Induction of experimental bone metastasis in mice by transfection of integrin α4β1 into tumor cells

Cell adhesion receptors (eg, integrins and CD44) play an important role in invasion and metastasis during tumor progression. The increase in integrin α4β1 expression on primary melanomas has been reported to significantly correlate with the development of metastases. α4β1 is a cell surface heterodimer that mediates cell-cell and cell-extracellular matrix interactions through adhesion to vascular cell adhesion molecule (VCAM)-1 and to the IIICS region of fibronectin. To test the effects of α4β1 expression on tumor cell metastasis, Chinese hamster ovary cells were transfected with human α4 cDNA. Whereas α4-negative Chinese hamster ovary cells developed only pulmonary metastasis, α4-positive Chinese hamster ovary cells developed bone and pulmonary metastasis in 3 to 4 weeks when injected intravenously into nude mice. Bone metastasis was inhibited by antibody against α4 or VCAM-1. Expression of α3β1, α6β1, or αVβ1 did not induce bone metastasis. Expression of α4β1 also induced bone metastasis in K562 human erythroleukemia cells injected into SCID mice. These results demonstrate that α4β1 can induce tumor cell trafficking to bone, probably via interaction with VCAM-1 that is constitutively expressed on bone marrow stromal cells.