scholarly journals The Preventive Effect of Decorin on Epidural Fibrosis and Epidural Adhesions After Laminectomy

2021 ◽  
Vol 12 ◽  
Author(s):  
Qing Ding ◽  
Qi Wei ◽  
Gaohong Sheng ◽  
Shanxi Wang ◽  
Shaoze Jing ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Transforming Growth Factor ◽  
Leg Pain ◽  
Spinal Diseases ◽  
Therapeutic Effects ◽  
Epidural Fibrosis ◽  
Preventive Effect ◽  
Failed Back Surgery ◽  
Tgf Β1

Laminectomy is commonly performed to treat degenerative spinal diseases by reducing compression on the spinal cord and nerve roots. The postoperative epidural fibrosis and epidural adhesions may result in failed back surgery syndrome, which is characterized by the symptoms of lower back pain or leg pain. There is currently no satisfactory treatment for this complication. The pathological processes of epidural fibrosis and epidural adhesions are relevant to the proliferation of fibroblasts, transdifferentiation of fibroblasts into myofibroblasts, and the excessive deposition of extracellular matrix (ECM) protein. According to reports, transforming growth factor-β1 (TGF-β1) played a vital role in the development of fibrosis by promoting aforementioned processes. Decorin, an endogenous proteoglycan and natural inhibitor of TGF-β1, has exhibited prominent anti-fibrosis activity in various scar formation and fibrosis models of many organs. However, the preventive effect of decorin on epidural fibrosis and epidural adhesions requires further investigation. Here, we investigated the therapeutic effects and potential mechanisms of decorin on epidural fibrosis and epidural adhesions. Our results indicated that decorin could significantly suppress the TGF-β1-induced proliferation, transdifferentiation, and extracellular matrix production in primary fibroblasts. Furthermore, Smad2/3 signaling pathway had been demonstrated to be involved in the preventive effect of decorin. Moreover, administration of decorin in vivo could notably inhibit epidural fibrosis and epidural adhesions after laminectomy. To date, there is no approved therapy to target TGF-β1 for the treatment of epidural fibrosis and epidural adhesions after laminectomy. Our research proved the anti-fibrosis effect of decorin, which may provide an effective and promising treatment for epidural fibrosis and epidural adhesions.

scholarly journals NADPH oxidase DUOX1 sustains TGF-β1 signalling and promotes lung fibrosis

2020 ◽  
pp. 1901949
Author(s):  
Ruy Andrade Louzada ◽  
Raphaël Corre ◽  
Rabii Ameziane El Hassani ◽  
Lydia Meziani ◽  
Madeleine Jaillet ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Pulmonary Fibrosis ◽  
Nadph Oxidase ◽  
Lung Fibrosis ◽  
Transforming Growth Factor ◽  
Lung Fibroblasts ◽  
Mouse Lung ◽  
Epithelial Surface ◽  
Tgf Β1

Interstitial lung fibroblast activation coupled with extracellular matrix production is a pathological signature of pulmonary fibrosis, and is governed by transforming growth factor (TGF-β1)/Smad signalling. TGF-β1 and oxidative stress cooperate to drive fibrosis. Cells can produce reactive oxygen species (ROS) through activation and/or induction of NADPH oxidases, such as dual oxidase (DUOX1/2). Since DUOX enzymes, as extracellular H2O2-generating systems, are involved in extracellular matrix formation and in wound healing in different experimental models, we hypothesised that DUOX-based NADPH oxidase plays a role in the pathophysiology of pulmonary fibrosis.Our in vivo data (IPF patients and mouse models of lung fibrosis) showed that the NADPH oxidase DUOX1 is induced in response to lung injury. DUOX1-deficient mice (DUOX1+/- and DUOX1-/-) had an attenuated fibrotic phenotype. In addition to being highly expressed at the epithelial surface of airways, DUOX1 appears to be also well expressed in the fibroblastic foci of remodelled lungs. By using primary human and mouse lung fibroblasts, we showed that TGF-β1 upregulates DUOX1 and its maturation factor DUOXA1 and that DUOX1-derived H2O2 promoted the duration of TGF-β1-activated Smad3 phosphorylation by preventing phospho-Smad3 degradation. Analysis of the mechanism revealed that DUOX1 inhibited the interaction between phospho-Smad3 and the ubiquitin ligase NEDD4L, preventing NEDD4L-mediated ubiquitination of phospho-Smad3 and its targeting for degradation.These findings highlight a role for DUOX1-derived H2O2 in a positive feedback that amplifies the signalling output of the TGF-β1 pathway and identify DUOX1 as a new therapeutic target in pulmonary fibrosis.

