Inhibition of thrombosis in melanoma allografts in mice by endogenous mast cell heparin.
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.
Samoszuk
Michael
M
Department of Pathology, University of California-Irvine, UCI Medical Center Building 10, Route 40, 101 The City Drive, Orange, CA 92868-3298, USA. msamoszu@uci.edu
Corwin
Mark
M
Yu
Hon
H
Wang
Jun
J
Nalcioglu
Orhan
O
Su
Min-Ying
MY
D000581:Amidohydrolases / Q000378:metabolism; D000818:Animals; D000925:Anticoagulants / Q000378:metabolism*; D001777:Blood Coagulation; D001783:Blood Flow Velocity; D006493:Heparin / Q000172:deficiency / Q000378:metabolism*; D006494:Heparin Antagonists / Q000494:pharmacology; D019763:Heparin Lyase / Q000494:pharmacology; D006801:Humans; D008407:Mast Cells / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009368:Neoplasm Transplantation; D011479:Protamines / Q000494:pharmacology; D015238:Sulfotransferases / Q000378:metabolism; D013927:Thrombosis / Q000517:prevention & control*; D014184:Transplantation, Homologous; D014407:Tumor Cells, Cultured
D000925:Anticoagulants; D006494:Heparin Antagonists; D011479:Protamines; D006493:Heparin; C113066:NDST2 protein, human; C491855:Ndst2 protein, mouse; D015238:Sulfotransferases; D000581:Amidohydrolases; D019763:Heparin Lyase