Tumor-host interactions in the gallbladder suppress distal angiogenesis and tumor growth: involvement of transforming growth factor beta1.
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.
Gohongi
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T
Edwin L. Steele Laboratory, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston Massachusetts 02114, USA.
Fukumura
D
D
Boucher
Y
Y
Yun
C O
CO
Soff
G A
GA
Compton
C
C
Todoroki
T
T
Jain
R K
RK
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*
D010446:Peptide Fragments; D019700:Thrombospondin 1; D016212:Transforming Growth Factor beta; D043168:Angiostatins; D010958:Plasminogen