VASCULAR ENDOTHELIAL GROWTH-FACTOR PROMOTES TUMOR DISSEMINATION BY A MECHANISM DISTINCT FROM ITS EFFECT ON PRIMARY TUMOR-GROWTH

Tumor growth is dependent on new blood vessel formation. Inhibition of vascular endothelial growth factor (VEGF), an endothelial cell mitoge n and angiogenic factor secreted by a variety of tumors and tumor cell lines, is sufficient to inhibit primary tumor growth. In the present study, we examined the effect of inhibiting VEGF on tumor cell microme tastasis. A transfectant of A431 (a human epidermoid carcinoma cell li ne) expressing chloramphenicol acetyltransferase (CAT) was injected s. c. into severe combined immunodeficiency (scid) mice, which were then sacrificed after 6 weeks. The presence of A431 metastases at distant s ites was demonstrated by detection of CAT activity in whole-organ lysa tes. Treatment of animals with VEGF-neutralizing antibodies not only i nhibited primary tumor growth but also suppressed metastases, as deter mined by CAT activity in organ lysates. In experiments to determine th e mechanism by which anti-VEGF antibody inhibited metastasis, control animals were sacrificed when their tumors had reached the same size as tumors in VEGF antibody-treated animals. Metastases were uniformly pr esent in these control animals. These findings show that inhibition of VEGF alone is sufficient to prevent tumor growth and dissemination in vivo. The inhibitory effect on metastases appears to be distinct from that on primary tumor growth.