title: Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1.
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)-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.
authors.affiliation: Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston Massachusetts 02114, USA.
authors.forename: T
authors.initials: T
authors.lastname: Gohongi
authors.forename: D
authors.initials: D
authors.lastname: Fukumura
authors.forename: Y
authors.initials: Y
authors.lastname: Boucher
authors.forename: C O
authors.initials: CO
authors.lastname: Yun
authors.forename: G A
authors.initials: GA
authors.lastname: Soff
authors.forename: C
authors.initials: C
authors.lastname: Compton
authors.forename: T
authors.initials: T
authors.lastname: Todoroki
authors.forename: R K
authors.initials: RK
authors.lastname: Jain
mesh_terms: D043168:Angiostatins; D000818:Animals; D001932:Brain Neoplasms / Q000098:blood supply*; D002277:Carcinoma / Q000378:metabolism* / Q000601:surgery; D005706:Gallbladder Neoplasms / Q000378:metabolism* / Q000601:surgery; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic / Q000378:metabolism*; D010446:Peptide Fragments / Q000302:isolation & purification; D010958:Plasminogen / Q000302:isolation & purification; D012886:Skull / Q000601:surgery; D019700:Thrombospondin 1 / Q000302:isolation & purification; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D010446:Peptide Fragments; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D043168:Angiostatins; D010958:Plasminogen