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BMC Cancer Sep 2022Adenocarcinomas of the esophagus (AEG) and stomach (AS) are among the most common cancers worldwide. Novel markers for risk stratification and guiding treatment are...
PURPOSE
Adenocarcinomas of the esophagus (AEG) and stomach (AS) are among the most common cancers worldwide. Novel markers for risk stratification and guiding treatment are strongly needed. Activin is a multi-functional cytokine with context specific pro- and anti-tumorigenic effects. We aimed to investigate the prognostic role of activin tumor protein expression in AEG/ASs.
METHODS
Tissue from a retrospective cohort of 277 patients with AEG/AS treated primarily by surgery at the Charité - Universitätsmedizin Berlin was collected and analyzed by immunohistochemistry using a specific antibody to the activin homodimer inhibin beta A. Additionally, we evaluated T-cell infiltration and PD1 expression as well as expression of PD-L1 by immunohistochemistry as possible confounding factors. Clinico-pathologic data were collected and correlated with activin protein expression.
RESULTS
Out of 277 tumor samples, 72 (26.0%) exhibited high activin subunit inhibin beta A protein expression. Higher expression was correlated with lower Union for International Cancer Control (UICC) stage and longer overall survival. Interestingly, activin subunit expression correlated with CD4 T-cell infiltration, and the correlation with higher overall survival was exclusively seen in tumors with high CD4 T-cell infiltration, pointing towards a role of activin in the tumor immune response in AEG/ASs.
CONCLUSION
In our cohort of AEG/AS, higher activin subunit levels were correlated with longer overall survival, an effect exclusively seen in tumors with high CD4 cell infiltration. Further mechanistic research is warranted discerning the exact effect of this context specific cytokine.
Topics: Humans; Activins; Adenocarcinoma; Cytokines; Esophageal Neoplasms; Inhibin-beta Subunits; Inhibins; Prognosis; Retrospective Studies; Stomach
PubMed: 36064338
DOI: 10.1186/s12885-022-10016-5 -
Andrology May 2017Activin A is an important regulator of testicular and epididymal development and function, as well as inflammation and immunity. In the adult murine reproductive tract,...
Activin A is an important regulator of testicular and epididymal development and function, as well as inflammation and immunity. In the adult murine reproductive tract, activin A mRNA (Inhba) expression levels are highest in the caput epididymis and decrease progressively towards the distal vas deferens. The activin-binding protein, follistatin (FST), shows the opposite expression pattern, with exceptionally high levels of the Fst288 mRNA variant in the vas deferens. This unique pattern of expression suggests that activin A and follistatin, in particular FST288, play region-specific roles in regulating the epididymis and vas deferens. The cellular distribution of activin and follistatin and structural organization of the male reproductive tract was examined in wild-type and transgenic (TghFST315) mice lacking FST288. Compared to wild-type littermates, TghFST315 mice showed a 50% reduction in serum follistatin and a significant elevation of both activin A and B. Testicular, epididymal and seminal vesicle weights were reduced, but intra-testicular testosterone was normal. A decrease in the epididymal duct diameter in the corpus and thickening of the peritubular smooth muscle in the cauda, together with increased coiling of the proximal vas deferens, were observed in TghFST315 mice. No immune cell infiltrates were detected. Immunohistochemistry indicated that epithelial cells are the main source of activins and follistatin in the epididymis and vas deferens. Activin A, but not activin B, was also localized to sperm heads in the lumen of the epididymis and vas deferens. Expression of Inhba and another immunoregulatory gene, indoleamine-2,3-dioxygenase (Ido-1), was increased approximately twofold in the TghFST315 caput epididymis, but several other genes associated with immunoregulation, inflammation or fibrosis were unaffected. Our novel data indicate that disruption of follistatin expression has significant effects on the testis and epididymis, and suggest an association between activin A and indoleamine-2,3-dioxygenase in the caput epididymis, with implications for the epididymal immunoenvironment.
Topics: Activins; Animals; Follistatin; Genitalia, Male; Humans; Immunohistochemistry; In Situ Nick-End Labeling; Male; Mice; Mice, Transgenic; Polymerase Chain Reaction
PubMed: 28235253
DOI: 10.1111/andr.12337 -
BMC Biology Feb 2022Activins and bone morphogenetic proteins (BMPs) play critical, sometimes opposing roles, in multiple physiological and pathological processes and diseases. They signal...