Extracellular matrix-related genes in kidney after ischemic injury: potential role for TGF-β in repair

1998 ◽  
Vol 275 (6) ◽  
pp. F894-F903 ◽  
Author(s):  
David P. Basile ◽  
Daniel R. Martin ◽  
Marc R. Hammerman
Keyword(s):  
Extracellular Matrix ◽  
Transforming Growth Factor ◽  
Ischemic Injury ◽  
Plasminogen Activator Inhibitor ◽  
Transforming Growth Factor Β1 ◽  
Proximal Tubules ◽  
Plasminogen Activator Inhibitor 1 ◽  
Tgf Β1 ◽  
Pai 1

The renal expression of transforming growth factor-β1 (TGF-β1) is enhanced following induction of ischemic injury in rat. In cultured renal cells, TGF-β stimulates the synthesis of extracellular matrix. To link TGF-β1 expression with the regulation of extracellular matrix postischemia, we characterized the expression of several genes known to regulate extracellular matrix synthesis at various times during recovery from acute ischemic renal injury in rat. Levels of mRNA for plasminogen activator inhibitor-1 (PAI-1), tissue inhibitor of metalloprotease-1 (TIMP-1), α1(IV) collagen, and fibronectin-EIIIA (FN-EIIIA) mRNAs were significantly enhanced in kidneys within 12 h to 3 days after injury and remained elevated at 7–28 days postischemia relative to levels in kidneys of sham-operated controls. PAI-1 mRNA and peptide were localized in regenerating proximal tubules at 3 and 7 days postischemic injury. α1(IV) Collagen and FN-EIIIA mRNAs were expressed primarily in regenerating proximal tubule cells. Immunoreactivity for FN-EIIIA was enhanced in the tubular basement membrane (TBM) of regenerating proximal tubules, and α1(IV) collagen immunoreactivity was detected in thickened tubulointerstitial spaces. In contrast, TIMP-1 immunoreactivity was enhanced in distal nephron structures postischemia. Immunoneutralization of TGF-β in vivo attenuated the increases in FN-EIIIA, α1(IV) collagen, PAI-1, and TIMP-1 mRNAs by 52%, 73%, 43%, and 27%, respectively. These data are consistent with TGF-β expression postischemic injury participating in renal regeneration of extracellular matrix homeostasis in the proximal TBM.

scholarly journals Biochemical role of the collagen-rich tumour microenvironment in pancreatic cancer progression

2011 ◽  
Vol 441 (2) ◽  
pp. 541-552 ◽  
Author(s):  
Mario A. Shields ◽  
Surabhi Dangi-Garimella ◽  
Amanda J. Redig ◽  
Hidayatullah G. Munshi
Keyword(s):  
Extracellular Matrix ◽  
Cancer Progression ◽  
Type I Collagen ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β1 ◽  
Ductal Adenocarcinoma ◽  
Type I ◽  
Desmoplastic Reaction ◽  
Tgf Β1

PDAC (pancreatic ductal adenocarcinoma) is among the most deadly of human malignances. A hallmark of the disease is a pronounced collagen-rich fibrotic extracellular matrix known as the desmoplastic reaction. Intriguingly, it is precisely these areas of fibrosis in which human PDAC tumours demonstrate increased expression of a key collagenase, MT1-MMP [membrane-type 1 MMP (matrix metalloproteinase); also known as MMP-14]. Furthermore, a cytokine known to mediate fibrosis in vivo, TGF-β1 (transforming growth factor-β1), is up-regulated in human PDAC tumours and can promote MT1-MMP expression. In the present review, we examine the regulation of PDAC progression through the interplay between type I collagen (the most common extracellular matrix present in human PDAC tumours), MT1-MMP and TGF-β1. Specifically, we examine the way in which signalling events through these pathways mediates invasion, regulates microRNAs and contributes to chemoresistance.

