Stromal metalloproteinase-9 is essential to angiogenesis and progressive growth of orthotopic human pancreatic cancer in parabiont nude mice.
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.
Nakamura
Toru
T
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77230-1429, USA.
Kuwai
Toshio
T
Kim
Jang-Seong
JS
Fan
Dominic
D
Kim
Sun-Jin
SJ
Fidler
Isaiah J
IJ
D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D006801:Humans; D008264:Macrophages / Q000201:enzymology / Q000502:physiology; D020780:Matrix Metalloproteinase 9 / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000209:etiology*; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D014183:Transplantation, Heterologous
D020780:Matrix Metalloproteinase 9