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

来源：

Angiogenesis | 2003年 / 6卷 / 1期

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.

引用

页码：15 / 24

页数：9

共 52 条

[31]

Nishie A., Ono M., Shono T., Et al., Macrophage infiltration and heme oxygenase-1 expression correlate with angiogenesis in human gliomas, Clin Cancer Res, 5, pp. 1107-1113, (1999)

[32]

Boring C.C., Squires T.S., Tong T., Montgomery S., Cancer statistics, 1994, CA Cancer J Clin, 44, pp. 7-26, (1994)

[33]

Bramhall S.R., Neoptolemos J.P., Advances in diagnosis and treatment of pancreatic cancer, Gastroenterologist, 3, pp. 301-310, (1995)

[34]

Ghaneh P., Greenhalf W., Humphreys M., Et al., Adenovirus-mediated transfer of p53 and p16(INK4a) results in pancreatic cancer regression in vitro and in vivo, Gene Ther, 8, pp. 199-208, (2001)

[35]

Abraham N.G., Lavrovsky Y., Schwartzman M.L., Et al., Transfection of the human heme oxygenase gene into rabbit coronary microvessel endothelial cells: Protective effect against heme and hemoglobin toxicity, Proc Natl Acad Sci USA, 92, pp. 6798-6802, (1995)

[36]

Quan S., Yang L., Abraham N.G., Kappas A., Regulation of human heme oxygenase in endothelial cells by using sense and antisense retroviral constructs, Proc Natl Acad Sci USA, 98, pp. 12203-12208, (2001)

[37]

Yang L., Quan S., Abraham N.G., Retrovirus-mediated HO gene transfer into endothelial cells protects against oxidant-induced injury, Am J Physiol, 277, (1999)

[38]

Lehr H.A., Leunig M., Menger M.D., Et al., Dorsal skinfold chamber technique for intravital microscopy in nude mice, Am J Pathol, 143, pp. 1055-1062, (1993)

[39]

Lozonschi L., Sunamura M., Kobari M., Et al., Controlling tumor angiogenesis and metastasis of C26 murine colon adenocarcinoma by a new matrix metalloproteinase inhibitor, KB-R7785, in two tumor models, Cancer Res, 59, pp. 1252-1258, (1999)

[40]

Ohtani H., Sasano N., Microvascular changes in the stroma of human colorectal carcinomas: Ultrastructural histochemical study, Jpn J Cancer Res, 80, pp. 360-365, (1989)

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