Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1

Nat Med. 1999 Oct;5(10):1203-8. doi: 10.1038/13524.


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)-beta1, 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-beta1 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-beta1 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-beta1 reversed both angiogenesis suppression and inhibition of leukocyte rolling induced by gallbladder tumors. TGF-beta1 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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Angiostatins
  • Animals
  • Brain Neoplasms / blood supply*
  • Carcinoma / metabolism*
  • Carcinoma / surgery
  • Gallbladder Neoplasms / metabolism*
  • Gallbladder Neoplasms / surgery
  • Mice
  • Mice, SCID
  • Neovascularization, Pathologic / metabolism*
  • Peptide Fragments / isolation & purification
  • Plasminogen / isolation & purification
  • Skull / surgery
  • Thrombospondin 1 / isolation & purification
  • Transforming Growth Factor beta / metabolism*


  • Peptide Fragments
  • Thrombospondin 1
  • Transforming Growth Factor beta
  • Angiostatins
  • Plasminogen