TGFβ Signaling in the Tumor Microenvironment

Goulet, Cassandra Ringuette; Pouliot, Frédéric

doi:10.1007/978-3-030-47189-7_6

Cited by 18 publications

(11 citation statements)

References 170 publications

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“…High epithelial expression of TGF-β1 in mammary cells of BPA-exposed gerbils indicates that this marker participates in susceptibility to BPA disruption (Betancourt et al 2014). As TGF-β1 amplifies the EMT process (Goulet & Pouliot 2021) and cancer modulation in ECM (Vandenberg et al 2012), its expression in normal epithelial cells and tissue of BPA groups indicates its role as a mediator in the tumor induction by this xenoestrogen in gerbil MG. Clearly, the tumorigenic process has several molecular influences, but TGF-β1 expression in disrupted tissue suggests its key role in BPA action.…”

Section: Endocrine-related Cancermentioning

confidence: 99%

Mammary carcinoma in aged gerbil mothers after endocrine disruption in pregnancy and lactation

Ruiz

Colleta

Leonel

et al. 2021

Endocrine-Related Cancer

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Compounds that trigger breast cancer onset and establishment are of great interest in biological research. Endocrine disruptors are relevant because they initiate carcinogenesis by changing endocrine pathways. Bisphenol A (BPA), as a ubiquitous xenoestrogen, is largely associated with dysfunctions in the female reproductive system and associated organs. This study proposes an investigation of the mammary gland (MG) in aged Mongolian gerbil (Meriones unguiculatus) mothers after their exposure to BPA in two windows of morphophysiological plasticity: pregnancy and lactation. A low dose (50 μg/kg), and a high dose (5000 μg/kg) were considered and results showed few differences between them. As expected, we observed contrasts among control and BPA-exposed MG. The control groups presented a regressive phase with high apoptotic activity and elastic stroma. However, BPA damaged mammary tissue and provoked multifocal carcinoma development supported by an apparent epithelial-mesenchymal transition (EMT) and reactive stroma establishment. BPA remodeled stromal fibers deposition and enhanced the recruitment of tumor-associated cells, contributing to a tumoral microenvironment. Overexpression of TGF-β1 was induced by BPA in the epithelial compartment of exposed MG and increased expression of metalloproteinases (MMP-2, MMP-3, MMP-9) was present in carcinoma cells. In conclusion, exposure of mothers to BPA during the gestational/lactational window of susceptibility leads to carcinogenic impacts with aging.

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Section: Endocrine-related Cancermentioning

confidence: 99%

Mammary carcinoma in aged gerbil mothers after endocrine disruption in pregnancy and lactation

Ruiz

Colleta

Leonel

et al. 2021

Endocrine-Related Cancer

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“…Most of them were NF-κB downstream target genes, which were reported to be responsible for the proliferation, survival, and invasion of breast cancer. − This finding indicated that Wpc/NS-E might downregulate oncogene-related chemokine expression via inhibition of NF-κB downstream signaling pathways. Moreover, TGFB2 was also observed in the DEGs, which could mediate TGF-beta, NF-κB, and other immune signaling pathways. − Next, we chose additional downstream candidate genes, including CXCL2, CX3CL1, CSF2, and TGFB2 for further validation. RT-qPCR results showed that the expressions of these genes were reduced significantly in MDA-MB-231 and 4T1 cells, consistent with the heatmap analysis (Figure D,E).…”

Section: Resultsmentioning

confidence: 99%

Intracellular Delivery of Stabilized Peptide Blocking MTDH-SND1 Interaction for Breast Cancer Suppression

Chen,

Zhan,

Zhang

et al. 2023

JACS Au

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Triple-negative breast cancer is one of the most prevalent malignant cancers worldwide. Disrupting the MTDH-SND1 protein−protein interaction has recently been shown to be a promising strategy for breast cancer therapy. In this work, a novel potent stabilized peptide with a stronger binding affinity was obtained through rational structure-based optimization. Furthermore, a sulfonium-based peptide delivery system was established to improve the cell penetration and antitumor effects of stabilized peptides in metastatic breast cancer. Our study further broadens the in vivo applications of the stabilized peptides for blocking MTDH-SND1 interaction and provides promising opportunities for breast cancer therapy.

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“…Conversion of the regulatory complexes could be induced by TGF-β, which initiated active demethylation to upregulate CD147 expression. The gene that encodes the essential cytokine TGF-β changes from a tumor suppressor gene to a tumor promoter gene during the early stages of carcinogenesis [ 37 , 38 ]. TGF-β induced lung cancer progression is associated with epigenetic regulation [ 39 – 41 ].…”

Section: Discussionmentioning

confidence: 99%

Active demethylation upregulates CD147 expression promoting non-small cell lung cancer invasion and metastasis

et al. 2022

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Non-small cell lung cancer (NSCLC) is a fatal disease, and its metastatic process is poorly understood. Although aberrant methylation is involved in tumor progression, the mechanisms underlying dynamic DNA methylation remain to be elucidated. It is significant to study the molecular mechanism of NSCLC metastasis and identify new biomarkers for NSCLC early diagnosis. Here, we performed MeDIP-seq and hMeDIP-seq analyses to detect the genes regulated by dynamic DNA methylation. Comparison of the 5mC and 5hmC sites revealed that the CD147 gene underwent active demethylation in NSCLC tissues compared with normal tissues, and this demethylation upregulated CD147 expression. Significantly high levels of CD147 expression and low levels of promoter methylation were observed in NSCLC tissues. Then, we identified the CD147 promoter as a target of KLF6, MeCP2, and DNMT3A. Treatment of cells with TGF-β triggered active demethylation involving loss of KLF6/MeCP2/DNMT3A and recruitment of Sp1, Tet1, TDG, and SMAD2/3 transcription complexes. A dCas9-SunTag-DNMAT3A-sgCD147-targeted methylation system was constructed to reverse CD147 expression. The targeted methylation system downregulated CD147 expression and inhibited NSCLC proliferation and metastasis in vitro and in vivo. Accordingly, we used cfDNA to detect the levels of CD147 methylation in NSCLC tissues and found that the CD147 methylation levels exhibited an inverse relationship with tumor size, lymphatic metastasis, and TNM stage. In conclusion, this study clarified the mechanism of active demethylation of CD147 and suggested that the targeted methylation of CD147 could inhibit NSCLC invasion and metastasis, providing a highly promising therapeutic target for NSCLC.

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TGFβ Signaling in the Tumor Microenvironment

Cited by 18 publications

References 170 publications

Mammary carcinoma in aged gerbil mothers after endocrine disruption in pregnancy and lactation

Mammary carcinoma in aged gerbil mothers after endocrine disruption in pregnancy and lactation

Intracellular Delivery of Stabilized Peptide Blocking MTDH-SND1 Interaction for Breast Cancer Suppression

Active demethylation upregulates CD147 expression promoting non-small cell lung cancer invasion and metastasis

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