Stromal Metalloproteinase-9 Is Essential to Angiogenesis and Progressive Growth of Orthotopic Human Pancreatic Cancer in Parabiont Nude Mice

Abstract

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.

Keywords

• MMP−9
• parabiosis
• pancreatic cancer
• angiogenesis
• orthotopic model