scholarly journals Regorafenib-Attenuated, Bleomycin-Induced Pulmonary Fibrosis by Inhibiting the TGF-β1 Signaling Pathway

2021 ◽  
Vol 22 (4) ◽  
pp. 1985
Author(s):  
Xiaohe Li ◽  
Ling Ma ◽  
Kai Huang ◽  
Yuli Wei ◽  
Shida Long ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Kinase Inhibitor ◽  
In Vivo Experiments ◽  
Age Related ◽  
And Migration ◽  
Tgf Β1

Idiopathic pulmonary fibrosis (IPF) is a fatal and age-related pulmonary disease. Nintedanib is a receptor tyrosine kinase inhibitor, and one of the only two listed drugs against IPF. Regorafenib is a novel, orally active, multi-kinase inhibitor that has similar targets to nintedanib and is applied to treat colorectal cancer and gastrointestinal stromal tumors in patients. In this study, we first identified that regorafenib could alleviate bleomycin-induced pulmonary fibrosis in mice. The in vivo experiments indicated that regorafenib suppresses collagen accumulation and myofibroblast activation. Further in vitro mechanism studies showed that regorafenib inhibits the activation and migration of myofibroblasts and extracellular matrix production, mainly through suppressing the transforming growth factor (TGF)-β1/Smad and non-Smad signaling pathways. In vitro studies have also indicated that regorafenib could augment autophagy in myofibroblasts by suppressing TGF-β1/mTOR (mechanistic target of rapamycin) signaling, and could promote apoptosis in myofibroblasts. In conclusion, regorafenib attenuates bleomycin-induced pulmonary fibrosis by suppressing the TGF-β1 signaling pathway.

Regulation of extracellular matrix synthesis by TNF-α and TGF-β1 in type II cells exposed to coal dust

1998 ◽  
Vol 275 (4) ◽  
pp. L637-L644 ◽  
Author(s):  
Yu-Chen Lee ◽  
D. Eugene Rannels
Keyword(s):  
Extracellular Matrix ◽  
Cell Cultures ◽  
Transforming Growth Factor ◽  
Coal Dust ◽  
Transforming Growth Factor Β1 ◽  
Type Ii ◽  
Tnf Α ◽  
Type Ii Cell ◽  
Primary Type ◽  
Tgf Β1

Type II pulmonary epithelial cells respond to anthracite coal dust PSOC 867 with increased synthesis of extracellular matrix (ECM) components. Alveolar macrophages modulate this response by pathways that may involve soluble mediators, including tumor necrosis factor-α (TNF-α) or transforming growth factor-β1 (TGF-β1). The effects of TNF-α (10 ng/ml) and/or TGF-β1 (2 ng/ml) were thus investigated in dust-exposed primary type II cell cultures. In control day 1 or day 3 cultures, TNF-α and/or TGF-β1 had little or no effect on the synthesis of type II cellular proteins, independent of whether the cells were exposed to dust. With PSOC 867 exposure, where ECM protein synthesis is elevated, TNF-α and TGF-β1 further increased both the absolute and relative rates of ECM synthesis on day 3 but had little effect on day 1. Each mediator increased expression of fibronectin mRNA, as well as of ECM fibronectin content, in a manner qualitatively similar to their effects on synthesis. Thus TNF-α and TGF-β1 modulate both ECM synthesis and fibronectin content in coal dust-exposed type II cell cultures.

scholarly journals Activation of transmembrane receptor tyrosine kinase DDR1-STAT3 cascade by extracellular matrix remodeling promotes liver metastatic colonization in uveal melanoma

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Wei Dai ◽  
Shenglan Liu ◽  
Shubo Wang ◽  
Li Zhao ◽  
Xiao Yang ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Cancer Cells ◽  
Uveal Melanoma ◽  
Specific Inhibitor ◽  
Type I ◽  
Matrix Remodeling ◽  
Metastatic Colonization ◽  
Tgf Β1

AbstractColonization is believed a rate-limiting step of metastasis cascade. However, its underlying mechanism is not well understood. Uveal melanoma (UM), which is featured with single organ liver metastasis, may provide a simplified model for realizing the complicated colonization process. Because DDR1 was identified to be overexpressed in UM cell lines and specimens, and abundant pathological deposition of extracellular matrix collagen, a type of DDR1 ligand, was noted in the microenvironment of liver in metastatic patients with UM, we postulated the hypothesis that DDR1 and its ligand might ignite the interaction between UM cells and their surrounding niche of liver thereby conferring strengthened survival, proliferation, stemness and eventually promoting metastatic colonization in liver. We tested this hypothesis and found that DDR1 promoted these malignant cellular phenotypes and facilitated metastatic colonization of UM in liver. Mechanistically, UM cells secreted TGF-β1 which induced quiescent hepatic stellate cells (qHSCs) into activated HSCs (aHSCs) which secreted collagen type I. Such a remodeling of extracellular matrix, in turn, activated DDR1, strengthening survival through upregulating STAT3-dependent Mcl-1 expression, enhancing stemness via upregulating STAT3-dependent SOX2, and promoting clonogenicity in cancer cells. Targeting DDR1 by using 7rh, a specific inhibitor, repressed proliferation and survival in vitro and in vivo outgrowth. More importantly, targeting cancer cells by pharmacological inactivation of DDR1 or targeting microenvironmental TGF-β1-collagen I loop exhibited a prominent anti-metastasis effect in mice. In conclusion, targeting DDR1 signaling and TGF-β signaling may be a novel approach to diminish hepatic metastasis in UM.

scholarly journals Featured Article: TGF-β1 dominates extracellular matrix rigidity for inducing differentiation of human cardiac fibroblasts to myofibroblasts

2018 ◽  
Vol 243 (7) ◽  
pp. 601-612 ◽  
Author(s):  
Nathan Cho ◽  
Shadi E Razipour ◽  
Megan L McCain
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cardiac Fibroblasts ◽  
Myofibroblast Differentiation ◽  
Matrix Rigidity ◽  
Growth Factor Beta ◽  
Human Cardiac Fibroblasts ◽  
Tgf Β1

Cardiac fibroblasts and their activated derivatives, myofibroblasts, play a critical role in wound healing after myocardial injury and often contribute to long-term pathological outcomes, such as excessive fibrosis. Thus, defining the microenvironmental factors that regulate the phenotype of cardiac fibroblasts and myofibroblasts could lead to new therapeutic strategies. Both chemical and biomechanical cues have previously been shown to induce myofibroblast differentiation in many organs and species. For example, transforming growth factor beta 1, a cytokine secreted by neutrophils, and rigid extracellular matrix environments have both been shown to promote differentiation. However, the relative contributions of transforming growth factor beta 1 and extracellular matrix rigidity, two hallmark cues in many pathological myocardial microenvironments, to the phenotype of human cardiac fibroblasts are unclear. We hypothesized that transforming growth factor beta 1 and rigid extracellular matrix environments would potentially have a synergistic effect on the differentiation of human cardiac fibroblasts to myofibroblasts. To test this, we seeded primary human adult cardiac fibroblasts onto coverslips coated with polydimethylsiloxane of various elastic moduli, introduced transforming growth factor beta 1, and longitudinally quantified cell phenotype by measuring expression of α-smooth muscle actin, the most robust indicator of myofibroblasts. Our data indicate that, although extracellular matrix rigidity influenced differentiation after one day of transforming growth factor beta 1 treatment, ultimately transforming growth factor beta 1 superseded extracellular matrix rigidity as the primary regulator of myofibroblast differentiation. We also measured expression of POSTN, FAP, and FSP1, proposed secondary indicators of fibroblast/myofibroblast phenotypes. Although these genes partially trended with α-smooth muscle actin expression, they were relatively inconsistent. Finally, we demonstrated that activated myofibroblasts incompletely revert to a fibroblast phenotype after they are re-plated onto new surfaces without transforming growth factor beta 1, suggesting differentiation is partially reversible. Our results provide new insights into how microenvironmental cues affect human cardiac fibroblast differentiation in the context of myocardial pathology, which is important for identifying effective therapeutic targets and dictating supporting cell phenotypes for engineered human cardiac disease models. Impact statement Heart disease is the leading cause of death worldwide. Many forms of heart disease are associated with fibrosis, which increases extracellular matrix (ECM) rigidity and compromises cardiac output. Fibrotic tissue is synthesized primarily by myofibroblasts differentiated from fibroblasts. Thus, defining the cues that regulate myofibroblast differentiation is important for understanding the mechanisms of fibrosis. However, previous studies have focused on non-human cardiac fibroblasts and have not tested combinations of chemical and mechanical cues. We tested the effects of TGF-β1, a cytokine secreted by immune cells after injury, and ECM rigidity on the differentiation of human cardiac fibroblasts to myofibroblasts. Our results indicate that differentiation is initially influenced by ECM rigidity, but is ultimately superseded by TGF-β1. This suggests that targeting TGF-β signaling pathways in cardiac fibroblasts may have therapeutic potential for attenuating fibrosis, even in rigid microenvironments. Additionally, our approach can be leveraged to engineer more precise multi-cellular human cardiac tissue models.

