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Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer

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Abstract

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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Authors and Affiliations

  1. Division of Gastroentrological Surgery, Tohoku University School of Medicine, Sendai, Japan

    Makoto Sunamura, Dan G. Duda, Lucian Lozonschi, Fuyuhiko Motoi, Jun-Ichiro Yamauchi & Seiki Matsuno

  2. Department of Pharmacology, New York Medical College, Valhalla, New York, USA

    Maivel H. Ghattas

  3. Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai, Japan

    Shigeki Shibahara

  4. Department of Pharmacology, New York Medical College, Valhalla, NY, 10595, USA

    Nader G. Abraham

Authors
  1. Makoto Sunamura
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  2. Dan G. Duda
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  3. Maivel H. Ghattas
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  9. Nader G. Abraham
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Correspondence to Nader G. Abraham.

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Sunamura, M., Duda, D.G., Ghattas, M.H. et al. Heme oxygenase-1 accelerates tumor angiogenesis of human pancreatic cancer. Angiogenesis 6, 15–24 (2003). https://doi.org/10.1023/A:1025803600840

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