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Cancers Dec 2022Current prognostic and diagnostic tests for prostate cancer are not able to accurately distinguish between aggressive and latent cancer. Members of the transforming...
Current prognostic and diagnostic tests for prostate cancer are not able to accurately distinguish between aggressive and latent cancer. Members of the transforming growth factor-β (TGFB) family are known to be important in regulating prostate cell growth and some have been shown to be dysregulated in prostate cancer. Therefore, the aims of this study were to examine expression of TGFB family members in primary prostate tumour tissue and the phenotypic effect of activins on prostate cell growth. Tissue cores of prostate adenocarcinoma and normal prostate were immuno-stained and protein expression was compared between samples with different Gleason grades. The effect of exogenous treatment with, or overexpression of, activins on prostate cell line growth and migration was examined. Activin B expression was increased in cores containing higher Gleason patterns and overexpression of activin B inhibited growth of PNT1A cells but increased growth and migration of the metastatic PC3 cells compared to empty vector controls. In contrast, activin C expression decreased in higher Gleason grades and overexpression increased growth of PNT1A cells and decreased growth of PC3 cells. In conclusion, increased activin B and decreased activin C expression is associated with increasing prostate tumor grade and therefore have potential as prognostic markers of aggressive prostate cancer.
PubMed: 36612143
DOI: 10.3390/cancers15010147 -
Metabolism: Clinical and Experimental Nov 2023The role of metabolic/inflammatory hormonal systems in metabolic dysfunction associated steatotic liver disease (MASLD) remains to be fully elucidated. (Observational Study)
Observational Study
BACKGROUND
The role of metabolic/inflammatory hormonal systems in metabolic dysfunction associated steatotic liver disease (MASLD) remains to be fully elucidated.
PURPOSE
To report the levels of the novel total and H-specific growth differentiation factor-15 (GDF-15) and other established hormonal systems and to describe hormonal patterns in controls and patients with MASLD and its stages.
METHODS
This is a multicenter study from two Gastroenterology-Hepatology Departments (Greece and Australia) and one Bariatric-Metabolic Surgery Department (Italy). Overall, n = 455 serum samples of patients with biopsy-proven MASLD (n = 374) and Controls (n = 81) were recruited.
RESULTS
We report for the first time that total and H-specific GDF-15 levels are higher in MASLD, at-risk metabolic dysfunction associated steatohepatitis (MASH), and severe fibrosis than in Controls. In addition, follistatin-like-3 (FSTL-3), free insulin-like growth factor-1 (IGF-1), leptin, and insulin levels were higher in MASLD patients than in Controls, while adiponectin levels were lower in MASLD subjects than in Controls. Activin-A, follistatin (FST), FSTL-3, and insulin levels significantly increased in severe fibrosis compared to no/mild fibrosis, while free IGF-1 decreased. In addition, adiponectin levels were lower in subjects without fibrosis vs. any fibrosis. Moreover, GDF-15 presented a strong positive association for the likelihood of having MASLD and at-risk MASH, while in adjusted analyses, FST and adiponectin showed inverse associations. Two different patterns of at-risk MASH were revealed through unsupervised analysis (total variation explained=54%). The most frequent pattern met in our sample (34.3%) was characterized by higher levels of total and H-specific GDF-15, follistatins, and activins, as well as low adiponectin levels. The second pattern revealed was characterized by high levels of free IGF-1, insulin, and leptin, with low levels of activin-A and adiponectin. Similar patterns were also generated in the case of overall MASLD.
CONCLUSIONS
Total and H-specific GDF-15 levels increase as MASLD severity progresses. FSTL-3, free IGF-1, leptin, and insulin are also higher, whereas adiponectin and activin-A levels are lower in the MASLD group than in Controls. Hormonal systems, including GDF-15, may not only be involved in the pathophysiology but could also prove useful for the diagnostic workup of MASLD and its stages and may potentially be of therapeutic value.
