[Proc Amer Assoc Cancer Res, Volume 47, 2006]
Tumor Biology 17: Molecular and Cellular Determinants of Metastasis
Impact of integrin vß3 expression and activation on osteosarcoma metastasis
Wolf A. Hassenpflug,
Mario P. Tschan,
Bruce E. Torbett,
Kim D. Janda and
The Scripps Research Institute, La Jolla, CA and Medical Oncology/Hematology, Department of Clinical Research, University of Bern, Bern, Switzerland
Osteosarcoma is a highly metastatic bone cancer in children that primarily spreads to lungs and bone. Eighty percent of the patients bear lung metastases, and less than half of them can be cured despite aggressive treatment regimens. To develop an improved therapy for prevention and inhibition of osteosarcoma metastasis, we need to identify key mechanisms that support osteosarcoma cell colonization of the lung tissue. Our hypothesis is that tumor cell adhesion receptor, integrin avb3, contributes to the metastatic activity of osteosarcoma cells and that the functional activation state of the integrin, due to its unique ligand binding properties, is critical for tumor cell survival and proliferation in the lung microenvironment. We found that expression of integrin avb3 on 8 different human osteosarcoma cell lines (TE85, KHOS, KRIB, LKRIB, SAOS2, U2OS, MG63, SJSA1) correlates with their migratory activity towards integrin ligands in vitro. To analyze a role of avb3 in vivo, we developed an orthotopic osteosarcoma model based on SJSA1 cells, which are not experimentally transformed and should more accurately reflect the human disease than osteosarcoma in vivo models established so far. We injected SJSA1 cells, with or without firefly luciferase gene tags, into the left tibia of 5 to 7 weeks old male C.B-17 SCID mice and derived tumor cells from primary tumors and spontaneous lung metastases. Reinjected into the venous circulation of immune deficient mice, the cells from primary tumors and particularly those from lung lesions were far more efficient in establishing lung metastases than the parental cells. This aggressive metastatic behavior seems to be promoted by the activated functional form of integrin avb3 because the highly metastatic cell variants from lung and primary tumors express a much higher percentage of avb3 receptor molecules in a constitutively activated state than the parental cells, even though the three cell lines express avb3 at similar levels. This was measured with ligand-mimetic human antibodies from combinatorial libraries of cancer patient immunoglobulins that specifically bind the activated, high affinity form of avb3. A functional role of activated avb3 in lung metastasis formation was indicated by non-invasive bioluminescence imaging that showed that tumor cells expressing predominantly activated avb3 have an early survival advantage in the lung microenvironment. Using our novel animal model, we currently assess whether treatment with our function blocking ligand-mimetic human antibodies against activated avb3 can inhibit osteosarcoma metastasis. Together, these studies will reveal if integrin avb3 in its activated, high affinity form is a potential therapeutic target for treatment of metastatic osteosarcoma as suggested by our initial findings.
Copyright © 2006 by the American Association for Cancer Research.