Ann Dermatol.  2013 May;25(2):135-144. 10.5021/ad.2013.25.2.135.

Insights into the Transforming Growth Factor-beta Signaling Pathway in Cutaneous Melanoma

• Perrot CY
• Javelaud D
• Mauviel A

• KMID: 2171779
• DOI: http://doi.org/10.5021/ad.2013.25.2.135

Abstract

Transforming growth factor-beta (TGF-beta) is a pleiotropic growth factor with broad tissue distribution that plays critical roles during embryonic development, normal tissue homeostasis, and cancer. While its cytostatic activity on normal epithelial cells initially defined TGF-beta signaling as a tumor suppressor pathway, there is ample evidence indicating that TGF-beta is a potent pro-tumorigenic agent, acting via autocrine and paracrine mechanisms to promote peri-tumoral angiogenesis, together with tumor cell migration, immune escape, and dissemination to metastatic sites. This review summarizes the current knowledge on the implication of TGF-beta signaling in melanoma.

Keyword

Melanoma; Metastasis; TGF-beta signaling; Therapeutic-targets

MeSH Terms

Cell Movement
Embryonic Development
Epithelial Cells
Female
Homeostasis
Melanoma
Neoplasm Metastasis
Pregnancy
Robenidine
Tissue Distribution
Transforming Growth Factor beta
United Nations
Robenidine
Transforming Growth Factor beta

Figure

• 

  Fig. 1 The transforming growth factor (TGF)-β signaling cascade. TGF-β binds to the type II receptor that recruits, phosphorylates and activates type I receptor (TβRI). TβRI in turn phosphorylates SMAD2/3 which then associate with the co-SMAD SMAD4 to form a heterocomplex that accumulates in the nucleus to regulate target gene transcription. Inhibitory SMAD7 binds activated TβRI to prevent SMAD2/3 phosphorylation, or recruits E3 ubiquitin ligases (SMURF1/2, WW1) or phosphatase GADD34/PP1 to the receptor complexes, inducing proteasomal degradation or dephosphorylation of the latter, respectively. C-SKI and SNON act as transcriptional co-repressors to repress TGF-β-induced, SMAD-driven, transcription. TβRII: TGF-βreceptor type II.

• 

  Fig. 2 Autocrine and paracrine effects of transforming growth factor (TGF)-β on melanoma cells and tumor microenvironment. Melanoma cells express and secrete high levels of TGF-β that are self-perpetuating, notably through enhanced protease activation of latent TGF-β and recruitment of TGF-β-secreting cells such as stromal fibroblasts. TGF-β, which exerts cytostatic effects on early stage tumor cells, switches to tumor promoter in advanced melanoma where it promotes invasion, mesenchymal transition and dissemination of tumor cells. TGF-β secretion by melanoma cells also affects the tumor microenvironment. TGF-β stimulates stromal fibroblasts and endothelial cells to promote tumor growth, invasion and angiogenesis, and inhibits the proliferation and activation of key immune cells, thus allowing melanoma cells to evade from immunosuppressive actions. ECM: extracellular matrix, EndMT: endothelial to mesenchymal transition, NK: natural killer.

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