Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion

Loomans, Holli A.; Andl, Claudia D.

doi:10.3390/cancers7010070

Cited by 130 publications

(136 citation statements)

References 150 publications

(462 reference statements)

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“…Firstly, the tumour expression of ActA, indirectly assessed by circulating levels, may reflect the severity or the extent of the cancer. The tumour expression of ActA and its role in carcinogenesis are variable depending of the tumour type 27. In esophageal and head and neck carcinoma, high ActA expression seems to be linked to a more aggressive tumour.…”

Section: Discussionmentioning

confidence: 99%

Circulating Activin A predicts survival in cancer patients

Loumaye

Barsy

Nachit

et al. 2017

J cachexia sarcopenia muscle

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BackgroundSeveral experimental evidences pinpoint the possible role of Activin A (ActA) as a driver of cancer cachexia. Supporting this hypothesis, we showed recently that human cancer cachexia is associated with high ActA levels. Moreover, ActA levels were correlated with body weight loss and skeletal muscle density, two prognostic factors in cancer patients. Our goal was therefore to investigate the value of ActA to predict survival in cancer patients.MethodsPatients with colorectal or lung cancer were prospectively enrolled at the time of diagnosis or relapse between January 2012 and March 2014. At baseline, patients had clinical, nutritional, and functional assessment. Body composition and skeletal muscle density were measured by CT scan, and plasma ActA concentrations were determined. Overall survival (OS) was analysed since inclusion to 24 months later.ResultsSurvival data were available for 149 patients out of 152. Patients with high ActA (≥408 pg/mL) had lower OS than those with low levels, regardless the type of cancer (OS in colorectal cancer, 50% vs. 79%, P < 0.05; and in lung cancer, 27% vs. 67%, P = 0.001). The multivariable analysis confirmed the prognostic value of ActA independently of tumour stage or inflammatory markers, particularly in lung cancer. Low muscularity was also an independent prognostic factor.ConclusionsOur study demonstrates that high ActA level is an independent prognosis factor of survival in cancer patients. More than a basic marker of the severity of the neoplastic disease or of the inflammatory process, ActA seems to influence survival by contributing to the development of cachexia and loss of skeletal muscle mass.

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Section: Discussionmentioning

confidence: 99%

Circulating Activin A predicts survival in cancer patients

Loumaye

Barsy

Nachit

et al. 2017

J cachexia sarcopenia muscle

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“…Consequently, TGFβ, activin, and BMPs engage in a complex signalling network, resulting in the transcription of target genes with vital influences on cell growth, differentiation, proliferation and survival. It is not surprising therefore, that these proteins are implicated in tumorigenesis (19)(20)(21)(22).…”

Section: Discussionmentioning

confidence: 99%

“…Activin and BMPs are both TGFβ superfamily members, that employ different combinations of serine-threonine kinase receptors that when phosphorylated, result in activation of canonical Smad 2/3 and Smad 1/5/8 intracellular signalling pathways respectively (19)(20)(21). Non-canonical Akt/PI3K, MAPK/ERK and Wnt/β-catenin pathways can also be activated, dependant on the combination of receptors recruited.…”

Section: Discussionmentioning

confidence: 99%

“…A balance between proliferation and differentiation is coordinated by TGFβ ligands and their antagonists. This is well recognised in TGFβ family members, such as TGFβ itself which, similarly to activin, is known to have inhibitory effects on cellular proliferation in several cancers, but is also associated with EMT, invasion and metastasis in aggressive and progressive disease (19,22).…”

Section: Cancer Genomics and Proteomicsmentioning

confidence: 99%

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Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival

Zabkiewicz

Resaul

Hargest

et al. 2017

CGP

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Abstract. Background Follistatin (FST) is a secreted extracellular regulatory protein that binds activin and, with less affinity, related TGFβ superfamily members such as bone morphogenetic proteins (BMPs), preventing access to their receptors (1, 2). Originally thought to act on the pituitary to regulate FSH release, FST has subsequently been noted in many other tissues, in particular co-localising with activin resulting in autocrine and paracrine cellular regulation (1, 3). As an antagonist of activin, FST has diverse regulatory roles in embryogenesis, tissue differentiation and repair, gonadal function and inflammatory and immune processes (3, 4).Three major FST isoforms can be produced, namely FST288 (from splice variant mRNA precursor FST317), FST315 (from splice variant mRNA precursor FST344) and a third FST isoform, FST303, produced from the post-translational truncation of the FST315 C-terminus (5). These three main FST isoforms can also be glycosylated to yield six further FST isoforms (6). FST288 and FST315 are differentially expressed in human tissues, but FST315 is the predominant isoform, whilst the FST288 isoform accounts for less than 5% of the encoded mRNA (6, 7) .The FST/activin interaction has been implicated in tumour proliferation, angiogenesis and metastasis in several solid tumours (8-11). Activin has primarily been seen as an inhibitor of cellular proliferation, although certain cell populations seem to be stimulated by activin. Thus, the overall result of activin/FST action in cancer may be both context and cell type specific (3, 6).In the breast, FST is expressed in the normal mammary gland and in different breast proliferative diseases, with additional experimental evidence suggesting that FST can modulate the breast cancer cell cycle (3,(12)(13)(14). However, its role in breast cancer growth and metastasis is far from clear. In this study we demonstrated a clinical correlation between FST expression and survival in breast cancer, and that overexpression of FST in vitro reduces invasion of breast cancer cells. Patients and MethodsCell lines and patient tissue samples. Human breast cell lines MCF-7,MDA MB 231, ZR-751, BT 549 and BT-20 were obtained from and cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% foetal calf serum and antibiotics (PAA Laboratories Ltd., Somerset, UK). Cells were incubated at 37˚C in 5% CO 2 at 95% humidity.Breast cancer tissue and normal breast tissue samples were collected during surgery at the University Hospital of Wales. In total, 93 tumour samples and 30 normal breast tissue samples were obtained from patients who were enrolled in the study. The tissues obtained during surgery were snap-frozen in liquid nitrogen and stored at −80˚C.

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“…As with other TGF-β superfamily members, activin A functions through the serine/threonine kinase pathway. Activin A initially binds to activin type II receptors (ActRII), and then recruits activin type I receptors to phosphorylate and activate SMAD family member (Smad) 2/3 in the cytoplasm, with this being the common signaling molecule between activin and TGF-β (6). The activated Smad2/3 forms a complex with Smad4 and then the complex is translocated into the nucleus, resulting in downstream target gene transcription to elicit biological effects, including cell differentiation, proliferation and apoptosis (7,8).…”

Section: Introductionmentioning

confidence: 99%

Activin A induces apoptosis of mouse myeloma cells via the mitochondrial pathway

Zhang

Zhao

et al. 2017

Oncol Lett

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Abstract. Activin A is a pleiotropic cytokine belonging to the transforming growth factor β superfamily. Abnormal expression of activin A is associated with tumorigenesis. Multiple myeloma is characterized by the development of osteolytic disease, which ultimately leads to cachexia. However, the involvement of activin A in myeloma cell viability and apoptosis remains to be fully elucidated. For this purpose, mouse myeloma NS-1 cells were treated with activin A, and subsequently subjected to 5-bromo-2'-deoxyuridine analysis, Hoechst 33342 staining, flow cytometry and western blot analysis. The results revealed that activin A significantly suppressed NS-1 cell viability, and induced NS-1 cell apoptosis. In addition, activin A-induced promotion of NS-1 cell apoptosis was accompanied by upregulated expression of BCL2 associated X, apoptosis regulator (Bax), but downregulated expression of B cell lymphoma-2 (Bcl-2), resulting in an increase of the Bax/Bcl-2 ratio. Furthermore, cytochrome c and caspase-3 protein expression also increased following treatment with activin A. These data suggest that activin A induces apoptosis in mouse myeloma NS-1 cells via the mitochondrial pathway, providing a novel insight into multiple myeloma treatment.

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Intertwining of Activin A and TGFβ Signaling: Dual Roles in Cancer Progression and Cancer Cell Invasion

Cited by 130 publications

References 150 publications

Circulating Activin A predicts survival in cancer patients

Circulating Activin A predicts survival in cancer patients

Increased Expression of Follistatin in Breast Cancer Reduces Invasiveness and Clinically Correlates with Better Survival

Activin A induces apoptosis of mouse myeloma cells via the mitochondrial pathway

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