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Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming

T Gohongi1, D Fukumura, Y Boucher

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

Nature Medicine
|September 30, 1999
PubMed

Insights

Gallbladder tumors create a systemic anti-angiogenic environment by increasing transforming growth factor-beta1 (TGF-β1). This suppresses tumor growth and angiogenesis at secondary sites, highlighting tumor-host interactions in cancer progression.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Primary tumors can induce systemic anti-angiogenic effects, potentially maintaining dormant metastases.
  • Transforming growth factor-beta1 (TGF-β1) is a known endogenous anti-angiogenic and anti-tumor factor.
  • The role of the gallbladder microenvironment in modulating TGF-β1 production and its systemic effects is not fully understood.

Purpose of the Study:

  • To investigate the role of the gallbladder microenvironment in regulating TGF-β1 production.
  • To determine the impact of gallbladder tumors on angiogenesis and tumor growth at a secondary site.
  • To elucidate the mechanism by which gallbladder tumors exert systemic anti-angiogenic effects.

Main Methods:

  • Implantation of basic fibroblast growth factor or Mz-ChA-2 tumor in cranial windows of mice.
  • Comparison of angiogenesis, leukocyte-endothelial interaction, and tumor growth in mice with and without tumors (subcutaneous or gallbladder).
  • Measurement of plasma TGF-β1 levels and other angiogenic factors.
  • Administration of neutralizing antibody against TGF-β1 to assess its role in reversing observed effects.

Main Results:

  • Gallbladder tumors significantly inhibited angiogenesis, leukocyte-endothelial interaction, and tumor growth in the cranial window.
  • Plasma TGF-β1 levels were significantly elevated (300%) in mice with gallbladder tumors compared to controls.
  • Neutralizing TGF-β1 antibody reversed the suppression of angiogenesis and leukocyte rolling.
  • TGF-β1 directly inhibited Mz-ChA-2 tumor cell proliferation in vitro.

Conclusions:

  • The gallbladder microenvironment actively modulates TGF-β1 production, creating a systemic anti-angiogenic state.
  • Gallbladder tumors utilize TGF-β1 as a key mediator to suppress angiogenesis and tumor growth at distant sites.
  • These findings underscore the importance of tumor-host interactions in regulating anti-angiogenic factor production and cancer progression.

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