Research Abstract:
The skeleton is the organ most commonly affected by metastatic cancer in humans. Mechanisms by which skeletal metastases are established are unclear; however, osteoclast activation plays a critical role in the pathogenesis of bone metastases. Our laboratory focuses on the molecular mechanisms through which tumor cells metastasize to bone. The projects in our laboratory include: The role of beta 3 integrin in skeletal metastases. The beta 3 integrin subunit (b3) has been implicated in the development of metastases because of its critical role in osteoclastic bone resorption (avb3), and its role in platelets in tumor cell homing (aIIbb3). We have established an in vivo model of bone metastasis using the osteolytic and osteoblastic tumor cell lines. To examine the role of the b3 integrins in skeletal metastases we utilize mice with a disruption of the beta 3 integrin subunit gene (b3-/-); The role of Tax oncogene in skeletal metastases. HTLV I associated Adult T cell leukemia (ATLL) is distinctive for its high rate of osteolytic skeletal metastases and hypercalcemia. Expression of HTLV-1 Tax oncogene, under the regulation of the granzyme B promoter, results in tumors. We find that these mice also develop lytic bone lesions, a clinical feature of ATLL. Our laboratory studies the molecular mechanisms of Tax oncogene induced bone disease; and, The role of CXCR4 in bone metastasis. SDF-1 and its receptor CXCR-4 have been shown to be one mechanism by which blood cell precursors home to the bone. We hypothesize that the SDF-1/CXCR-4 interaction plays a role in tumor cell homing to bone as well. We are evaluating if the disruption of the CXCR-4/SDF-1 interaction can prevent bone metastasis in a murine model.
Selected Publications:
Hirbe A, Rubin J, Uluckan O, Morgan E, Eagleton MC, Prior J, Piwnica-Worms D, Weilbaecher K. Disruption of CXCR4 enhances osteoclastogenesis and tumor growth in bone. PNAS 2007 in press.
Hirbe AC, Uluçkan Ö , Eagleton MC, Morgan EA, Prior JL, Trinhaus K, Piwnica-Worms D, Weilbaecher K. Granulocyte colony stimulating factor (G-CSF) stimulates osteoclast activity and bone-associated tumor growth in mice. Blood 2007 109:3424-3431.
Gao L, Deng H, Zhao H, Hirbe A, Harding J, Ratner L, Weilbaecher K. HTLV-1 Tax transgenic mice develop Spontaneous Osteolytic bone metastases prevented by osteoclast inhibition. Blood 2005 106:4294-4302.
Bakewell S, Nestor P, Prasad S, Tomasson M, Dowland N, Mehrotra M, Scarborough R, Kanter J, Abe K, Phillips D, Weilbaecher K. Platelet and osteoclast b3 integrins are critical for Bone Metastasis. PNAS 2003 100:14199-14204.
Weilbaecher KN, Motyckova G, Huber WE, Takemoto C, Hemesath T, Xu Y, Hershey CL, Dowland N, Wells A, and Fisher DE. Linkage of M-CSF Signaling to Mitf, TFE3, and the Osteoclast Defect in Mitfmi/mi Mice. Molecular Cell 2001 8:749-758.
Last Updated: 09/05/2007 |