Journal of the National Cancer Institute Advance Access originally published online on April 7, 2009
JNCI Journal of the National Cancer Institute 2009 101(8):592-604; doi:10.1093/jnci/djp058
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Diffuse-Type Gastric Carcinoma: Progression, Angiogenesis, and Transforming Growth Factor β Signaling
Affiliations of authors: Department of Molecular Pathology and the Global Center of Excellence Program for "Integrative Life Science Based on the Study of Biosignaling Mechanisms," Graduate School of Medicine (AK, CI, YMo, EJ, YMa, KK, Y-tS, HIS, MRK, KM), Center for NanoBio Integration (MRK, KM), and Genome Science Division, Research Center for Advanced Science and Technology (AW, HA), University of Tokyo, Tokyo, Japan; Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan (MY, KH); Subteam for Manipulation of Cell Fate, Bio Resource Center, RIKEN, Tsukuba, Japan (HM)
Correspondence to: Kohei Miyazono, MD, Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan (e-mail: miyazono-ind{at}umin.ac.jp).
Background: Diffuse-type gastric carcinoma is a cancer with poor prognosis that has high levels of transforming growth factor β (TGF-β) expression and thick stromal fibrosis. However, the association of TGF-β signaling with diffuse-type gastric carcinoma has not been investigated in detail.
Methods: We used a lentiviral infection system to express a dominant-negative TGF-β type II receptor (dnTβRII) or green fluorescent protein (GFP) as a control in the diffuse-type gastric carcinoma cell lines, OCUM-2MLN and OCUM-12. These infected cells and the corresponding parental control cells were subcutaneously or orthotopically injected into nude mice. Angiogenesis was inhibited by infecting cells with a lentivirus carrying the gene for angiogenic inhibitor thrombospondin-1 or by injecting mice intraperitoneally with the small-molecule angiogenic inhibitor sorafenib or with anti-vascular endothelial growth factor (VEGF) neutralizing antibody (six or eight mice per group). Expression of phospho-Smad2 and thrombospondin-1 was investigated immunologically in human gastric carcinoma tissues from 102 patients. All statistical tests were two-sided.
Results: Expression of dnTβRII into OCUM-2MLN cells did not affect their proliferation in vitro, but it accelerated the growth of subcutaneously or orthotopically transplanted tumors in vivo (eg, for mean volume of subcutaneous tumors on day 10 relative to that on day 0: dnTβRII tumors = 3.49 and GFP tumors = 2.46, difference = 1.02, 95% confidence interval [CI] = 0.21 to 1.84; P = .003). The tumors expressing dnTβRII had higher levels of angiogenesis than those expressing GFP because of decreased thrombospondin-1 production. Similar results were obtained with OCUM-12 cells. Expression of thrombospondin-1 in the dnTβRII tumor or treatment with sorafenib or anti-VEGF antibody reduced tumor growth, whereas knockdown of thrombospondin-1 expression resulted in more accelerated growth of OCUM-2MLN tumors than of GFP tumors (eg, mean tumor volumes on day 14 relative to those on day 0: thrombospondin-1–knockdown tumors = 4.91 and GFP tumors = 3.79, difference = 1.12, 95% CI = 0.80 to 1.44; P < .001). Positive association between phosphorylated Smad2 and thrombospondin-1 immunostaining was observed in human gastric carcinoma tissues.
Conclusions: Disruption of TGF-β signaling in diffuse-type gastric carcinoma models appeared to accelerate tumor growth, apparently through increased tumor angiogenesis that was induced by decreased expression of thrombospondin-1.
| CONTEXT AND CAVEATS Prior knowledge Diffuse-type gastric carcinoma has poor prognosis. Patients have high levels of transforming growth factor β (TGF-β) expression and thick stromal fibrosis. Study design The roles of TGF-β and thrombospondin-1, an angiogenic inhibitor that is regulated by TGF-β, were investigated in vitro studies in diffuse-type gastric carcinoma cell lines and in vivo studies in mouse models of diffuse-type gastric carcinoma and human diffuse-type gastric carcinoma tissue specimens from 102 patients. Contribution Growth of diffuse-type gastric carcinomas appeared to be accelerated by disruption of TGF-β signaling in mouse models (which may be analogous to what occurs during progression of this disease in humans), apparently because of increased tumor angiogenesis that was induced by decreased expression of thrombospondin-1. Implications Because loss of a receptor for TGF-β has been reported to induce tumor angiogenesis in various cancers, administration of angiogenesis inhibitors, such as sorafenib or thrombospondin-1 analogues, should be investigated as a treatment for cancers with disrupted TGF-β signaling pathways. Limitations Although mouse models of subcutaneous and orthotopic transplantation models were used, the experiments were conducted with immunocompromised mice. The growth of metastatic tumors was not investigated. From the Editors
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Manuscript received August 6, 2008; revised January 28, 2009; accepted February 20, 2009.
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J Natl Cancer Inst 2009 101: 539.
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