Topics: Humans; Leptin; Insulin-Like Growth Factor I; Non-alcoholic Fatty Liver Disease; Follistatin; Growth Differentiation Factor 15; Adiponectin; Insulin; Activins; Fibrosis; Biopsy
PubMed: 37757973
DOI: 10.1016/j.metabol.2023.155694 -
The Journal of Clinical Endocrinology... May 2020Circulating follistatin (Fst) binds activin A and thereby regulates biological functions such as muscle growth and β-cell survival. However, Fst and activin A's...
BACKGROUND
Circulating follistatin (Fst) binds activin A and thereby regulates biological functions such as muscle growth and β-cell survival. However, Fst and activin A's implication in metabolic regulation is unclear.
OBJECTIVE
To investigate circulating Fst and activin A in obesity and type 2 diabetes (T2D) and determine their association with metabolic parameters. Further, to examine regulation of Fst and activin A by insulin and the influence of obesity and T2D hereon.
METHODS
Plasma Fst and activin A levels were analyzed in obese T2D patients (N = 10) closely matched to glucose-tolerant lean (N = 12) and obese (N = 10) individuals in the fasted state and following a 4-h hyperinsulinemic-euglycemic clamp (40 mU·m-2·min-1) combined with indirect calorimetry.
RESULTS
Circulating Fst was ~30% higher in patients with T2D compared with both lean and obese nondiabetic individuals (P < .001), while plasma activin A was unaltered. In the total cohort, fasting plasma Fst correlated positively with fasting plasma glucose, serum insulin and C-peptide levels, homeostasis model assessment of insulin resistance, and hepatic and adipose tissue insulin resistance after adjusting for age, gender and group (all r > 0.47; P < .05). However, in the individual groups these correlations only achieved significance in patients with T2D (not plasma glucose). Acute hyperinsulinemia at euglycemia reduced circulating Fst by ~30% (P < .001) and this response was intact in patients with T2D. Insulin inhibited FST expression in human hepatocytes after 2 h and even further after 48 h.
CONCLUSIONS
Elevated circulating Fst, but not activin A, is strongly associated with measures of insulin resistance in patients with T2D. However, the ability of insulin to suppress circulating Fst is preserved in T2D.
Topics: Activins; Blood Glucose; C-Peptide; Case-Control Studies; Diabetes Mellitus, Type 2; Fasting; Female; Follistatin; Hep G2 Cells; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Obesity
PubMed: 32112102
DOI: 10.1210/clinem/dgaa090 -
Nature Communications Aug 2022Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals...
Body fat distribution is a major, heritable risk factor for cardiometabolic disease, independent of overall adiposity. Using exome-sequencing in 618,375 individuals (including 160,058 non-Europeans) from the UK, Sweden and Mexico, we identify 16 genes associated with fat distribution at exome-wide significance. We show 6-fold larger effect for fat-distribution associated rare coding variants compared with fine-mapped common alleles, enrichment for genes expressed in adipose tissue and causal genes for partial lipodystrophies, and evidence of sex-dimorphism. We describe an association with favorable fat distribution (p = 1.8 × 10), favorable metabolic profile and protection from type 2 diabetes (~28% lower odds; p = 0.004) for heterozygous protein-truncating mutations in INHBE, which encodes a circulating growth factor of the activin family, highly and specifically expressed in hepatocytes. Our results suggest that inhibin βE is a liver-expressed negative regulator of adipose storage whose blockade may be beneficial in fat distribution-associated metabolic disease.
Topics: Adipose Tissue; Adiposity; Diabetes Mellitus, Type 2; Exome; Humans; Inhibin-beta Subunits; Mutation
PubMed: 35999217
DOI: 10.1038/s41467-022-32398-7 -
Hepatology (Baltimore, Md.) Feb 2022In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately...
BACKGROUND AND AIMS
In patients with acute liver failure (ALF) who suffer from massive hepatocyte loss, liver progenitor cells (LPCs) take over key hepatocyte functions, which ultimately determines survival. This study investigated how the expression of hepatocyte nuclear factor 4α (HNF4α), its regulators, and targets in LPCs determines clinical outcome of patients with ALF.