BACKGROUND
Activins and bone morphogenetic proteins (BMPs) play critical, sometimes opposing roles, in multiple physiological and pathological processes and diseases. They signal to distinct Smad branches; activins signal mainly to Smad2/3, while BMPs activate mainly Smad1/5/8. This gives rise to the possibility that competition between the different type I receptors through which activin and BMP signal for common type II receptors can provide a mechanism for fine-tuning the cellular response to activin/BMP stimuli. Among the transforming growth factor-β superfamily type II receptors, ACVR2A/B are highly promiscuous, due to their ability to interact with different type I receptors (e.g., ALK4 vs. ALK2/3/6) and with their respective ligands [activin A (ActA) vs. BMP9/2]. However, studies on complex formation between these full-length receptors situated at the plasma membrane, and especially on the potential competition between the different activin and BMP type I receptors for a common activin type II receptor, were lacking.
RESULTS
We employed a combination of IgG-mediated patching-immobilization of several type I receptors in the absence or presence of ligands with fluorescence recovery after photobleaching (FRAP) measurements on the lateral diffusion of an activin type II receptor, ACVR2A, to demonstrate the principle of competition between type I receptors for ACVR2. Our results show that ACVR2A can form stable heteromeric complexes with ALK4 (an activin type I receptor), as well as with several BMP type I receptors (ALK2/3/6). Of note, ALK4 and the BMP type I receptors competed for binding ACVR2A. To assess the implications of this competition for signaling output, we first validated that in our cell model system (U2OS cells), ACVR2/ALK4 transduce ActA signaling to Smad2/3, while BMP9 signaling to Smad1/5/8 employ ACVR2/ALK2 or ACVR2/ALK3. By combining ligand stimulation with overexpression of a competing type I receptor, we showed that differential complex formation of distinct type I receptors with a common type II receptor balances the signaling to the two Smad branches.
CONCLUSIONS
Different type I receptors that signal to distinct Smad pathways (Smad2/3 vs. Smad1/5/8) compete for binding to common activin type II receptors. This provides a novel mechanism to balance signaling between Smad2/3 and Smad1/5/8.
Topics: Activins; Bone Morphogenetic Protein Receptors; Bone Morphogenetic Protein Receptors, Type I; Bone Morphogenetic Proteins; Ligands; Smad Proteins; Transforming Growth Factor beta
PubMed: 35177083
DOI: 10.1186/s12915-022-01252-z -
Biology Open Nov 2021Bovine embryonic stem cells (ESC) have features associated with the primed pluripotent state including low expression of one of the core pluripotency transcription...
Bovine embryonic stem cells (ESC) have features associated with the primed pluripotent state including low expression of one of the core pluripotency transcription factors, NANOG. It has been reported that NANOG expression can be upregulated in porcine ESC by treatment with activin A and the WNT agonist CHIR99021. Accordingly, it was tested whether expression of NANOG and another pluripotency factor SOX2 could be stimulated by activin A and the WNT agonist CHIR99021. Immunoreactive NANOG and SOX2 were analyzed for bovine ESC lines derived under conditions in which activin A and CHIR99021 were added singly or in combination. Activin A enhanced NANOG expression but also reduced SOX2 expression. CHIR99021 depressed expression of both NANOG and SOX2. In a second experiment, activin A enhanced blastocyst development while CHIR99021 treatment impaired blastocyst formation and reduced number of blastomeres. Activin A treatment decreased blastomeres in the blastocyst that were positive for either NANOG or SOX2 but increased those that were CDX2+ and that were GATA6+ outside the inner cell mass. CHIR99021 reduced SOX2+ and NANOG+ blastomeres without affecting the number or percent of blastomeres that were CDX2+ and GATA6+. Results indicate activation of activin A signaling stimulates NANOG expression during self-renewal of bovine ESC but suppresses cells expressing pluripotency markers in the blastocyst and increases cells expressing CDX2. Actions of activin A to promote blastocyst development may involve its role in promoting trophectoderm formation. Furthermore, results demonstrate the negative role of canonical WNT signaling in cattle for pluripotency marker expression in ESC and in formation of the inner cell mass and epiblast during embryonic development. This article has an associated First Person interview with the first author of the paper.
Topics: Activins; Animals; Blastocyst; Cattle; Cell Line; Embryonic Development; Embryonic Stem Cells; Germ Layers; Nanog Homeobox Protein; Pyridines; Pyrimidines; SOXB1 Transcription Factors; Swine; Wnt Proteins; Wnt Signaling Pathway
PubMed: 34643229
DOI: 10.1242/bio.058669 -
ELife Sep 2013Researchers have identified two genes-follistatin and activin-as having an important role in the ability of certain flatworms to identify wounds that require the...
Researchers have identified two genes-follistatin and activin-as having an important role in the ability of certain flatworms to identify wounds that require the production of new tissue.
