Resistance to transforming growth factor β-mediated tumor suppression in melanoma: are multiple mechanisms in place?

• Published in: Carcinogenesis (New York) 2010-10, Vol.31 (10), p.1710-1717
• Main Authors: Lasfar, Ahmed, Cohen-Solal, Karine A.
• Format: Article
• Language: English
• Subjects: Apoptosis; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Cell Cycle; Contractile Proteins - physiology; Cyclin-Dependent Kinase 4 - metabolism; Cyclin-Dependent Kinase Inhibitor p21 - analysis; Dermatology; Disease Progression; Filamins; Forkhead Box Protein O1; Forkhead Transcription Factors - physiology; Genes, myc; Humans; Intracellular Signaling Peptides and Proteins - physiology; Medical sciences; Melanoma - pathology; Melanoma - prevention & control; Microfilament Proteins - physiology; Paired Box Transcription Factors - physiology; PAX3 Transcription Factor; Phosphorylation; Proto-Oncogene Proteins - physiology; Reviews; Signal Transduction; Smad2 Protein - physiology; Smad3 Protein - physiology; Transforming Growth Factor beta - physiology; Tumors; Tumors of the skin and soft tissue. Premalignant lesions
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgq155

Resistance to transforming growth factor (TGF) β-mediated tumor suppression in melanoma appears to be a crucial step in tumor aggressiveness since it is usually coupled with the ability of TGFβ to drive the oncogenic process via autocrine and paracrine effects. In this review, we will focus mainly on the mechanisms of escape from TGFβ-induced cell cycle arrest because the mechanisms of resistance to TGFβ-mediated apoptosis are still essentially speculative. As expected, some of these mechanisms can directly affect the function of the main downstream effectors of TGFβ, Smad2 and Smad3, resulting in compromised Smad-mediated antiproliferative activity. Other mechanisms can counteract or overcome TGFβ-mediated cell cycle arrest independently of the Smads. In melanoma, some models of resistance to TGFβ have been suggested and will be described. In addition, we propose additional models of resistance taking into consideration the information available on the dysregulation of fundamental cellular effectors and signaling pathways in melanoma.