APPROACH AND RESULTS
Clinicopathological associations were scrutinized in 19 patients with ALF (9 recovered and 10 receiving liver transplantation). Regulatory mechanisms between follistatin, activin, HNF4α, and coagulation factor expression in LPC were investigated in vitro and in metronidazole-treated zebrafish. A prospective clinical study followed up 186 patients with cirrhosis for 80 months to observe the relevance of follistatin levels in prevalence and mortality of acute-on-chronic liver failure. Recovered patients with ALF robustly express HNF4α in either LPCs or remaining hepatocytes. As in hepatocytes, HNF4α controls the expression of coagulation factors by binding to their promoters in LPC. HNF4α expression in LPCs requires the forkhead box protein H1-Sma and Mad homolog 2/3/4 transcription factor complex, which is promoted by the TGF-β superfamily member activin. Activin signaling in LPCs is negatively regulated by follistatin, a hepatocyte-derived hormone controlled by insulin and glucagon. In contrast to patients requiring liver transplantation, recovered patients demonstrate a normal activin/follistatin ratio, robust abundance of the activin effectors phosphorylated Sma and Mad homolog 2 and HNF4α in LPCs, leading to significantly improved coagulation function. A follow-up study indicated that serum follistatin levels could predict the incidence and mortality of acute-on-chronic liver failure.
CONCLUSIONS
These results highlight a crucial role of the follistatin-controlled activin-HNF4α-coagulation axis in determining the clinical outcome of massive hepatocyte loss-induced ALF. The effects of insulin and glucagon on follistatin suggest a key role of the systemic metabolic state in ALF.
Topics: Activins; Acute-On-Chronic Liver Failure; Adult; Aged; Animals; Blood Coagulation; Cell Line; Factor V; Female; Follistatin; Follow-Up Studies; Forkhead Transcription Factors; Gene Expression; Hepatocyte Nuclear Factor 4; Hepatocytes; Humans; Liver Failure, Acute; Liver Regeneration; Liver Transplantation; Male; Metronidazole; Mice; Middle Aged; Prognosis; Promoter Regions, Genetic; Prospective Studies; Prothrombin; Signal Transduction; Smad2 Protein; Smad3 Protein; Smad4 Protein; Stem Cells; Transforming Growth Factor beta1; Zebrafish
PubMed: 34435364
DOI: 10.1002/hep.32119 -
ELife Dec 2023Insufficient bone fracture repair represents a major clinical and societal burden and novel strategies are needed to address it. Our data reveal that the transforming...
Insufficient bone fracture repair represents a major clinical and societal burden and novel strategies are needed to address it. Our data reveal that the transforming growth factor-β superfamily member Activin A became very abundant during mouse and human bone fracture healing but was minimally detectable in intact bones. Single-cell RNA-sequencing revealed that the Activin A-encoding gene was highly expressed in a unique, highly proliferative progenitor cell (PPC) population with a myofibroblast character that quickly emerged after fracture and represented the center of a developmental trajectory bifurcation producing cartilage and bone cells within callus. Systemic administration of neutralizing Activin A antibody inhibited bone healing. In contrast, a single recombinant Activin A implantation at fracture site in young and aged mice boosted: PPC numbers; phosphorylated SMAD2 signaling levels; and bone repair and mechanical properties in endochondral and intramembranous healing models. Activin A directly stimulated myofibroblastic differentiation, chondrogenesis and osteogenesis in periosteal mesenchymal progenitor culture. Our data identify a distinct population of Activin A-expressing PPCs central to fracture healing and establish Activin A as a potential new therapeutic tool.
Topics: Mice; Humans; Animals; Fracture Healing; Bony Callus; Osteogenesis; Stem Cells; Cell Differentiation; Activins
PubMed: 38079220
DOI: 10.7554/eLife.89822 -
Journal of Cachexia, Sarcopenia and... Aug 2022Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma (PDAC). The reproductive hormone and cytokine Activin is a mediator of...
