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Science 303 (5659): 848-851

Copyright © 2004 by the American Association for the Advancement of Science

TGF-ß Signaling in Fibroblasts Modulates the Oncogenic Potential of Adjacent Epithelia

Neil A. Bhowmick,1,4 Anna Chytil,1 David Plieth,2 Agnieszka E. Gorska,1,4 Nancy Dumont,2,4 Scott Shappell,3,4 M. Kay Washington,3,4 Eric G. Neilson,2,4 Harold L. Moses1,3,4*

Abstract: Stromal cells can have a significant impact on the carcinogenic process in adjacent epithelia. The role of transforming growth factor–ß (TGF-ß) signaling in such epithelial-mesenchymal interactions was determined by conditional inactivation of the TGF-ß type II receptor gene in mouse fibroblasts (Tgfbr2fspKO). The loss of TGF-ß responsiveness in fibroblasts resulted in intraepithelial neoplasia in prostate and invasive squamous cell carcinoma of the forestomach, both associated with an increased abundance of stromal cells. Activation of paracrine hepatocyte growth factor (HGF) signaling was identified as one possible mechanism for stimulation of epithelial proliferation. Thus, TGF-ß signaling in fibroblasts modulates the growth and oncogenic potential of adjacent epithelia in selected tissues.

1 Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
2 Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
3 Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
4 the Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.

* To whom correspondence should be addressed. E-mail: hal.moses{at}

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J. M. Garcia, V. Garcia, C. Pena, G. Dominguez, J. Silva, R. Diaz, P. Espinosa, M. J. Citores, M. Collado, and F. Bonilla (2008)
RNA 14, 1424-1432
   Abstract »    Full Text »    PDF »
Endocannabinoids in endocrine and related tumours.
M. Bifulco, A. M. Malfitano, S. Pisanti, and C. Laezza (2008)
Endocr. Relat. Cancer 15, 391-408
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An Anti-Transforming Growth Factor {beta} Antibody Suppresses Metastasis via Cooperative Effects on Multiple Cell Compartments.
J.-S. Nam, M. Terabe, M. Mamura, M.-J. Kang, H. Chae, C. Stuelten, E. Kohn, B. Tang, H. Sabzevari, M. R. Anver, et al. (2008)
Cancer Res. 68, 3835-3843
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Methylation Silencing of Transforming Growth Factor-{beta} Receptor Type II in Rat Prostate Cancers.
S. Yamashita, S. Takahashi, N. McDonell, N. Watanabe, T. Niwa, K. Hosoya, Y. Tsujino, T. Shirai, and T. Ushijima (2008)
Cancer Res. 68, 2112-2121
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Transforming Growth Factor {beta} Controls the Directional Migration of Hepatocyte Cohorts by Modulating Their Adhesion to Fibronectin.
F. Biname, P. Lassus, and U. Hibner (2008)
Mol. Biol. Cell 19, 945-956
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Cancer-Associated Stromal Fibroblasts Promote Pancreatic Tumor Progression.
R. F. Hwang, T. Moore, T. Arumugam, V. Ramachandran, K. D. Amos, A. Rivera, B. Ji, D. B. Evans, and C. D. Logsdon (2008)
Cancer Res. 68, 918-926
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Direct Evidence for Epithelial-Mesenchymal Transitions in Breast Cancer.
A. J. Trimboli, K. Fukino, A. de Bruin, G. Wei, L. Shen, S. M. Tanner, N. Creasap, T. J. Rosol, M. L. Robinson, C. Eng, et al. (2008)
Cancer Res. 68, 937-945
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Somatic acquisition of TGFBR1*6A by epithelial and stromal cells during head and neck and colon cancer development.
Y. Bian, T. J. Knobloch, M. Sadim, V. Kaklamani, A. Raji, G.-Y. Yang, C. M. Weghorst, and B. Pasche (2007)
Hum. Mol. Genet. 16, 3128-3135
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Androgen Receptor Regulation of the Versican Gene through an Androgen Response Element in the Proximal Promoter.
J. T. Read, M. Rahmani, S. Boroomand, S. Allahverdian, B. M. McManus, and P. S. Rennie (2007)
J. Biol. Chem. 282, 31954-31963
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Actin cytoskeleton dynamics linked to synovial fibroblast activation as a novel pathogenic principle in TNF-driven arthritis.
Y Vasilopoulos, V Gkretsi, M Armaka, V Aidinis, and G Kollias (2007)
Ann Rheum Dis 66, iii23-iii28
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Tissue-Specific Consequences of Cyclin D1 Overexpression in Prostate Cancer Progression.
Y. He, O. E. Franco, M. Jiang, K. Williams, H. D. Love, I. M. Coleman, P. S. Nelson, and S. W. Hayward (2007)
Cancer Res. 67, 8188-8197
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TGF-{beta} signaling is essential for joint morphogenesis.
A. Spagnoli, L. O'Rear, R. L. Chandler, F. Granero-Molto, D. P. Mortlock, A. E. Gorska, J. A. Weis, L. Longobardi, A. Chytil, K. Shimer, et al. (2007)
J. Cell Biol. 177, 1105-1117
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Integrin {alpha}11 regulates IGF2 expression in fibroblasts to enhance tumorigenicity of human non-small-cell lung cancer cells.
C.-Q. Zhu, S. N. Popova, E. R. S. Brown, D. Barsyte-Lovejoy, R. Navab, W. Shih, M. Li, M. Lu, I. Jurisica, L. Z. Penn, et al. (2007)
PNAS 104, 11754-11759
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