Nakamura Toru, Kuwai Toshio, Kim Jang-Seong, Fan Dominic, Kim Sun-Jin, Fidler Isaiah J
Department of Cancer Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77230-1429, USA.
Neoplasia. 2007 Nov;9(11):979-86. doi: 10.1593/neo.07742.
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.
我们研究了宿主基质金属蛋白酶（MMP）9对血管生成以及植入野生型（MMP-9(+/+)）和基因敲除型（MMP-9(-/-)）裸鼠胰腺的L3.6pl人胰腺癌细胞生长是否至关重要。注射肿瘤细胞四周后，MMP-9(+/+)小鼠的胰腺肿瘤较大，有许多血管，且含有许多表达MMP-9的巨噬细胞。相比之下，MMP-9(-/-)小鼠的胰腺肿瘤明显较小，血管较少，巨噬细胞也较少。接下来，我们将MMP-9(+/+)小鼠与MMP-9(+/+)小鼠、MMP-9(-/-)小鼠与MMP-9(-/-)小鼠以及MMP-9(+/+)小鼠与MMP-9(-/-)小鼠进行联体共生。联体共生两周后，我们将L3.6pl细胞植入每对受体小鼠的胰腺。四周后，对小鼠进行尸检。联体共生实验揭示了肿瘤内表达MMP-9(+/+)的巨噬细胞、血管生成和肿瘤进展性生长之间的直接关联。由于L3.6pl肿瘤细胞在所有联体共生小鼠中的MMP-9表达相似，这些数据清楚地表明宿主来源的MMP-9在裸鼠胰腺中对血管生成和人胰腺癌生长起着主要作用。
