Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy

Sheen, Yhun Yhong; Kim, Min Jin; Park, Sang A; Park, So Yeon; Nam, Jeong Seok

doi:10.4062/biomolther.2013.072

Cited by 95 publications

(74 citation statements)

References 85 publications

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“…In this work, we show that blockade of the TbR1/PDGFR axis or downstream PI3K-AKT pathway impaired invadosome formation, a process previously linked to cartilage damage (5,6). Various small-molecule inhibitors of TGF-b are being evaluated in preclinical and clinical trials (96). Furthermore, several inhibitors that target PI3Ks are currently being tested in clinical trials for treatment of human cancers (97,98) and are under consideration for the treatment of RA (99).…”

Section: Discussionmentioning

confidence: 87%

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

Charbonneau

Lavoie

Lauzier

et al. 2016

The Journal of Immunology

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Fibroblast-like synoviocytes (FLS) play a major role in invasive joint destruction in rheumatoid arthritis (RA). This prodestructive phenotype has been shown to involve autocrine TGF-β that triggers formation of matrix-degrading invadosomes through molecular mechanisms that are not fully elucidated. The platelet-derived growth factor (PDGF) receptor (PDGFR) family of receptor tyrosine kinases (RTK) has been shown to cooperate with TGF-β in various pathological conditions. We therefore sought to determine whether RTK activity played a role in invadosome biogenesis. We demonstrated that, among the common RTKs, PDGFR-αβ was specifically phosphorylated in FLS from RA patients. Phosphorylation of PDGFR-αβ was also elevated in RA synovial tissues. Interference with PDGFR activation or PDGF neutralization inhibited invadosome formation in RA synoviocytes, indicating the presence of an autocrine PDGFR activation loop that involved endogenous PDGF. Among the PDGF-A–D isoforms, only PDGF-B was found both significantly elevated in FLS lines from RA patients, and related to high-invadosome forming cells. Addition of TGF-β upregulated invadosome formation, PDGF-B mRNA expression, and phosphorylation of PDGFR. All of these functions were efficiently suppressed by TGF-β neutralization or interference with the Smad/TβR1or PI3K/Akt pathway. Among the class 1 PI3K family proteins known to be expressed in RA synoviocytes, PI3Kα was selectively involved in PDGF-B expression, whereas both PI3Kα and PI3Kδ participated in invadosome formation. Our findings demonstrate that PDGFR is a critical RTK required for the prodestructive phenotype of RA synovial cells. They also provide evidence for an association between autocrine TGF-β and PDGFR-mediated invadosome formation in RA synoviocytes that involves the production of PDGF-B induced by TGF-β.

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Section: Discussionmentioning

confidence: 87%

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

Charbonneau

Lavoie

Lauzier

et al. 2016

The Journal of Immunology

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“…However, several reports have indicated that puerarin suppressed TGF-β expression in diabetic rats (She et al, 2014), mice with myocardial fibrosis (Chen et al, 2012b), and rats with hepatic fibrosis . The TGF-β pathway has a dual role in both tumor suppression and tumor promotion (Sheen et al, 2013). Zarzynska reported that in the early stages of breast cancer, TGF-β inhibited epithelial cell cycle progression and promoted apoptosis to suppress tumorigenesis (Zarzynska, 2014).…”

Section: Journal Of Agricultural Sciencementioning

confidence: 99%

Suppressive Effects of Puerariae Radix on the Breast Tumor Incidence in Rats Treated with DMBA

Chen¹,

Wu²,

Tseng³

et al. 2017

JAS

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Puerariae Radix (PR) is the root of Pueraria lobata, an herb widely used in traditional Chinese medicine and as a food seasoning. Owing to its potential anti-oxidative ability, the effects of PR on the inhibition of breast tumors were investigated in this study using the 7,12-dimethylbenz[a]anthracene (DMBA)-treated rat model. Thirty-two female Sprague-Dawley rats were randomly assigned to one of four different treatment groups, with or without PR and/or DMBA administration. At the age of 177 days, all rats were sacrificed, the number and size of tumors were recorded, and blood and tissue samples were collected for assessment of hematological parameters, redox status, and tumorigenesis-related factors. We found that PR supplementation decreased tumor incidence and WBC count but increased the IgM levels, and significantly altered the redox status, elevated serum TGF-β levels, and reduced serum VEGF-C and ICAM-1 levels. The mechanism by which PR decreased the incidence of DMBA-induced rat breast tumors might include ameliorating immunity, enhancing the antioxidant status, increasing the hepatic excretion of carcinogenic metabolites of DMBA, and influencing the expression of tumorigenesis-related factors.

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“…3,4 A wide variety of signaling pathways and transcription factors have been found to be deregulated during the multistep processes of tumorigenesis of colorectal cancer, such as Wnt/b-catenin, Hedgehog, TGFb/Smad, Snail, and Notch signaling pathways. [5][6][7] It is, thus, widely accepted that colorectal cancer results from the accumulation of the alteration of multiple, not a single, signaling pathway. However, the coordination of these deregulated cancer signal pathways in the development, progression and maintenance of colorectal cancer is largely unknown.…”

Section: Introductionmentioning

confidence: 99%

FOXQ1 mediates the crosstalk between TGF-β and Wnt signaling pathways in the progression of colorectal cancer

Peng

Luo

Kang

et al. 2015

Cancer Biology & Therapy

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A wide variety of signaling transduction pathways contribute to tumorigenesis. Forkhead box Q1 (FOXQ1) is a member of the forkhead transcription factor family and its upregulation is closely correlated with tumor progression and prognosis of multiple cancer types, including colorectal cancer. However, the molecular mechanisms by which FOXQ1 promotes tumorigenesis, especially cancer cell invasion and metastasis in colorectal cancer, have not been fully elucidated. In the present study, we demonstrate that FOXQ1 is overexpressed in colorectal tumor tissues and its expression level is closely correlated with the stage and lymph node metastasis of colorectal cancer. In in vitro cultured SW480 colorectal cancer cells, knockdown of FOXQ1 expression by small interfering RNA greatly diminished the aggressive tumor behaviors of SW480 cells, including angiogenesis, invasion, epithelial-mesenchymal transition, and resistance to chemotherapy drug-induced apoptosis. Further mechanistic investigation showed that FOXQ1 silencing prevents the nuclear translocation of b-catenin, thus reducing the activity of Wnt signaling. Moreover, TGF-b1 induced the expression of FOXQ1 as well as the migration and invasion of SW480 cells, which was partially prevented following knockdown of FOXQ1. Our results demonstrate that FOXQ1 plays a critical role during the tumorigenesis of colorectal cancer and is a mediator of the crosstalk between Wnt and TGF-b signaling pathways. Our findings provide further insight into the cancer biology of colorectal cancer and suggest that FOXQ1 is a potential therapeutic target for the development of therapies for colorectal cancer.

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Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy

Cited by 95 publications

References 85 publications

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

Platelet-Derived Growth Factor Receptor Activation Promotes the Prodestructive Invadosome-Forming Phenotype of Synoviocytes from Patients with Rheumatoid Arthritis

Suppressive Effects of Puerariae Radix on the Breast Tumor Incidence in Rats Treated with DMBA

FOXQ1 mediates the crosstalk between TGF-β and Wnt signaling pathways in the progression of colorectal cancer

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