The myostatin/activin type II receptor (ActRII) pathway has been identified to be critical in regulating skeletal muscle size. Several other ligands, including GDF11 and the activins, signal through this pathway, suggesting that the ActRII receptors are major regulatory nodes in the regulation of muscle mass. We have developed a novel, human anti-ActRII antibody (bimagrumab, or BYM338) to prevent binding of ligands to the receptors and thus inhibit downstream signaling. BYM338 enhances differentiation of primary human skeletal myoblasts and counteracts the inhibition of differentiation induced by myostatin or activin A. BYM338 prevents myostatin- or activin A-induced atrophy through inhibition of Smad2/3 phosphorylation, thus sparing the myosin heavy chain from degradation. BYM338 dramatically increases skeletal muscle mass in mice, beyond sole inhibition of myostatin, detected by comparing the antibody with a myostatin inhibitor. A mouse version of the antibody induces enhanced muscle hypertrophy in myostatin mutant mice, further confirming a beneficial effect on muscle growth beyond myostatin inhibition alone through blockade of ActRII ligands. BYM338 protects muscles from glucocorticoid-induced atrophy and weakness via prevention of muscle and tetanic force losses. These data highlight the compelling therapeutic potential of BYM338 for the treatment of skeletal muscle atrophy and weakness in multiple settings.

An Antibody Blocking Activin Type II Receptors Induces Strong Skeletal Muscle Hypertrophy and Protects from Atrophy

Activin A (ActA)/follistatin (FST) signaling has been shown to be deregulated in different tumor types including lung adenocarcinoma (LADC). Here, we report that serum ActA protein levels are significantly elevated in LADC patients (n=64) as compared to controls (n=46, p=0.015). ActA levels also correlated with more advanced disease stage (p<0.0001) and T (p=0.0035) and N (p=0.0002) factors. M1 patients had significantly higher ActA levels than M0 patients (p<0.001). High serum ActA level was associated with poor overall survival (p<0.0001) and was confirmed as an independent prognostic factor (p=0.004). Serum FST levels were increased only in female LADC patients (vs. female controls, p=0.031). Two out of five LADC cell lines secreted biologically active ActA, while FST was produced in all of them. Transcripts of both type I and II ActA receptors were detected in all five LADC cell lines. In conclusion, our study does not only suggest that measuring blood ActA levels in LADC patients might improve the prediction of prognosis, but also indicates that this parameter might be a novel non-invasive biomarker for identifying LADC patients with organ metastases.

/pdf/high-circulating-activin-a-level-is-associated-with-tumor-2m3obweobi.pdf

High circulating activin A level is associated with tumor progression and predicts poor prognosis in lung adenocarcinoma

Background

The presence of regional lymph node metastasis has an important impact on clinical management and prognostication of patients with oral tongue squamous cell carcinoma (SCC). Approximately 30% to 50% of patients with oral tongue SCC have regional metastasis at diagnosis, but the limited sensibility of the current diagnostic methods used for neck staging does not allow detection of all cases, leaving a significant number of undiagnosed metastasis (occult lymph node metastasis). In this study, we evaluated whether clinicopathologic features and immunohistochemical detection of carcinoma-associated fibroblasts (CAFs) and activin A could be predictive markers for occult lymph node metastasis in oral tongue SCC.



Methods

One hundred ten patients with primary oral tongue SCC, who were classified with early stage tumor (stage I and II) and received surgical treatment with elective neck dissection, were enrolled in the study.



Results

Among all examined features, only high immunohistochemical expression of activin A was significantly associated with presence of occult lymph node metastasis (p = .006). Multivariate survival analysis using the Cox proportional hazard model showed that the expression of activin A was an independent marker of reduced overall survival with a 5-year survival of 89.7% for patients with low expression compared to 76.5% for those with high expression (hazard ratio [HR], 2.44; 95% confidence interval [CI], 1.55–3.85; p = .012).



