INDUCTION OF EXPERIMENTAL BONE METASTASIS IN MICE BY TRANSFECTION OF INTEGRIN ALPHA-4-BETA-1 INTO TUMOR-CELLS

Cell adhesion receptors (eg, integrins and CD44) play an important rol e in invasion and metastasis during tumor progression. The increase in integrin alpha 4 beta 1 expression on primary melanomas has been repo rted to significantly correlate with the development of metastases. al pha 4 beta 1 is a cell surface heterodimer that mediates cell-cell and cell-extracellular matrix interactions through adhesion to vascular c ell adhesion molecule (VCAM)-1 and to the IIICS region of fibronectin. To test the effects of alpha 4 beta 1 expression on tumor cell metast asis, Chinese hamster ovary cells were transfected with human alpha 4 cDNA. Whereas alpha 4-negative Chinese hamster ovary cells developed o nly pulmonary metastasis, alpha 4-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 antibo dy against alpha 4 or VCAM-1. Expression of alpha 3 beta 1, alpha 6 be ta 1, or alpha V beta 1 did not induce bone metastasis. Expression of alpha 4 beta 1 also induced bone metastasis in K562 human erythroleuke mia cells injected into SCID mice. These results demonstrate that alph a 4 beta 1 can induce tumor cell trafficking to bone, probably via int eraction with VCAM-1 that is constitutively expressed on bone marrow s tromal cells.