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Activin signaling is an essential component of the TGF-? induced pro-metastatic phenotype in colorectal cancer.

ABSTRACT: Advanced colorectal cancer (CRC) remains a critical health care challenge worldwide. Various TGF-? superfamily members are important in colorectal cancer metastasis, but their signaling effects and predictive value have only been assessed in isolation. Here, we examine cross-regulation and combined functions of the two most prominent TGF-? superfamily members activin and TGF-? in advanced colorectal cancer. In two clinical cohorts we observed by immune-based assay that combined serum and tissue activin and TGF-? ligand levels predicts outcome in CRC patients and is superior to single ligand assessment. While TGF-? growth suppression is independent of activin, TGF-? treatment leads to increased activin secretion in colon cancer cells and TGF-? induced cellular migration is dependent on activin, indicating pathway cross-regulation and functional interaction in vitro. mRNA expression of activin and TGF-? pathway members were queried in silico using the TCGA data set. Coordinated ligand and receptor expression is common in solid tumors for activin and TGF-? pathway members. In conclusion, activin and TGF-? are strongly connected signaling pathways that are important in advanced CRC. Assessing activin and TGF-? signaling as a unit yields important insights applicable to future diagnostic and therapeutic interventions.

SUBMITTER: Staudacher JJ

PROVIDER: S-EPMC5514149 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Activin signaling is an essential component of the TGF-β induced pro-metastatic phenotype in colorectal cancer.

Staudacher Jonas J JJ Bauer Jessica J Jana Arundhati A Tian Jun J Carroll Timothy T Mancinelli Georgina G Özden Özkan Ö Krett Nancy N Guzman Grace G Kerr David D Grippo Paul P Jung Barbara B

Scientific reports 20170717 1

Advanced colorectal cancer (CRC) remains a critical health care challenge worldwide. Various TGF-β superfamily members are important in colorectal cancer metastasis, but their signaling effects and predictive value have only been assessed in isolation. Here, we examine cross-regulation and combined functions of the two most prominent TGF-β superfamily members activin and TGF-β in advanced colorectal cancer. In two clinical cohorts we observed by immune-based assay that combined serum and tissue ...[more]

PMID: 28717230

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Project description:Transforming growth factor ? (TGF-?) superfamily signaling pathways are ubiquitous and essential for several cellular and physiological processes. The overexpression of TGF-? results in excessive fibrosis in multiple human disorders. Among them, stiff skin syndrome (SSS) is an ultrarare and untreatable condition characterized by the progressive thickening and hardening of the dermis, and acquired joint limitations. SSS is distinct in a widespread form, caused by recurrent germline variants of FBN1 encoding a key molecule of the TGF-? signaling, and a segmental form with unknown molecular basis. Here, we report a 12-year-old female with segmental SSS, affecting the right upper limb with acquired thickening of the dermis evident at the magnetic resonance imaging, and progressive limitation of the elbow and shoulder. To better explore the molecular and cellular mechanisms that drive segmental SSS, several functional studies on patient's fibroblasts were employed. We hypothesized an impairment of TGF-? signaling and, consequently, a dysregulation of the associated downstream signaling. Lesional fibroblast studies showed a higher phosphorylation level of extracellular signal-regulated kinase 1/2 (ERK1/2), increased levels of nuclear factor-kB (NFkB), and a nuclear accumulation of phosphorylated Smad2 via Western blot and microscopy analyses. Quantitative PCR expression analysis of genes encoding key extracellular matrix proteins revealed increased levels of COL1A1, COL3A1, AGT, LTBP and ITGB1, while zymography assay reported a reduced metalloproteinase 2 enzymatic activity. In vitro exposure of patient's fibroblasts to losartan led to the partial restoration of normal transforming growth factor ? (TGF-?) marker protein levels. Taken together, these data demonstrate that in our patient, segmental SSS is characterized by the overactivation of multiple TGF-? signaling pathways, which likely results in altered extracellular matrix composition and fibroblast homeostasis. Our results for the first time reported that aberrant TGF-? signaling may drive the pathogenesis of segmental SSS and might open the way to novel therapeutic approaches.

Dataset Information

Activin signaling is an essential component of the TGF-? induced pro-metastatic phenotype in colorectal cancer.

Publications

Activin signaling is an essential component of the TGF-β induced pro-metastatic phenotype in colorectal cancer.

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