The Journal of Cell Biology, Vol 118, 715-726, Copyright © 1992 by The Rockefeller University Press

ARTICLES

Altered metabolic and adhesive properties and increased tumorigenesis associated with increased expression of transforming growth factor beta 1

BA Arrick, AR Lopez, F Elfman, R Ebner, CH Damsky and R Derynck
Department of Developmental Biology, Genentech Inc., South San Francisco, California 94080.

Transforming growth factor-beta (TGF-beta) is a potent mediator of cell proliferation and extracellular matrix formation, depending on the cell type and the physiological conditions. TGF-beta is usually secreted in a "latent" complex that needs activation before it can exert its effects. Several observations correlate increased expression of TGF- beta 1 with tumorigenesis. To evaluate the physiological relevance of increased TGF-beta 1 synthesis in tumor cells we established cell clones overexpressing TGF-beta 1 and observed the resulting physiological changes in TGF-beta overproducing cells in vitro and in vivo. As a model system we used the human E1A-transformed 293 tumor cells, which are insensitive to the direct growth modulatory effects of TGF-beta. The selection of this cell line allows an assessment of physiological alterations independent of TGF-beta induced proliferative changes. The use of two TGF-beta 1 expression vectors containing either the natural or a modified TGF-beta 1 precursor cDNA permitted the establishment of separate 293 cell lines overexpressing latent or active TGF-beta. Comparison of the resulting changes in glycolytic rate, adhesiveness and integrin and plasminogen activator expression established that, in vitro, both types of clones behaved similarly, indicating that expression of latent TGF-beta induces autocrine changes in the tumor cells and thus suggesting that some level of cell- associated activation occurs. TGF-beta overexpression resulted in an increased metabolic rate due to enhanced glycolysis, a property long associated with tumor cells. This increased glycolysis was not associated with altered proliferation. Cells overexpressing TGF-beta also displayed enhanced fibronectin mRNA and plasminogen activator synthesis and increased adhesiveness in vitro. They showed enhanced survival when plated sparsely on plastic in the absence of serum, and attached more readily to laminin. In addition, synthesis of several beta 1 integrins, in particular the alpha 1/beta 1, alpha 2/beta 1, and alpha 3/beta 1, all of which recognize laminin, were enhanced. Finally, cells overexpressing active TGF-beta, but not latent TGF-beta, also showed increased tumorigenicity in nude mice. Thus, an increase in endogenous TGF-beta synthesis confers several proliferation-independent phenotypic changes which may be of significance for the survival of the tumor cell inoculum or its subsequent growth, and for tumor formation and development. In the case of cells expressing active TGF-beta, the release of active TGF-beta into the vicinity of the tumor cells may also result in a more hospitable environment for tumor growth.
CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

This article has been cited by other articles:

• Mazzieri, R., Jurukovski, V., Obata, H., Sung, J., Platt, A., Annes, E., Karaman-Jurukovska, N., Gleizes, P.-E., Rifkin, D. B. (2005). Expression of truncated latent TGF-{beta}-binding protein modulates TGF-{beta} signaling. J. Cell Sci. 118: 2177-2187 [Abstract] [Full Text]  
• Lee, J. H., Seo, Y.-W., Park, S. R., Kim, Y. J., Kim, K. K. (2003). Expression of a Splice Variant of KAI1, a Tumor Metastasis Suppressor Gene, Influences Tumor Invasion and Progression. Cancer Res. 63: 7247-7255 [Abstract] [Full Text]  
• Chen, W., Kirkbride, K. C., How, T., Nelson, C. D., Mo, J., Frederick, J. P., Wang, X.-F., Lefkowitz, R. J., Blobe, G. C. (2003). {beta}-Arrestin 2 Mediates Endocytosis of Type III TGF-{beta} Receptor and Down-Regulation of Its Signaling. Science 301: 1394-1397 [Abstract] [Full Text]  
• Lottin, S., Adriaenssens, E., Dupressoir, T., Berteaux, N., Montpellier, C., Coll, J., Dugimont, T., Curgy, J. J. (2002). Overexpression of an ectopic H19 gene enhances the tumorigenic properties of breast cancer cells. Carcinogenesis 23: 1885-1895 [Abstract] [Full Text]  
• Bandyopadhyay, A., Lopez-Casillas, F., Malik, S. N., Montiel, J. L., Mendoza, V., Yang, J., Sun, L-Z. (2002). Antitumor Activity of a Recombinant Soluble Betaglycan in Human Breast Cancer Xenograft. Cancer Res. 62: 4690-4695 [Abstract] [Full Text]  
• Zhu, Y., Yang, G.-Y., Ahlemeyer, B., Pang, L., Che, X.-M., Culmsee, C., Klumpp, S., Krieglstein, J. (2002). Transforming Growth Factor-beta 1 Increases Bad Phosphorylation and Protects Neurons Against Damage. J. Neurosci. 22: 3898-3909 [Abstract] [Full Text]  
• Rowland-Goldsmith, M. A., Maruyama, H., Matsuda, K., Idezawa, T., Ralli, M., Ralli, S., Korc, M. (2002). Soluble Type II Transforming Growth Factor-{beta} Receptor Attenuates Expression of Metastasis-associated Genes and Suppresses Pancreatic Cancer Cell Metastasis. Molecular Cancer Therapeutics 1: 161-167 [Abstract] [Full Text]  
• Kim, K.-Y., Jeong, S.-Y., Won, J., Ryu, P.-D., Nam, M.-J. (2001). Induction of Angiogenesis by Expression of Soluble Type II Transforming Growth Factor-beta Receptor in Mouse Hepatoma. J. Biol. Chem. 276: 38781-38786 [Abstract] [Full Text]  
• Ellenrieder, V., Hendler, S. F., Boeck, W., Seufferlein, T., Menke, A., Ruhland, C., Adler, G., Gress, T. M. (2001). Transforming Growth Factor {beta}1 Treatment Leads to an Epithelial-Mesenchymal Transdifferentiation of Pancreatic Cancer Cells Requiring Extracellular Signal-regulated Kinase 2 Activation. Cancer Res. 61: 4222-4228 [Abstract] [Full Text]  
• Pang, L., Ye, W., Che, X.-M., Roessler, B. J., Betz, A. L., Yang, G.-Y. (2001). Reduction of Inflammatory Response in the Mouse Brain With Adenoviral-Mediated Transforming Growth Factor-{beta}1 Expression. Stroke 32: 544-552 [Abstract] [Full Text]  
• Bandyopadhyay, A., Zhu, Y., Cibull, M. L., Bao, L., Chen, C., Sun, L. (1999). A Soluble Transforming Growth Factor {beta} Type III Receptor Suppresses Tumorigenicity and Metastasis of Human Breast Cancer MDA-MB-231 Cells. Cancer Res. 59: 5041-5046 [Abstract] [Full Text]  
• Ye, S.-C., Foster, J. M., Li, W., Liang, J., Zborowska, E., Venkateswarlu, S., Gong, J., Brattain, M. G., Willson, J. K. V. (1999). Contextual Effects of Transforming Growth Factor {beta} on the Tumorigenicity of Human Colon Carcinoma Cells. Cancer Res. 59: 4725-4731 [Abstract] [Full Text]  
• Maehara, Y., Kakeji, Y., Kabashima, A., Emi, Y., Watanabe, A., Akazawa, K., Baba, H., Kohnoe, S., Sugimachi, K. (1999). Role of Transforming Growth Factor-{beta}1 in Invasion and Metastasis in Gastric Carcinoma. JCO 17: 607-607 [Abstract] [Full Text]  
• Chen, J., Sun, Y., Nabel, G. J. (1998). Regulation of the Proinflammatory Effects of Fas Ligand (CD95L). Science 282: 1714-1717 [Abstract] [Full Text]  
• Gerdes, M. J., Larsen, M., McBride, L., Dang, T. D., Lu, B., Rowley, D. R. (1998). Localization of Transforming Growth Factor-b1 and Type II Receptor in Developing Normal Human Prostate and Carcinoma Tissues. J. Histochem. Cytochem. 46: 379-388 [Abstract] [Full Text]  
• Sun, L., Chen, C. (1997). Expression of Transforming Growth Factor beta  Type III Receptor Suppresses Tumorigenicity of Human Breast Cancer MDA-MB-231 Cells. J. Biol. Chem. 272: 25367-25372 [Abstract] [Full Text]  
• Dobbertin, A., Schmid, P., Gelman, M., Glowinski, J., Mallat, M. (1997). Neurons Promote Macrophage Proliferation by Producing Transforming Growth Factor-beta 2. J. Neurosci. 17: 5305-5315 [Abstract] [Full Text]  
• Gleizes, P.-E., Beavis, R. C., Mazzieri, R., Shen, B., Rifkin, D. B. (1996). Identification and Characterization of an Eight-cysteine Repeat of the Latent Transforming Growth Factor-beta Binding Protein-1 that Mediates Bonding to the Latent Transforming Growth Factor-beta 1. J. Biol. Chem. 271: 29891-29896 [Abstract] [Full Text]  
• Shi, Y., O'Brien, J. E., Fard, A., Zalewski, A. (1996). Transforming Growth Factor-ß1 Expression and Myofibroblast Formation During Arterial Repair. Arterioscler. Thromb. Vasc. Bio. 16: 1298-1305 [Abstract] [Full Text]  
• Yamamoto, H., Ueno, H., Ooshima, A., Takeshita, A. (1996). Adenovirus-mediated Transfer of a Truncated Transforming Growth Factor-beta (TGF-beta ) Type II Receptor Completely and Specifically Abolishes Diverse Signaling by TGF-beta in Vascular Wall Cells in Primary Culture. J. Biol. Chem. 271: 16253-16259 [Abstract] [Full Text]  
• Feng, X.-H., Filvaroff, E. H., Derynck, R. (1995). Transforming Growth Factor-beta (TGF-beta)-induced Down-regulation of Cyclin A Expression Requires a Functional TGF-beta Receptor Complex. J. Biol. Chem. 270: 24237-24245 [Abstract] [Full Text]  
• Glick, A B, Lee, M M, Darwiche, N, Kulkarni, A B, Karlsson, S, Yuspa, S H (1994). Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma.. Genes Dev. 8: 2429-2440 [Abstract]  
• Chen, R., Ebner, R, Derynck, R (1993). Inactivation of the type II receptor reveals two receptor pathways for the diverse TGF-beta activities. Science 260: 1335-1338 [Abstract]  
• Tzarfaty-Majar, V., Lopez-Alemany, R., Feinstein, Y., Gombau, L., Goldshmidt, O., Soriano, E., Munoz-Canoves, P., Klar, A. (2001). Plasmin-mediated Release of the Guidance Molecule F-spondin from the Extracellular Matrix. J. Biol. Chem. 276: 28233-28241 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents