Soluble factors regulated by epithelial–mesenchymal transition mediate tumour angiogenesis and myeloid cell recruitment

Suarez-Carmona, Meggy; Bourcy, Morgane; Lesage, Julien; Leroi, Natacha; Syne, Laïdya; Blacher, Silvia; Hubert, Pascale; Erpicum, Charlotte; Foidart, Jean‐Michel; Delvenne, Philippe; Birembaut, Philippe; Noël, Agnès; Polette, Myriam; Gilles, Christine

doi:10.1002/path.4546

Cited by 53 publications

(50 citation statements)

References 76 publications

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“…Our finding that ZEB1 and ZEB2 are inducers of inflammatory cytokines is supported by a report by Suarez‐Carmona et al . (2015) that Slug, Snail, and other EMT‐related transcription factors regulate the production of soluble factors, such as IL‐8, IL‐6, sICAM‐1, PAI‐1, and GM‐CSF/CSF2. Taken together, these data indicate that inflammatory cytokines induce EMT‐related transcription factors and vice versa in certain cancer cells to enhance tumor progression.…”

Section: Discussionmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

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Zinc finger E‐box binding protein 1 (ZEB1) and ZEB2 induce epithelial‐mesenchymal transition (EMT) and enhance cancer progression. However, the global view of transcriptional regulation by ZEB1 and ZEB2 is yet to be elucidated. Here, we identified a ZEB1‐regulated inflammatory phenotype in breast cancer cells using chromatin immunoprecipitation sequencing and RNA sequencing, followed by gene set enrichment analysis (GSEA) of ZEB1‐bound genes. Knockdown of ZEB1 and/or ZEB2 resulted in the downregulation of genes encoding inflammatory cytokines related to poor prognosis in patients with cancer, including IL6 and IL8, therefore suggesting that ZEB1 and ZEB2 have similar functions in terms of the regulation of production of inflammatory cytokines. Antibody array and ELISA experiments confirmed that ZEB1 controlled the production of the IL‐6 and IL‐8 proteins. The secretory proteins regulated by ZEB1 enhanced breast cancer cell proliferation and tumor growth. ZEB1 expression in breast cancer cells also affected the growth of fibroblasts in cell culture, and the accumulation of myeloid‐derived suppressor cells in tumors in vivo. These findings provide insight into the role of ZEB1 in the progression of cancer, mediated by inflammatory cytokines, along with the initiation of EMT.

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Section: Discussionmentioning

confidence: 99%

ZEB1‐regulated inflammatory phenotype in breast cancer cells

et al. 2017

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“…qRT-PCR, Western blotting analyses, and flow cytometry qRT-PCR was performed as described previously (9). Primer sequences are provided in Supplementary Table S2.…”

Section: Sirna Transfectionmentioning

confidence: 99%

“…These transcription factors directly or indirectly repress or activate a variety of EMT target genes to provide cells with enhanced migratory and invasive ability, enhanced resistance to apoptosis and senescence, and proangiogenic and proinflammatory activities. While their repressive activity on several epithelial genes has been shown to involve a direct binding to promoter regions, their ability to induce mesenchymal genes rather implicates indirect and often unknown mechanisms (6)(7)(8)(9). Closely linking EMT to CTC, the expression of EMT mediators has been detected in CTCs in animal models (2,10) and in subpopulations of CTCs isolated from cancer patients including breast cancer patients, where they associate with poor clinical parameters and to the particularly aggressive "triple-negative breast cancer" (TNBC) subtype (5,11,12).…”

Section: Introductionmentioning

confidence: 99%

Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells

et al. 2016

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Epithelial-mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific microenvironment for tumor cells, we explored a potential link between EMT and coagulation that may provide EMT-positive CTCs with enhanced colonizing properties. Here we report that EMT induces tissue factor (TF), a major cell-associated initiator of coagulation and related procoagulant properties in the blood. TF blockade by antibody or shRNA diminished the procoagulant activity of EMT-positive cells, confirming a functional role for TF in these processes. Silencing the EMT transcription factor ZEB1 inhibited both EMT-associated TF expression and coagulant activity, further strengthening the link between EMT and coagulation. Accordingly, EMT-positive cells exhibited a higher persistance/survival in the lungs of mice colonized after intravenous injection, a feature diminished by TF or ZEB1 silencing. In tumor cells with limited metastatic capability, enforcing expression of the EMT transcription factor Snail increased TF, coagulant properties, and early metastasis. Clinically, we identified a subpopulation of CTC expressing vimentin and TF in the blood of metastatic breast cancer patients consistent with our observations. Overall, our findings define a novel EMT-TF regulatory axis that triggers local activation of coagulation pathways to support metastatic colonization of EMT-positive CTCs.

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“…Multiple studies have now demonstrated that IL-8 can function in a paracrine or autocrine manner to affect the various cellular components of the TME. Functioning in a paracrine manner, for example, IL-8 released by cancer cells has been shown to promote the recruitment of various immune cell populations, mainly macrophages, neutrophils and suppressor cells of myeloid origin (see below), as well as to stimulate the angiogenic response in vascular endothelial cells leading to the formation of new blood vessels [39]. In addition, IL-8 released by tumor cells can function in an autocrine fashion to induce carcinoma cells to acquire a mesenchymal-like phenotype (i.e., induction of an EMT), as described in detail below.…”

Section: Tumor-driven Inflammation: Key Soluble Immune-mediatorsmentioning

confidence: 99%

“…Work conducted by Suarez-Carmona and colleagues [39] recently investigated the potential association between EMT and inflammation both in vitro and in vivo with xenograft models and with patient clinical samples. Similar to other studies, induction of EMT via epidermal growth factor (EGF)-treatment of TNBC lines resulted in a significant enhancement of secreted IL-6, IL-8, and other soluble factors.…”

Section: Emt Induces the Secretion Of Inflammatory Soluble Factorsmentioning

confidence: 99%

Epithelial-mesenchymal transition and inflammation at the site of the primary tumor

Dominguez

David

Palena

2017

Seminars in Cancer Biology

122

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Tumor growth and progression are the products of complex signaling networks between different cell types within the tumor and its surrounding stroma. In particular, established tumors are known to stimulate an inflammatory reaction via the secretion of cytokines, chemokines, and growth factors that favor the recruitment of a range of infiltrating immune cell populations into the tumor microenvironment. While potentially able to exert tumor control, this inflammatory reaction is typically seized upon by the tumor to promote its own growth and progression towards metastasis. This review focuses on recent advances in understanding how an established tumor can initiate an inflammatory response via the release of pro-inflammatory mediators, such as IL-6 and IL-8, and their roles in cancer metastasis. In particular, the role of the epithelial-mesenchymal transition (EMT), a phenotypic switch observed in carcinomas that promotes progression towards metastasis, is discussed here in relation to cancer inflammation.

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Soluble factors regulated by epithelial–mesenchymal transition mediate tumour angiogenesis and myeloid cell recruitment

Cited by 53 publications

References 76 publications

ZEB1‐regulated inflammatory phenotype in breast cancer cells

ZEB1‐regulated inflammatory phenotype in breast cancer cells

Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells

Epithelial-mesenchymal transition and inflammation at the site of the primary tumor

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