Activin A balance regulates epithelial invasiveness and tumorigenesis

Bras, Grégoire F. Le; Loomans, Holli A.; Taylor, Chase J.; Revetta, Frank; Andl, Claudia D.

doi:10.1038/labinvest.2014.97

Cited by 21 publications

(31 citation statements)

References 58 publications

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“…Activin A is also associated with the maintenance of neuron survival, induction of hepatocyte apoptosis, promotion of erythroid differentiation and dual regulation of macrophage activation (14)(15)(16)(17). The involvement of activin A in the process of tumor genesis and progression has been previously reported (18), and a significant increase of activin A in the serum of certain patients with colorectal adenocarcinoma has been observed (19). However, the function of activin A in tumor progression is controversial.…”

Section: Discussionmentioning

confidence: 92%

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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Section: Discussionmentioning

confidence: 92%

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

Zhang

Zhao

et al. 2017

Oncol Lett

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“…We have previously shown the ability of nAb and A83-01 to neutralize Activin A signaling in this model system [34, 48]. Treatment with nAb increased cell invasion in dysplastic empty vector control cells, yet could not overcome the inhibition of cell invasion in the context of Fibro-ActA cultures (Fig.…”

Section: Resultsmentioning

confidence: 77%

“…Considering elevated levels of Activin A are found in the stroma despite the characteristic function of Activin A as an inducer of growth arrest, we first aimed to investigate the role of microenvironment-derived Activin A in a three-dimensional organotypic reconstruct (OTC) model in the presence of dysplastic esophageal keratinocytes (ECdnT) [29]. As normal esophageal fibroblasts secrete low to negligible levels of Activin A ([34] and data not shown), we retroviral transduced fibroblasts with INHBA to achieve Activin A overexpression levels similar to those observed in cancer-associated fibroblasts [34, 43]. Upon embedding Activin A overexpressing fibroblasts (Fibro-ActA) in the organotypic culture matrix, we validated overexpression and secretion of Activin A by ELISA (Additional file 2: Figure S2a).…”

Section: Resultsmentioning

confidence: 99%

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Esophageal squamous cell carcinoma invasion is inhibited by Activin A in ACVRIB-positive cells

et al. 2016

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BackgroundEsophageal squamous cell carcinoma (ESCC) is a global public health issue, as it is the eighth most common cancer worldwide. The mechanisms behind ESCC invasion and progression are still poorly understood, and warrant further investigation into these processes and their drivers. In recent years, the ligand Activin A has been implicated as a player in the progression of a number of cancers. The objective of this study was to investigate the role of Activin A signaling in ESCC.MethodsTo investigate the role Activin A plays in ESCC biology, tissue microarrays containing 200 cores from 120 ESCC patients were analyzed upon immunofluorescence staining. We utilized three-dimensional organotypic reconstruct cultures of dysplastic and esophageal squamous tumor cells lines, in the context of fibroblast-secreted Activin A, to identify the effects of Activin A on cell invasion and determine protein expression and localization in epithelial and stromal compartments by immunofluorescence. To identify the functional consequences of stromal-derived Activin A on angiogenesis, we performed endothelial tube formation assays.ResultsAnalysis of ESCC patient samples indicated that patients with high stromal Activin A expression had low epithelial ACVRIB, the Activin type I receptor. We found that overexpression of stromal-derived Activin A inhibited invasion of esophageal dysplastic squamous cells, ECdnT, and TE-2 ESCC cells, both positive for ACVRIB. This inhibition was accompanied by a decrease in expression of the extracellular matrix (ECM) protein fibronectin and podoplanin, which is often expressed at the leading edge during invasion. Endothelial tube formation was disrupted in the presence of conditioned media from fibroblasts overexpressing Activin A. Interestingly, ACVRIB-negative TE-11 cells did not show the prior observed effects in the context of Activin A overexpression, indicating a dependence on the presence of ACVRIB.ConclusionsWe describe the first observation of an inhibitory role for Activin A in ESCC progression that is dependent on the expression of ACVRIB.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2920-y) contains supplementary material, which is available to authorized users.

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“…Although ActA levels were reported to be increased in patients with breast cancer (40) and in some mouse tumor models (41), new data showed that ActA protein in lung adenocarcinoma tissue was significantly lower than in normal lung tissue (42) and ActA may inhibit proliferation of breast cancer cell lines (43,44). It is likely that ActA can activate autocrine and paracrine signaling affecting crosstalk between the epithelial compartment and the surrounding microenvironment (45) in a cell-type and context-dependent manner supporting or inhibiting tumor development (38). Without better understanding the controversial role of ActA in cancer, the use of ActA as a systemic pharmacological agent appears not suitable (39).…”

Section: Discussionmentioning

confidence: 99%

BAFF and APRIL from Activin A–Treated Dendritic Cells Upregulate the Antitumor Efficacy of Dendritic Cells In Vivo

Shurin

Keskinov

et al. 2016

Cancer Research

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The members of the TGF-β superfamily play a key role in regulating developmental and homeostasis programs by controlling differentiation, proliferation, polarization and survival of different cell types. Although the role of TGF-β1 in inflammation and immunity is well evident, the contribution of other TGF-β family cytokines in the modulation of the antitumor immune response remains less documented. Here we show that activin A triggers SMAD2 and ERK1/2 pathways in dendritic cells (DC) expressing type I and II activin receptors, and up-regulates production of the TNF-α family cytokines BAFF (TALL-1, TNFSF13B) and APRIL (TALL-2, TNFSF13A), which is blocked by SMAD2 and ERK1/2 inhibitors, respectively. BAFF and APRIL derived from activin A-treated DC up-regulate proliferation and survival of T cells expressing the corresponding receptors - BAFF-R and TACI. In vivo, activin A stimulated DC demonstrate a significantly increased ability to induce tumor-specific CTL and inhibit the growth of melanoma and lung carcinoma, which relays on DC-derived BAFF and APRIL since knockdown of the BAFF and APRIL gene expression in activin A-treated DC blocks augmentation of their antitumor potential. Though systemic administration of activin A, BAFF or APRIL for the therapeutic purposes is not likely due to the pluripotent effects on malignant and non-malignant cells, our data open a novel opportunity for improving the efficacy of DC vaccines. In fact, a significant augmentation of the antitumor activity of DC pre-treated with activin A and the proven role of DC-derived BAFF and APRIL in the induction of antitumor immunity in vivo support this direction.

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Activin A balance regulates epithelial invasiveness and tumorigenesis

Cited by 21 publications

References 58 publications

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

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

Esophageal squamous cell carcinoma invasion is inhibited by Activin A in ACVRIB-positive cells

BAFF and APRIL from Activin A–Treated Dendritic Cells Upregulate the Antitumor Efficacy of Dendritic Cells In Vivo

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