An unexplained paradox of
malignant melanoma is the apparent failure of the blood within the
tumor to clot despite the presence of multiple factors that should promote blood clotting. Here we present histochemical evidence that human and murine
melanomas are extensively infiltrated by abundant mast cells. Because mast cells contain the natural
anticoagulant heparin, the present studies were aimed at defining the role of mast cell
heparin in preventing the blood from clotting within
B16 melanoma grafts in C57BL/6 J mice. Mice bearing
B16 melanoma grafts were treated with non-specific or specific inhibitors of mast cell
heparin (
protamine or
heparinase, respectively). After the
drug treatment there was histologic and functional evidence of selective
thrombosis of the blood vessels within the
protamine and
heparinase treated
melanoma grafts. A similar, high degree of
thrombosis was also observed in B16
tumors grown in transgenic NDST-2 knockout mice bearing a targeted disruption in the gene coding for mast cell
heparin synthesis. The
tumors grown in the
protamine-treated animals were significantly smaller than the
tumors from control (untreated mice). By contrast, the
tumors treated with
heparinase or grown in the NDST-2 knockout mice were significantly larger than the
tumors from control (untreated) mice. We conclude that the intrinsic procoagulant properties of
malignant melanoma are neutralized in vivo by the
anticoagulant properties of endogenous
heparin produced by mast cells that naturally infiltrate the
tumor. Our results also suggest that
thrombosis and hemostasis within
melanoma may play a complex role in modulating the growth of the
tumor.