Beta 3 integrin null-mice are protected from osteolytic bone metastases

Skeletal metastases are the cause of significant morbidity and mortality. Cross-talk between tumor cells and host cells strongly influences the development of migration and metastasis to bone. Many of these interactions are mediated by transmembrane heterodimeric receptors called integrins. In particular, the integrin subunit β3 has been implicated in the pathophysiology of metastasis to bone. To examine the role of the β3 integrin on host cells in skeletal metastases, mice with a germline-targeted disruption of the subunit gene (β3−/−) and B16 murine melanoma cell line (F10) were utilized in an animal model of metastasis. The β3 −/− mice have dysfunctional osteoclast resorption mediated by α_vβ₃ and diminished platelet aggregation mediated by α_IIbβ₃. After left ventricle (LV) injection of 1 × 105 B16 cells into β3 +/+ mice (n = 35), extensive osteolytic bone lesions were observed in 74% (26/35) of mice after 14 days. After injecting β3−/− littermates (n = 24) 23/24 mice had no evidence of osteolytic lesions or histologic evidence of tumor invasion of bone. Bone marrow transplantation of β3+/+ bone marrow into β3−/− mice resulted in B16 bone invasion whereas transplantation of β3 −/− marrow into β3+/+ mice conferred protection from bone metastases, suggesting that the protection is provided by bone marrow cells. Direct inoculation of B16 cells into the tibia produced growth of B16 cells throughout the marrow cavity of β3−/− and β3+/+ mice, suggesting that the bone environment of β3−/− can support B16 tumor growth. However in β3−/− mice, little associated trabecular bone destruction was found compared to β3+/+ mice. Mutant src−/− mice with defective osteoclasts but normal platelet function developed widespread bone marrow metastases after LV injection of B16 cells, but no associated osteolysis. Co-injection of B16 cells and treatment with a platelet specific α_IIbβ₃ inhibitor resulted in diminished bone metastases in β3+/+ mice. These data support a role for platelet-associated α_IIbβ ₃ in facilitating tumor entry to bone and α_vβ ₃ for tumor associated bone invasion and together suggest that host cell β3 integrin expression facilitates the processes of tumor cell metastasis to bone and osteolysis.