Extracellular Matrix-Associated Transforming Growth Factor-β: Role in Cancer Cell Growth and Invasion

https://doi.org/10.1016/S0065-230X(08)60740-XGet rights and content

Growth factors of the transforming growth factor-β (TGF-β) family inhibit the proliferation of epithelial, endothelial, and hematopoietic cells, and stimulate the synthesis of extracellular matrix components. TGF-βs are secreted from cells in high-molecular-mass protein complexes that are composed of three proteins, the mature TGF-β-dimer, the TGF-β propeptide dimer, or latency-associated protein (LAP), and the latent TGF-β binding protein (LTBP). Mature TGF-β is cleaved from its propeptide during secretion, but the proteins remain associated by noncovalent interactions. LTBP is required for efficient secretion and processing of latent TGF-β and it binds to LAP via disulfide bond(s). LTBP is a component of extracellular matrix microfibrils, and it targets the latent TGF-β complex to the extracellular matrix. TGF-β signaling is initiated by proteolytic cleavage of LTBP that results in the release of the latent TGF-β complex from the extracellular matrix. TGF-β is activated by dissociation of LAP from the mature TGF-β. Subsequent signaling involves binding of active TGF-β to its type II cell surface receptors, which phosphorylate and activate type I TGF-β receptors. Type I receptors, in turn, phosphorylate cytoplasmic transcriptional activator proteins Smad2 and Smad3, inducing their translocation to the nucleus. Recent evidence suggests that acquisition of resistance to TGF-β growth inhibition plays a major role in the progression of epithelial and hematopoietic cell malignancies. The role of secretion of TGF-β in tumorigenesis is more complex. The secretion of TGF-βs by tumor cells may contribute to autocrine growth inhibition, but on the other hand, it may also promote invasion, metastasis, angiogenesis, and even immunosuppression. Tumor cells may also fail to deposit LTBP:TGF-β complexes to the extracellular matrix. The elucidation of the mechanisms of the release of TGF-β from the matrix and its subsequent activation aids the understanding of the pathophysiologic roles of TGF-β in malignant growth, and allows the development of therapeutic agents that regulate the activity of TGF-β.

References (403)

  • K. Arora et al.

    Cell

    (1995)
  • A. Atfi et al.

    J. Biol. Chem.

    (1997)
  • K. Basler et al.

    Cell

    (1993)
  • A. Bassols et al.

    J. Biol. Chem.

    (1988)
  • E.J. Battegay et al.

    Cell

    (1990)
  • M. Benezra et al.

    Blood

    (1993)
  • L. Borsi et al.

    FEBS Lett.

    (1990)
  • P.R. Brauer et al.

    Dev. Biol.

    (1993)
  • A.M. Brunner et al.

    J. Biol. Chem.

    (1989)
  • S. Cheifetz et al.

    J. Biol. Chem.

    (1991)
  • S. Cheifetz et al.

    Cell

    (1987)
  • S. Cheifetz et al.

    J. Biol. Chem.

    (1992)
  • S.P. Chellappan et al.

    Cell

    (1991)
  • K.P. Crookston et al.

    J. Biol. Chem.

    (1994)
  • W. Cui et al.

    Cell

    (1996)
  • S.L. Dallas et al.

    J. Biol. Chem.

    (1994)
  • M.B. Datto et al.

    J. Biol. Chem.

    (1995)
  • J.W. De Caprio et al.

    Cell

    (1989)
  • A.K. Downing et al.

    Cell

    (1996)
  • C.M. Dubois et al.

    J. Biol. Chem.

    (1995)
  • E. Dumermuth et al.

    J. Biol. Chem.

    (1991)
  • K. Eppert et al.

    Cell

    (1996)
  • M.E. Ewen et al.

    Cell

    (1989)
  • M.E. Ewen et al.

    Cell

    (1993)
  • D.J. Falcone et al.

    J. Biol. Chem.

    (1993)
  • L.A. Falk et al.

    Blood

    (1991)
  • E.L. Ferguson et al.

    Cell

    (1992)
  • P. Franzén et al.

    Cell

    (1993)
  • A.G. Geiser et al.

    J. Biol. Chem.

    (1992)
  • R. Giltay et al.

    FEBS Lett.

    (1997)
  • F.M. Amara et al.

    Nucleic Acids Res.

    (1995)
  • M.S. Anscher et al.

    N. Engl. J. Med.

    (1993)
  • A. Antonelli-Orlidge et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (1989)
  • M.A. Anzano et al.

    Cancer Res.

    (1982)
  • M.A. Anzano et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (1983)
  • B.A. Arrick et al.

    Mol. Cell. Biol.

    (1991)
  • C.L. Arteaga et al.

    Cell Growth Differ.

    (1993)
  • R.K. Assoian et al.

    J. Cell Biol.

    (1986)
  • R.K. Assoian et al.

    Nature (London)

    (1984)
  • A. Atfi et al.

    J. Biol. Chem.

    (1994)
  • M.H. Barcellos-Hoff

    Cancer Res.

    (1993)
  • T. Bellón et al.

    Eur. J. Immunol.

    (1993)
  • M.C. Birchenall-Roberts et al.

    Mol. Cell. Biol.

    (1990)
  • M. Bonyadi et al.

    Nature Genet.

    (1997)
  • W.A. Border et al.

    J. Clin. Invest.

    (1992)
  • E.P. Böttinger et al.

    EMBO J.

    (1997)
  • J. Boulanger et al.

    Int. J. Cancer

    (1995)
  • T.J. Broekelmann et al.

    Proc. Natl. Acad. Sci. U.S.A.

    (1991)
  • P.D. Brown et al.

    Growth Factors

    (1990)
  • T.H. Bugge et al.

    Genes. Dev.

    (1995)
  • Cited by (0)

    View full text