Inhibition by vasoactive intestinal polypeptide (VIP) of angiogenesis induced by murine Colon 26-L5 carcinoma cells metastasized in liver

We investigated the effect of VIP on the liver metastases and angiogenesis by Colon 26-L5 carcinoma cells in mice. Daily systemic administration of VI P, beginning 3 days after tumor inoculation into a portal vein of mice, inh ibited significantly the development of their liver metastases. Immunohisto chemical staining for factor VIII-related antigen in the sections of liver metastases showed that the systemic administration of VIP caused significan t prevention of angiogenesis within tumor masses. VIP (10(-10) to 10(-6) M) inhibited the invasion of reconstituted basement membrane (Matrigel) by he patic sinusoidal endothelial (HSE) cells in a concentration-dependent manne r in a Transwell chamber assay in vitro and achieved approximately 50% redu ction of control at 10(-)6 M. VIP (10(-6) M) also significantly suppressed the haptotactic migration of HSE cells to fibronectin, laminin or type I co llagen substrates with a similar inhibition rate to the invasion assay. Exp osure of VIP to HSE cells induced accumulation of intracellular cAMP in a c oncentration-dependent manner. The inhibitory effect of VIP (10(-6) M) on H SE cell migration was significantly abrogated in the presence of 3 x 10(-6) M H-89, a cAMP-dependent protein kinase inhibitor. VIP (10(-6) M) inhibite d the morphogenesis of HSE cells into capillary-like structures on Matrigel -coated wells. VIP did not affect the proliferation of HSE cells and the pr oduction of gelatinases in HSE cells in vitro at the concentrations used in the invasion assay. These observations suggest that the anti-metastatic ef fect of VIP on liver metastases by Colon 26-L5 carcinoma cells in mice is p artly due to the prevention of tumor angiogenesis probably through suppress ion of the motility of endothelial cells.