Journal
CANCERS
Volume 10, Issue 6, Pages -Publisher
MDPI
DOI: 10.3390/cancers10060159
Keywords
transforming growth factor-beta 1; PTEN; PPM1A; Klotho; SMAD7; BMP7; Ski/Sno; BAMBI; tumor progression; cellular plasticity
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Funding
- NIH [GM057242]
- Capital Region Medical Research Institute
- Charlotte Graver Foundation
- Butler Family Foundation
- Friedman Cancer Research Fund
- Roach Foundation
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The multi-functional cytokine transforming growth factor-beta 1 (TGF-beta 1) has growth inhibitory and anti-inflammatory roles during homeostasis and the early stages of cancer. Aberrant TGF-beta activation in the late-stages of tumorigenesis, however, promotes development of aggressive growth characteristics and metastatic spread. Given the critical importance of this growth factor in fibrotic and neoplastic disorders, the TGF-beta 1 network is subject to extensive, multi-level negative controls that impact receptor function, mothers against decapentaplegic homolog 2/3 (SMAD2/3) activation, intracellular signal bifurcation into canonical and non-canonical pathways and target gene promotor engagement. Such negative regulators include phosphatase and tensin homologue (PTEN), protein phosphatase magnesium 1A (PPM1A), Klotho, bone morphogenic protein 7 (BMP7), SMAD7, Sloan-Kettering Institute proto-oncogene/Ski related novel gene (Ski/SnoN), and bone morphogenetic protein and activin membrane-bound Inhibitor (BAMBI). The progression of certain cancers is accompanied by loss of expression, overexpression, mislocalization, mutation or deletion of several endogenous repressors of the TGF-beta 1 cascade, further modulating signal duration/intensity and phenotypic reprogramming. This review addresses how their aberrant regulation contributes to cellular plasticity, tumor progression/metastasis and reversal of cell cycle arrest and discusses the unexplored therapeutic value of restoring the expression and/or function of these factors as a novel approach to cancer treatment.
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