scholarly journals Store-operated calcium entry suppressed the TGF-β1/Smad3 signaling pathway in glomerular mesangial cells

2017 ◽  
Vol 313 (3) ◽  
pp. F729-F739 ◽  
Author(s):  
Sarika Chaudhari ◽  
Weizu Li ◽  
Yanxia Wang ◽  
Hui Jiang ◽  
Yuhong Ma ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Mesangial Cells ◽  
Underlying Mechanism ◽  
Glomerular Mesangial Cells ◽  
Critical Pathway ◽  
Smad3 Phosphorylation ◽  
Tgf Β1

Our previous study demonstrated that the abundance of extracellular matrix proteins was suppressed by store-operated Ca2+entry (SOCE) in mesangial cells (MCs). The present study was conducted to investigate the underlying mechanism focused on the transforming growth factor-β1 (TGF-β1)/Smad3 pathway, a critical pathway for ECM expansion in diabetic kidneys. We hypothesized that SOCE suppressed ECM protein expression by inhibiting this pathway in MCs. In cultured human MCs, we observed that TGF-β1 (5 ng/ml for 15 h) significantly increased Smad3 phosphorylation, as evaluated by immunoblot. However, this response was markedly inhibited by thapsigargin (1 µM), a classical activator of store-operated Ca2+channels. Consistently, both immunocytochemistry and immunoblot showed that TGF-β1 significantly increased nuclear translocation of Smad3, which was prevented by pretreatment with thapsigargin. Importantly, the thapsigargin effect was reversed by lanthanum (La3+; 5 µM) and GSK-7975A (10 µM), both of which are selective blockers of store-operated Ca2+channels. Furthermore, knockdown of Orai1, the pore-forming subunit of the store-operated Ca2+channels, significantly augmented TGF-β1-induced Smad3 phosphorylation. Overexpression of Orai1 augmented the inhibitory effect of thapsigargin on TGF-β1-induced phosphorylation of Smad3. In agreement with the data from cultured MCs, in vivo knockdown of Orai1 specific to MCs using a targeted nanoparticle small interfering RNA delivery system resulted in a marked increase in abundance of phosphorylated Smad3 and in nuclear translocation of Smad3 in the glomerulus of mice. Taken together, our results indicate that SOCE in MCs negatively regulates the TGF-β1/Smad3 signaling pathway.

scholarly journals IL-15 regulates fibrosis and inflammation in a mouse model of chronic pancreatitis

2018 ◽  
Vol 315 (6) ◽  
pp. G954-G965 ◽  
Author(s):  
Murli Manohar ◽  
Hemanth Kumar Kandikattu ◽  
Alok Kumar Verma ◽  
Anil Mishra
Keyword(s):  
Chronic Pancreatitis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Interferon Γ ◽  
Cancer Tissue ◽  
Inkt Cells ◽  
Interleukin 15 ◽  
Potential Strategy ◽  
Tgf Β1