Topics: Activins; Animals; Follistatin; Platyhelminths; Regeneration
PubMed: 24040510
DOI: 10.7554/eLife.00533 -
Biomolecules Jan 2024Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodic yet cumulative heterotopic ossification (HO) of skeletal muscles,... (Review)
Review
Fibrodysplasia ossificans progressiva (FOP) is a rare genetic disorder characterized by episodic yet cumulative heterotopic ossification (HO) of skeletal muscles, tendons, ligaments, and fascia. FOP arises from missense mutations in Activin Receptor type I (ACVR1), a type I bone morphogenetic protein (BMP) receptor. Although initial findings implicated constitutive activity of FOP-variant ACVR1 (ACVR1) and/or hyperactivation by BMPs, it was later shown that HO in FOP requires activation of ACVR1 by Activin A. Inhibition of Activin A completely prevents HO in FOP mice, indicating that Activin A is an obligate driver of HO in FOP, and excluding a key role for BMPs in this process. This discovery led to the clinical development of garetosmab, an investigational antibody that blocks Activin A. In a phase 2 trial, garetosmab inhibited new heterotopic bone lesion formation in FOP patients. In contrast, antibodies to ACVR1 activate ACVR1 and promote HO in FOP mice. Beyond their potential clinical relevance, these findings have enhanced our understanding of FOP's pathophysiology, leading to the identification of fibroadipogenic progenitors as the cells that form HO, and the discovery of non-signaling complexes between Activin A and wild type ACVR1 and their role in tempering HO, and are also starting to inform biological processes beyond FOP.
Topics: Humans; Animals; Mice; Myositis Ossificans; Activins; Antibodies, Monoclonal; Bone Morphogenetic Protein Receptors, Type I
PubMed: 38254701
DOI: 10.3390/biom14010101 -
Journal For Immunotherapy of Cancer May 2022Activin-A, a transforming growth factor β family member, is secreted by many cancer types and is often associated with poor disease prognosis. Previous studies have...
BACKGROUND
Activin-A, a transforming growth factor β family member, is secreted by many cancer types and is often associated with poor disease prognosis. Previous studies have shown that Activin-A expression can promote cancer progression and reduce the intratumoral frequency of cytotoxic T cells. However, the underlying mechanisms and the significance of Activin-A expression for cancer therapies are unclear.
METHODS
We analyzed the expression of the Activin-A encoding gene in melanoma patients and the influence of its gain- or loss-of-function on the immune infiltration and growth of -driven YUMM3.3 and iBIP2 mouse melanoma grafts and in B16 models. Using antibody depletion strategies, we investigated the dependence of Activin-A tumor-promoting effect on different immune cells. Immune-regulatory effects of Activin-A were further characterized in vitro and by an adoptive transfer of T cells. Finally, we assessed expression in melanoma patients who received immune checkpoint therapy and tested whether it impairs the response in preclinical models.
RESULTS
We show that Activin-A secretion by melanoma cells inhibits adaptive antitumor immunity irrespective of status by inhibiting CD8 T cell infiltration indirectly and even independently of CD4 T cells, at least in part by attenuating the production of CXCL9/10 by myeloid cells. In addition, we show that Activin-A/ expression correlates with anti-PD1 therapy resistance in melanoma patients and impairs the response to dual anti-cytotoxic T-Lymphocyte associated protein 4/anti-PD1 treatment in preclinical models.
CONCLUSIONS
Our findings suggest that strategies interfering with Activin-A induced immune-regulation offer new therapeutic opportunities to overcome CD8 T cell exclusion and immunotherapy resistance.
Topics: Activins; Animals; CD8-Positive T-Lymphocytes; Humans; Immunity, Cellular; Inhibin-beta Subunits; Melanoma; Mice; Proto-Oncogene Proteins B-raf
PubMed: 35580932
DOI: 10.1136/jitc-2022-004533 -
Bone Apr 2018Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder that presents at birth with only minor patterning defects, but manifests its debilitating... (Review)
Review
Fibrodysplasia Ossificans Progressiva (FOP) is a rare genetic disorder that presents at birth with only minor patterning defects, but manifests its debilitating pathology early in life with episodic, yet progressive and cumulative, heterotopic ossification (HO) of ligaments, tendons, and a subset of major skeletal muscles. The resulting HO lesions are endochondral in nature, and appear to be linked to inflammatory stimuli arising in association with known injuries, or from inflammation linked to normal tissue repair. FOP is caused by gain-of-function mutations in ACVR1, which encodes a type I BMP receptor. Initial studies on the pathogenic mechanism of FOP-causing mutations in ACVR1 focused on the enhanced function of this receptor in response to certain BMP ligands, or independently of ligands, but did not directly address the fact that HO in FOP is episodic and inflammation-driven. Recently, we and others demonstrated that Activin A is an obligate factor for the initiation of HO in FOP, signaling aberrantly via mutant ACVR1 to transduce osteogenic signals and trigger heterotopic bone formation (Hatsell et al., 2015; Hino et al., 2015). Subsequently, we identified distinct tissue-resident mesenchymal progenitor cells residing in muscles and tendons that recognize Activin A as a pro-osteogenic signal (solely in the context of FOP-causing mutant ACVR1), and give rise to the cartilaginous anlagen that form heterotopic bone (Dey et al., 2016). During the course of these studies, we also found that the activity of FOP-causing ACVR1 mutations does not by itself explain the triggered or inflammatory nature of HO in FOP, suggesting the importance of other, inflammation-introduced, factors or processes. This review presents a synthesis of these findings with a focus on the role of Activin A and inflammation in HO, and lays out perspectives for future research.