Conclusion

Our results demonstrated that immunodetection of activin A can be useful for prognostication of oral tongue SCC, revealing patients with occult lymph node metastasis and lower overall survival. © 2014 Wiley Periodicals, Inc. Head Neck 37: 479–486, 2015

Activin A immunoexpression as predictor of occult lymph node metastasis and overall survival in oral tongue squamous cell carcinoma.

To identify biological markers related to the progression and prognosis of GBC. The expressions of pyruvate kinase isoenzyme type M2 (PKM2) and activin A receptor type IC (ACVR 1C) in 46 squamous cell/adenosquamous carcinomas (SC/ASC) and 80 adenocarcinomas (AC) were examined using immunohistochemistry. Positive PKM2 and negative ACVR 1C expressions were significantly associated with lymph node metastasis, invasion and TNM stage of SC/ASCs and ACs. Univariate Kaplan–Meier analysis showed that either elevated PKM2 or loss of ACVR 1C expression significantly correlated with shorter average survival times in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive PKM2 expression and loss of ACVR 1C expression were poor prognosis biomarkers in both SC/ASC and AC patients. Our study suggested that PKM2 overexpression is a marker of metastasis, invasion and poor prognosis of GBC. ACVR 1C is a tumor suppressor, and lowered ACVR 1C expression is an important marker for the metastasis, invasion, and prognosis of GBC.

PKM2 and ACVR 1C are prognostic markers for poor prognosis of gallbladder cancer.

// Miao Yin 1, 2 , Mira Tissari 1, 2 , Jenni Tamminen 1, 2 , Irene Ylivinkka 1 , Mikko Ronty 3 , Pernilla von Nandelstadh 4 , Kaisa Lehti 4, 5, 6 , Marko Hyytiainen 4 , Marjukka Myllarniemi 7 and Katri Koli 1, 2 1 Research Programs Unit, Translational Cancer Biology, University of Helsinki, Helsinki, Finland 2 Transplantation Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland 3 Department of Pathology, University of Helsinki and Fimlab Laboratories, Pathology, Tampere, Finland 4 Research Programs Unit, Genome Scale Biology, University of Helsinki, Helsinki, Finland 5 K. Albin Johansson Foundation, Finnish Cancer Institute, Helsinki, Finland 6 Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Solna, Sweden 7 Department of Pulmonary Medicine, University of Helsinki and Helsinki University Hospital, Heart and Lung Center, Helsinki, Finland Correspondence to: Katri Koli, email: katri.koli@helsinki.fi Keywords: gremlin, mesothelioma, invasion Received: June 07, 2017      Accepted: September 21, 2017      Published: October 06, 2017 ABSTRACT Malignant mesothelioma originates from mesothelial cells and is a cancer type that aggressively invades into the surrounding tissue, has poor prognosis and no effective treatment. Gremlin-1 is a cysteine knot protein that functions by inhibiting BMP-pathway activity during development. BMP-independent functions have also been described for gremlin-1. We have previously shown high gremlin-1 expression in mesothelioma tumor tissue. Here, we investigated the functions of gremlin-1 in mesothelioma cell migration and invasive growth. Gremlin-1 promoted mesothelioma cell sprouting and invasion into three dimensional collagen and Matrigel matrices. The expression level of gremlin-1 was linked to changes in the expression of SNAI2, integrins, matrix metalloproteinases (MMP) and TGF-β family signaling - all previously associated with a mesenchymal invasive phenotype. Small molecule inhibitors of MMPs completely blocked mesothelioma cell invasive growth. In addition, inhibitors of TGF-β receptors significantly reduced invasive growth. This was associated with reduced expression of MMP2 but not SNAI2, indicating that gremlin-1 has both TGF-β pathway dependent and independent mechanisms of action. Results of in vivo mesothelioma xenograft experiments indicated that gremlin-1 overexpressing tumors were more vascular and had a tendency to send metastases. This suggests that by inducing a mesenchymal invasive cell phenotype together with enhanced tumor vascularization, gremlin-1 drives mesothelioma invasion and metastasis. These data identify gremlin-1 as a potential therapeutic target in mesothelioma.

https://www.oncotarget.com/index.php?journal=oncotarget&page=article&op=download&path%5B%5D=21550&path%5B%5D=68463

Gremlin-1 is a key regulator of the invasive cell phenotype in mesothelioma.