BACKGROUND
Cachexia is frequent, deadly, and untreatable for patients with pancreatic ductal adenocarcinoma (PDAC). The reproductive hormone and cytokine Activin is a mediator of PDAC cachexia, and Activin receptor targeting was clinically tested for cancer cachexia therapy. However, sex-specific manifestations and mechanisms are poorly understood, constraining development of effective treatments.
METHODS
Cachexia phenotypes, muscle gene/protein expression, and effects of the Activin blocker ACVR2B/Fc were assessed in LSL-Kras , LSL-Trp53 , and Pdx-1-Cre (KPC) mice with autochthonic PDAC. Effects of PDAC and sex hormones were modelled by treating C2C12 myotubes with KPC-cell conditioned medium (CM) and estradiol. Muscle gene expression by RNAseq and change in muscle from serial CT scans were measured in patients with PDAC.
RESULTS
Despite equivalent tumour latency (median 17 weeks) and mortality (24.5 weeks), male KPC mice showed earlier and more severe cachexia than females. In early PDAC, male gastrocnemius, quadriceps, and tibialis anterior muscles were reduced (-21.7%, -18.9%, and -20.8%, respectively, all P < 0.001), with only gastrocnemius reduced in females (-16%, P < 0.01). Sex differences disappeared in late PDAC. Plasma Activin A was similarly elevated between sexes throughout, while oestrogen and testosterone levels suggested a virilizing effect of PDAC in females. Estradiol partially protected myotubes from KPC-CM induced atrophy and promoted expression of the potential Activin inhibitor Fstl1. Early-stage female mice showed greater muscle expression of Activin inhibitors Fst, Fstl1, and Fstl3; this sex difference disappeared by late-stage PDAC. ACVR2B/Fc initiated in early PDAC preserved muscle and fat only in male KPC mice, with increases of 41.2%, 52.6%, 39.3%, and 348.8%, respectively, in gastrocnemius, quadriceps, tibialis, and fat pad weights vs. vehicle controls, without effect on tumour. No protection was observed in females. At protein and RNA levels, pro-atrophy pathways were induced more strongly in early-stage males, with sex differences less evident in late-stage disease. As with mass, ACVR2B/Fc blunted atrophy-associated pathways only in males. In patients with resectable PDAC, muscle expression of Activin inhibitors FSTL1, FSLT3, and WFIKKN2/GASP2 were higher in women than men. Overall, among 124 patients on first-line gemcitabine/nab-paclitaxel for PDAC, only men displayed muscle loss (P < 0.001); average muscle wasting in men was greater (-6.63 ± 10.70% vs. -1.62 ± 12.00% mean ± SD, P = 0.038) and more rapid (-0.0098 ± 0.0742%/day vs. -0.0466 ± 0.1066%/day, P = 0.017) than in women.
CONCLUSIONS
Pancreatic ductal adenocarcinoma cachexia displays sex-specific phenotypes in mice and humans, with Activin a preferential driver of muscle wasting in males. Sex is a major modulator of cachexia mechanisms. Consideration of sexual dimorphism is essential for discovery and development of effective treatments.
Topics: Activins; Adenocarcinoma; Animals; Cachexia; Carcinoma, Pancreatic Ductal; Estradiol; Female; Follistatin-Related Proteins; Humans; Male; Mice; Muscle, Skeletal; Muscular Atrophy; Pancreatic Neoplasms; Phenotype; Sex Factors
PubMed: 35510530
DOI: 10.1002/jcsm.12998 -
American Journal of Physiology. Cell... Feb 2023Activins and inhibins are unique members of the transforming growth factor-β (TGFβ) family of growth factors, with the ability to exert autocrine, endocrine, and... (Review)
Review
Activins and inhibins are unique members of the transforming growth factor-β (TGFβ) family of growth factors, with the ability to exert autocrine, endocrine, and paracrine effects in a wide range of complex physiologic and pathologic processes. Although first isolated within the pituitary, emerging evidence suggests broader influence beyond reproductive development and function. Known roles of activin and inhibin in angiogenesis and immunity along with correlations between gene expression and cancer prognosis suggest potential roles in tumorigenesis. Here, we present a review of the current understanding of the biological role of activins and inhibins as it relates to ovarian cancers, summarizing the underlying signaling mechanisms and physiologic influence, followed by detailing their roles in cancer progression, diagnosis, and treatment.
