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Tumor–host interactions in the gallbladder suppress distal angiogenesis and tumor growth: Involvement of transforming growth factor β1

Nature Medicine volume 5, pages 1203–1208 (1999)Cite this article

Abstract

Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy1,2. We show here that the gallbladder microenvironment modulates the production of transforming growth factor (TGF)-β1, a multifunctional cytokine that functions as an endogenous anti-angiogenic and anti-tumor factor in a cranial window preparation. We found that a wide variety of human gallbladder tumors express TGF-β1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor3 or Mz-ChA-2 tumor in the cranial windows of mice without tumors or mice with subcutaneous or gallbladder tumors to study angiogenesis and tumor growth at a secondary site. Angiogenesis, leukocyte–endothelial interaction in vessels and tumor growth in the cranial window were substantially inhibited in mice with gallbladder tumors. The concentration of TGF-β1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mice without tumors or with subcutaneous tumors. In contrast, there was no difference in the plasma levels of other anti- and pro-angiogenic factors. Treatment with neutralizing antibody against TGF-β1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-β1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation factors is regulated by tumor–host interactions.

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Figure 1: Gallbladder wall tumors inhibit angiogenesis and tumor growth at a secondary site (cranial window).
Figure 2: Gallbladder wall tumor inhibits angiogenesis and tumor growth at a distant cranial site and TGF-β1 mediates this process.
Figure 3: Immunohistochemical staining of human gallbladder carcinomas and precursor lesions for TGF-β1.

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Acknowledgements

We thank N. Bouck and C. Koike for the TSP-1 assay; H.C. Lichtenbeld and E. di Tomaso for immunostaining; G. Koenig for ELISA; M. Ancukiewcz for statistical analysis; J. Ang, A. Kadambi, R. Öklü, K. Burton, T. Shioda and B. Seed for comments. This work was supported by National Cancer Institute-Outstanding Investigator Grant R35-CA56591 to R.K.J.

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  1. Department of Radiation Oncology, Edwin L. Steele Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, 02114, Massachusetts, USA

    Takeshi Gohongi, Dai Fukumura, Yves Boucher, Chae-Ok Yun & Rakesh K. Jain

  2. Department of Medicine, Division of Hematology/Oncology, Northwestern University Medical School, Chicago, 60611, Illinois, USA

    Gerald A. Soff

  3. Department of Pathology, Massachusetts General Hospital, Harvard Medical School, 02114, Boston, Massachusetts, USA

    Carolyn Compton

  4. Department of Surgery, Institute of Clinical Medicine, University of Tsukuba, 305, Ibaraki, Japan

    Takeshi Todoroki

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  1. Takeshi Gohongi
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Correspondence to Rakesh K. Jain.

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Gohongi, T., Fukumura, D., Boucher, Y. et al. Tumor–host interactions in the gallbladder suppress distal angiogenesis and tumor growth: Involvement of transforming growth factor β1. Nat Med 5, 1203–1208 (1999). https://doi.org/10.1038/13524

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