Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth

Involvement of transforming growth factor β1

Takeshi Gohongi, Dai Fukumura, Yves Boucher, Chae Ok Yun, Gerald A. Soff, Carolyn Compton, Takeshi Todoroki, Rakesh K. Jain

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

Angiogenesis inhibitors produced by a primary tumor can create a systemic anti-angiogenic environment and maintain metastatic tumor cells in a state of dormancy. 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 antitumor 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 factor 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.

Original languageEnglish (US)
Pages (from-to)1203-1208
Number of pages6
JournalNature Medicine
Volume5
Issue number10
DOIs
StatePublished - Oct 1999
Externally publishedYes

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Transforming Growth Factors
Gallbladder
Tumors
Growth
Neoplasms
Angiogenesis Inducing Agents
Plasmas
Leukocyte Rolling
Angiogenesis Inhibitors
Cell proliferation
Fibroblast Growth Factor 2
Neutralizing Antibodies

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth : Involvement of transforming growth factor β1. / Gohongi, Takeshi; Fukumura, Dai; Boucher, Yves; Yun, Chae Ok; Soff, Gerald A.; Compton, Carolyn; Todoroki, Takeshi; Jain, Rakesh K.

In: Nature Medicine, Vol. 5, No. 10, 10.1999, p. 1203-1208.

Research output: Contribution to journalArticle

Gohongi, Takeshi ; Fukumura, Dai ; Boucher, Yves ; Yun, Chae Ok ; Soff, Gerald A. ; Compton, Carolyn ; Todoroki, Takeshi ; Jain, Rakesh K. / Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth : Involvement of transforming growth factor β1. In: Nature Medicine. 1999 ; Vol. 5, No. 10. pp. 1203-1208.
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