Topics: Humans; Female; Inhibins; Activins; Ovarian Neoplasms; Signal Transduction; Endocrine System
PubMed: 36622068
DOI: 10.1152/ajpcell.00178.2022 -
Expert Opinion on Therapeutic Targets Oct 2020Activin A is involved in the regulation of a surprisingly broad number of processes that are relevant for cancer development and treatment; it is implicated in cell... (Review)
Review
INTRODUCTION
Activin A is involved in the regulation of a surprisingly broad number of processes that are relevant for cancer development and treatment; it is implicated in cell autonomous functions and multiple regulatory functions in the tumor microenvironment.
AREAS COVERED
This article summarizes the current knowledge about activin A in cell growth and death, migration and metastasis, angiogenesis, stemness and drug resistance, regulation of antitumor immunity, and cancer cachexia. We explore the role of activin A as a biomarker and discuss strategies for using it as target for cancer therapy. Literature retrieved from Medline until 25 June 2020 was considered.
EXPERT OPINION
While many functions of activin A were investigated in preclinical models, there is currently limited experience from clinical trials. Activin A has growth- and migration-promoting effects, contributes to immune evasion and cachexia and is associated with shorter survival in several cancer types. Targeting activin A could offer the chance to simultaneously limit tumor growth and spreading, improve drug response, boost antitumor immune responses and improve cancer-associated or treatment-associated cachexia, bone loss, and anemia. Nevertheless, defining which patients have the highest likelihood of benefiting from these effects is challenging and will require further work.
Topics: Activins; Animals; Biomarkers, Tumor; Cachexia; Drug Resistance, Neoplasm; Humans; Molecular Targeted Therapy; Neoplasms; Neovascularization, Pathologic; Tumor Microenvironment
PubMed: 32700590
DOI: 10.1080/14728222.2020.1799350 -
Hepatology Communications Oct 2022The role of activin B, a transforming growth factor β (TGFβ) superfamily cytokine, in liver health and disease is largely unknown. We aimed to investigate whether...
The role of activin B, a transforming growth factor β (TGFβ) superfamily cytokine, in liver health and disease is largely unknown. We aimed to investigate whether activin B modulates liver fibrogenesis. Liver and serum activin B, along with its analog activin A, were analyzed in patients with liver fibrosis from different etiologies and in mouse acute and chronic liver injury models. Activin B, activin A, or both was immunologically neutralized in mice with progressive or established carbon tetrachloride (CCl )-induced liver fibrosis. Hepatic and circulating activin B was increased in human patients with liver fibrosis caused by several liver diseases. In mice, hepatic and circulating activin B exhibited persistent elevation following the onset of several types of liver injury, whereas activin A displayed transient increases. The results revealed a close correlation of activin B with liver injury regardless of etiology and species. Injured hepatocytes produced excessive activin B. Neutralizing activin B largely prevented, as well as improved, CCl -induced liver fibrosis, which was augmented by co-neutralizing activin A. Mechanistically, activin B mediated the activation of c-Jun-N-terminal kinase (JNK), the induction of inducible nitric oxide synthase (iNOS) expression, and the maintenance of poly (ADP-ribose) polymerase 1 (PARP1) expression in injured livers. Moreover, activin B directly induced a profibrotic expression profile in hepatic stellate cells (HSCs) and stimulated these cells to form a septa structure. Conclusions: We demonstrate that activin B, cooperating with activin A, mediates the activation or expression of JNK, iNOS, and PARP1 and the activation of HSCs, driving the initiation and progression of liver fibrosis.
Topics: Activins; Adenosine Diphosphate; Animals; Carbon Tetrachloride; Humans; Liver Cirrhosis; Mice; Nitric Oxide Synthase Type II; Ribose; Transforming Growth Factor beta
PubMed: 35866567
DOI: 10.1002/hep4.2037