Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer

被引:219
作者
Makoto Sunamura
Dan G. Duda
Maivel H. Ghattas
Lucian Lozonschi
Fuyuhiko Motoi
Jun-Ichiro Yamauchi
Seiki Matsuno
Shigeki Shibahara
Nader G. Abraham
机构
[1] Div. of Gastroentrological Surgery, Tohoku University School of Medicine, Sendai
[2] Department of Pharmacology, New York Medical College, Valhalla
[3] Dept. of Molec. Biol./Appl. Physiol., Tohoku University School of Medicine, Sendai
关键词
Cell proliferation and growth; Human heme oxygenase; Metastasis; Retrovirus; Vascular endothelial growth factor;
D O I
10.1023/A:1025803600840
中图分类号
学科分类号
摘要
Angiogenesis is necessary for the continued growth of solid tumors, invasion and metastasis. Several studies clearly showed that heme oxygenase-1 (HO-1) plays an important role in angiogenesis. In this study, we used the vital microscope system, transparent skinfold model, lung colonization model and transduced pancreatic cancer cell line (Panc-1)/human heme oxygenase-1 (hHO-1) cells, to precisely analyze, for the first time, the effect of hHO-1 gene on tumor growth, angiogenesis and metastasis. Our results revealed that HO-1 stimulates angiogenesis of pancreatic carcinoma in severe combined immune deficient mice. Overexpression of human hHO-1 after its retroviral transfer into Panc-1 cells did not interfere with tumor growth in vitro. While in vivo the development of tumors was accelerated upon transfection with hHO-1. On the other hand, inhibition of heme oxygenase (HO) activity by stannous mesoporphyrin was able transiently to delay tumor growth in a dose dependent manner. Tumor angiogenesis was markedly increased in Panc-1/hHO-1 compared to mock transfected and wild type. Lectin staining and Ki-67 proliferation index confirmed these results. In addition hHO-1 stimulated in vitro tumor angiogenesis and increased endothelial cell survival. In a lung colonization model, overexpression of hHO-1 increased the occurrence of metastasis, while inhibition of HO activity by stannous mesoporphyrin completely inhibited the occurrence of metastasis. In conclusion, overexpression of HO-1 genes potentiates pancreatic cancer aggressiveness, by increasing tumor growth, angiogenesis and metastasis and that the inhibition of the HO system may be of useful benefit for the future treatment of the disease.
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页码:15 / 24
页数:9
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