Topics: Activin Receptors, Type I; Activins; Humans; Mutation; Myositis Ossificans; Ossification, Heterotopic; Signal Transduction; Stem Cells
PubMed: 28629737
DOI: 10.1016/j.bone.2017.06.011 -
Developmental Biology Oct 2001Development of glandular organs such as the kidney, lung, and prostate involves the process of branching morphogenesis. The developing organ begins as an epithelial bud... (Review)
Review
Development of glandular organs such as the kidney, lung, and prostate involves the process of branching morphogenesis. The developing organ begins as an epithelial bud that invades the surrounding mesenchyme, projecting dividing epithelial cords or tubes away from the site of initiation. This is a tightly regulated process that requires complex epithelial-mesenchymal interactions, resulting in a three-dimensional treelike structure. We propose that activins are key growth and differentiation factors during this process. The purpose of this review is to examine the direct, indirect, and correlative lines of evidence to support this hypothesis. The expression of activins is reviewed together with the effect of activins and follistatins in the development of branched organs. We demonstrate that activin has both negative and positive effects on cell growth during branching morphogenesis, highlighting the complex nature of activin in the regulation of proliferation and differentiation. We propose potential mechanisms for the way in which activins modify branching and address the issue of whether activin is a regulator of branching morphogenesis.
Topics: Activins; Animals; Breast; Cell Differentiation; Cell Division; Epithelium; Female; Gene Expression Regulation, Developmental; Humans; Inhibins; Kidney; Lung; Male; Mesoderm; Mice; Models, Biological; Pancreas; Prostate; Salivary Glands; Signal Transduction; Transforming Growth Factor beta
PubMed: 11783989
DOI: 10.1006/dbio.2001.0399 -
Cellular & Molecular Biology Letters Jan 2023TGFβ1 is a major profibrotic mediator in chronic kidney disease (CKD). Its direct inhibition, however, is limited by adverse effects. Inhibition of activins, also...
BACKGROUND
TGFβ1 is a major profibrotic mediator in chronic kidney disease (CKD). Its direct inhibition, however, is limited by adverse effects. Inhibition of activins, also members of the TGFβ superfamily, blocks TGFβ1 profibrotic effects, but the mechanism underlying this and the specific activin(s) involved are unknown.
METHODS
Cells were treated with TGFβ1 or activins A/B. Activins were inhibited generally with follistatin, or specifically with neutralizing antibodies or type I receptor downregulation. Cytokine levels, signaling and profibrotic responses were assessed with ELISA, immunofluorescence, immunoblotting and promoter luciferase reporters. Wild-type or TGFβ1-overexpressing mice with unilateral ureteral obstruction (UUO) were treated with an activin A neutralizing antibody.
RESULTS
In primary mesangial cells, TGFβ1 induces secretion primarily of activin A, which enables longer-term profibrotic effects by enhancing Smad3 phosphorylation and transcriptional activity. This results from lack of cell refractoriness to activin A, unlike that for TGFβ1, and promotion of TGFβ type II receptor expression. Activin A also supports transcription through regulating non-canonical MRTF-A activation. TGFβ1 additionally induces secretion of activin A, but not B, from tubular cells, and activin A neutralization prevents the TGFβ1 profibrotic response in renal fibroblasts. Fibrosis induced by UUO is inhibited by activin A neutralization in wild-type mice. Worsened fibrosis in TGFβ1-overexpressing mice is associated with increased renal activin A expression and is inhibited to wild-type levels with activin A neutralization.
CONCLUSIONS
Activin A facilitates TGFβ1 profibrotic effects through regulation of both canonical (Smad3) and non-canonical (MRTF-A) signaling, suggesting it may be a novel therapeutic target for preventing fibrosis in CKD.
Topics: Mice; Animals; Activins; Renal Insufficiency, Chronic; Fibrosis; Transforming Growth Factor beta
PubMed: 36717814
DOI: 10.1186/s11658-023-00424-1