tumor cell homing to and growth in bone and may uncover novel molecular targets to more effectively treat skeletal metastasis.
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