Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: Involvement of transforming growth factor beta 1

Angiogenesis inhibitors produced by a primary tumor can create a systemic a nti-angiogenic environment and maintain metastatic tumor cells in a state o f dormancy(1,2). We show here that the gallbladder microenvironment modulat es the production of transforming growth factor (TGF)-beta 1, a multifuncti onal cytokine that functions as an endogenous anti-angiogenic and antitumor factor in a cranial window preparation. We found that a wide variety of hu man gallbladder tumors express TGF-beta 1 irrespective of histologic type. We implanted a gel impregnated with basic fibroblast growth factor(3) or Mz -ChA-2 tumor in the cranial windows of mice without tumors or mice with sub cutaneous 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 mic e with gallbladder tumors. The concentration of TGF-beta 1 in the plasma of mice with gallbladder tumors was 300% higher than that in the plasma of mi ce without tumors or with subcutaneous tumors. In contrast, there was no di fference in the plasma levels of other anti- and pro-angiogenic factors. Tr eatment with neutralizing antibody against TGF-beta 1 reversed both angioge nesis suppression and inhibition of leukocyte rolling induced by gallbladde r tumors. TGF-beta 1 also inhibited Mz-ChA-2 tumor cell proliferation. Our results indicate that the production of anti-angiogenesis/proliferation fac tors is regulated by tumor-host interactions.