We determined whether host matrix metalloproteinase (MMP) 9 is essential to angiogenesis and to the growth of L3.6pl human pancreatic cancer cells implanted into the pancreas of wild-type (MMP−9+/+) and knockout (MMP−9−/−) nude mice. Four weeks after tumor cell injection, pancreatic tumors in MMP−9+/+ mice were large, had many blood vessels, and contained many macrophages expressing MMP−9. In contrast, pancreatic tumors in MMP−9−/− mice were significantly smaller, had few blood vessels, and had few macrophages. Next, we parabiosed MMP−9+/+ mice with MMP−9+/+ mice, MMP−9−/− mice with MMP−9−/− mice, and MMP−9+/+ mice with MMP−9−/− mice. Two weeks after parabiosis, we implanted L3.6pl cells into the pancreas of the recipient mouse in each pair. Four weeks later, the mice were necropsied. The parabiosis experiment revealed a direct correlation between intratumoral MMP−9+/+ expressing macrophages, angiogenesis, and progressive tumor growth. Because the expression of MMP−9 by L3.6pl tumor cells was similar in all parabionts, the data clearly demonstrate a major role for host-derived MMP−9 in angiogenesis and in the growth of human pancreatic cancer in the pancreas of nude mice.
1This research was supported, in part, by Cancer Center Support Core grant CA16672 and SPORE in Prostate Cancer grant CA90270 from the National Cancer Institute, National Institutes of Health.