Activins control the growth of several tumour types including thoracic malignancies. In the present study, we investigated their expression and function in malignant pleural mesothelioma (MPM). The expression of activins and activin receptors was analysed by quantitative PCR in a panel of MPM cell lines. Activin A expression was further analysed by immunohistochemistry in MPM tissue specimens (N=53). Subsequently, MPM cells were treated with activin A, activin receptor inhibitors or activin-targeting siRNA and the impact on cell viability, proliferation, migration and signalling was assessed. Concomitant expression of activin subunits and receptors was found in all cell lines, and activin A was overexpressed in most cell lines compared with non-malignant mesothelial cells. Similarly, immunohistochemistry demonstrated intense staining of tumour cells for activin A in a subset of patients. Treatment with activin A induced SMAD2 phosphorylation and stimulated clonogenic growth of mesothelioma cells. In contrast, treatment with kinase inhibitors of activin receptors (SB-431542, A-8301) inhibited MPM cell viability, clonogenicity and migration. Silencing of activin A expression by siRNA oligonucleotides further confirmed these results and led to reduced cyclin D1/3 expression. Our study suggests that activin A contributes to the malignant phenotype of MPM cells via regulation of cyclin D and may represent a valuable candidate for therapeutic interference.

/pdf/suppression-of-activin-a-signals-inhibits-growth-of-39nh72niud.pdf

Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells

Handle everyday research tasks with reliable, citation-backed results

Your personal Research Agent to handle research tasks with citation-backed results

Popular Tasks used by Researchers

How can I help with your research?

Meet SciSpace

Get more enhanced response by uploading the PDFs you want me to reference.

No relevant PDFs in your library

SciSpace is the AI research assistant for academics. Run systematic literature reviews on 280M+ papers, and write papers with cited sources. Trusted by 1M+ students, PhDs & researchers.

SciSpace | AI for Research

Analyze PDFs

Code & Manuscripts

Funding & Grants

Literature & Patents

Medical & Clinical Data

Systematic Review

Visualize & Present

Web & Data

Build a Google Scholar-like website for your research.

Build a website

Create charts and images for your research

Create a Chart

Write a paper for submission to a journal

Draft a manuscript

Patent Search

Design eye-catching scientific posters in minutes.

Scientific Poster Generation

Systematic Literature Review

One task is running at the moment. Your messages will be shown right after.

Drag and drop or click here to browse

Loved by <highlight>1 million+</highlight> researchers

Extract a list of specific topics and their sources from unstructured text

Topics

Compare and analyze relevant papers that matches with your search

Papers

Get insights from PDFs and bookmarked papers from your library

My library

Recent searches

Try searching for:

Catch AI-generated content in scholarly and non-scholarly content

{ai} Detector

Ai Writer

Get PDF Summaries, highlighted text explanations 

Chat with PDF

Effortlessly create in-text citations and bibliographies in APA and 2,500 other formats

Citation generator

Get explanations, summaries, and answers on academic papers

Ease up your research workflow with {scispace}'s cohort of exciting AI tools

Elevate your academic writing skills and convey your ideas the way you want

Paraphraser

Explore our range of reading and writing tools

Your file is being prepared and should be ready in a few minutes. If it's a large file, it might take a bit longer. You can close this window, and we'll email you the file when it's done.

You have reached a maximum limit of <strong>{limit}</strong> columns in the table. Remove at least <strong>1</strong> column to add or create another one.

A Bedeir

Author Tools

Chat about Author

Papers

Suppression of activin A signals inhibits growth of malignant pleural mesothelioma cells