Pancreatitis is an inflammatory disease characterized by the induction of several proinflammatory cytokines like interleukin (IL)-6, IL-8, IL-1β, and IL-1. Recently, the multifunctional innate cytokine IL-15 has been implicated in the protection of several diseases, including cancer. Tissue fibrosis is one of the major problems in successfully treating chronic pancreatitis pathogenesis. Therefore, we tested the hypothesis that recombinant IL-15 (rIL-15) treatment may induce innate tissue responses and its overexpression will improve the pathogenesis of cerulein-induced chronic pancreatitis, associated remodeling, and fibrosis. We observed atrophy of acinar cells, increased inflammation, and increased deposition of perivascular collagen, the upregulated protein level of transforming growth factor (TGF)-β1, α-smooth muscle actin (α-SMA), and collagen-1 in cerulein-induced chronic pancreatitis in mice. Furthermore, we reported that rIL-15 treatment protects mice from the cerulein-induced chronic pancreatitis pathogenesis, including acinar cell atrophy, and perivascular accumulation of tissue collagen followed by downregulation of profibrotic genes such as TGF-β1, α-SMA, collagen-1, collagen-3, and fibronectin in cerulein-induced chronic pancreatitis in mice. Mechanistically, we show that IL-15-mediated increase of interferon-γ-responsive invariant natural killer T (iNKT) cells in the blood and tissue protects cerulein-induced pancreatic pathogenesis in mice. Of note, a reduction in iNKT cells was also observed in human chronic pancreatitis compared with normal individuals. Taken together, these data suggest that IL-15 treatment may be a novel therapeutic strategy for treating chronic pancreatitis pathogenesis. NEW & NOTEWORTHY Pancreatic fibrosis is a major concern for the successful treatment of chronic pancreatitis and pancreatic cancer. Therefore, restriction in the progression of fibrosis is the promising approach to manage the pancreatitis pathogenesis. Herein, we present in vivo evidences that pharmacological treatment of recombinant interleukin-15 improves remodeling and fibrosis in cerulein-induced chronic pancreatitis in mice. Our observations indicate that interleukin-15 immunotherapy may be a possible and potential strategy for restricting the progression of fibrosis in chronic pancreatitis.

scholarly journals LY2157299 Monohydrate, a TGF-βR1 Inhibitor, Suppresses Tumor Growth and Ascites Development in Ovarian Cancer

Cancers ◽  
2018 ◽  
Vol 10 (8) ◽  
pp. 260 ◽  
Author(s):  
Qing Zhang ◽  
Xiaonan Hou ◽  
Bradley Evans ◽  
Jamison VanBlaricom ◽  
Saravut Weroha ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Tumor Growth ◽  
Cell Lines ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Migration And Invasion ◽  
Ascites Formation ◽  
Tgf Β1

Transforming growth factor beta (TGF-β) signaling has pleiotropic functions regulating cancer initiation, development, and metastasis, and also plays important roles in the interaction between stromal and cancer cells, making the pathway a potential therapeutic target. LY2157299 monohydrate (LY), an inhibitor of TGF-β receptor I (TGFBRI), was examined for its ability to inhibit ovarian cancer (OC) growth both in high-grade serous ovarian cancer (HGSOC) cell lines and xenograft models. Immunohistochemistry, qRT-PCR, and Western blot were performed to study the effect of LY treatment on expression of cancer- and fibroblast-derived genes. Results showed that exposure to TGF-β1 induced phosphorylation of SMAD2 and SMAD3 in all tested OC cell lines, but this induction was suppressed by pretreatment with LY. LY alone inhibited the proliferation, migration, and invasion of HGSOC cells in vitro. TGF-β1-induced fibroblast activation was blocked by LY. LY also delayed tumor growth and suppressed ascites formation in vivo. In addition, independent of tumor inhibition, LY reduces ascites formation in vivo. Using OVCAR8 xenograft specimens we confirmed the inhibitory effect of LY on TGF-β signaling and tumor stromal expression of collagen type XI chain 1 (COL11A1) and versican (VCAN). These observations suggest a role for anti-TGF-β signaling-directed therapy in ovarian cancer.

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