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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 carcinogenicprocess in adjacent epithelia. The role of transforming growthfactor–ß (TGF-ß) signaling in suchepithelial-mesenchymal interactions was determined by conditionalinactivation of the TGF-ß type II receptor gene inmouse fibroblasts (Tgfbr2fspKO). The loss of TGF-ßresponsiveness in fibroblasts resulted in intraepithelial neoplasiain 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) signalingwas identified as one possible mechanism for stimulation ofepithelial proliferation. Thus, TGF-ß signaling infibroblasts modulates the growth and oncogenic potential ofadjacent 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}vanderbilt.edu.
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Transforming Growth Factor-{beta} Signaling in Prostate Stromal Cells Supports Prostate Carcinoma Growth by Up-regulating Stromal Genes Related to Tissue Remodeling.
E. V. Verona, A. G. Elkahloun, J. Yang, A. Bandyopadhyay, I-T. Yeh, and L.-Z. Sun (2007)
Cancer Res.
67, 5737-5746
|Abstract »|Full Text »|PDF »
Interaction between Cancer Cells and Stromal Fibroblasts Is Required for Activation of the uPAR-uPA-MMP-2 Cascade in Pancreatic Cancer Metastasis.
Y. He, X.-d. Liu, Z.-y. Chen, J. Zhu, Y. Xiong, K. Li, J.-h. Dong, and X. Li (2007)
Clin. Cancer Res.
13, 3115-3124
|Abstract »|Full Text »|PDF »
Tumor-Specific Efficacy of Transforming Growth Factor-{beta}RI Inhibition in Eker Rats.
N. J. Laping, J. I. Everitt, K. S. Frazier, M. Burgert, M. J. Portis, C. Cadacio, L. I. Gold, and C. L. Walker (2007)
Clin. Cancer Res.
13, 3087-3099
|Abstract »|Full Text »|PDF »
Cross-talk between Paracrine-Acting Cytokine and Chemokine Pathways Promotes Malignancy in Benign Human Prostatic Epithelium.
M. Ao, O. E. Franco, D. Park, D. Raman, K. Williams, and S. W. Hayward (2007)
Cancer Res.
67, 4244-4253
|Abstract »|Full Text »|PDF »
Role of Heat Shock Protein 47, a Collagen-Binding Chaperone, in Lacrimal Gland Pathology in Patients with cGVHD.
Y. Ogawa, M. S. Razzaque, K. Kameyama, G. Hasegawa, S. Shimmura, M. Kawai, S. Okamoto, Y. Ikeda, K. Tsubota, Y. Kawakami, et al. (2007)
Invest. Ophthalmol. Vis. Sci.
48, 1079-1086
|Abstract »|Full Text »|PDF »
Epithelial-derived TGF-beta2 modulates basal and wound-healing subepithelial matrix homeostasis.
H. G. R. Thompson, J. D. Mih, T. B. Krasieva, B. J. Tromberg, and S. C. George (2006)
Am J Physiol Lung Cell Mol Physiol
291, L1277-L1285
|Abstract »|Full Text »|PDF »
Tgf{beta} signaling is required for atrioventricular cushion mesenchyme remodeling during in vivo cardiac development.
K. Jiao, M. Langworthy, L. Batts, C. B. Brown, H. L. Moses, and H. S. Baldwin (2006)
Development
133, 4585-4593
|Abstract »|Full Text »|PDF »
Transforming Growth Factor {beta} Receptor Type II Inactivation Induces the Malignant Transformation of Intestinal Neoplasms Initiated by Apc Mutation..
N. M. Munoz, M. Upton, A. Rojas, M. K. Washington, L. Lin, A. Chytil, E. G. Sozmen, B. B. Madison, A. Pozzi, R. T. Moon, et al. (2006)
Cancer Res.
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|Abstract »|Full Text »|PDF »
Transforming Growth Factor-{beta} Promotes Invasion in Tumorigenic but not in Nontumorigenic Human Prostatic Epithelial Cells.
M. Ao, K. Williams, N. A. Bhowmick, and S. W. Hayward (2006)
Cancer Res.
66, 8007-8016
|Abstract »|Full Text »|PDF »
Synergistic Function of Smad4 and PTEN in Suppressing Forestomach Squamous Cell Carcinoma in the Mouse..
Y. Teng, A.-N. Sun, X.-C. Pan, G. Yang, L.-L. Yang, M.-R. Wang, and X. Yang (2006)
Cancer Res.
66, 6972-6981
|Abstract »|Full Text »|PDF »
Inhibition of Transforming Growth Factor-{beta} Signaling in Human Cancer: Targeting a Tumor Suppressor Network as a Therapeutic Strategy..
S. Biswas, T. L. Criswell, S. E. Wang, and C. L. Arteaga (2006)
Clin. Cancer Res.
12, 4142-4146
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Inhibition of Growth and Metastasis of Mouse Mammary Carcinoma by Selective Inhibitor of Transforming Growth Factor-{beta} Type I Receptor Kinase In vivo..
R. Ge, V. Rajeev, P. Ray, E. Lattime, S. Rittling, S. Medicherla, A. Protter, A. Murphy, J. Chakravarty, S. Dugar, et al. (2006)
Clin. Cancer Res.
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|Abstract »|Full Text »|PDF »
Genetic variants of Tgfb1 act as context-dependent modifiers of mouse skin tumor susceptibility.
J.-H. Mao, E. F. Saunier, J. P. de Koning, M. M. McKinnon, M. N. Higgins, K. Nicklas, H.-T. Yang, A. Balmain, and R. J. Akhurst (2006)
PNAS
103, 8125-8130
|Abstract »|Full Text »|PDF »
Human mesenchymal stem cells exert potent antitumorigenic effects in a model of Kaposi's sarcoma.
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