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Journal ArticleDOI

EMT and inflammation: inseparable actors of cancer progression

TL;DR: The interconnections between EMT programs and cellular and molecular actors of inflammation are described, and data linking the EMT/inflammation axis to metastasis is recapitulate.
About: This article is published in Molecular Oncology.The article was published on 2017-07-01 and is currently open access. It has received 368 citations till now. The article focuses on the topics: Epithelial–mesenchymal transition & Cancer cell.
Citations
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Journal ArticleDOI
16 Jul 2019-Immunity
TL;DR: How tumor-promoting inflammation closely resembles inflammatory processes typically found during development, immunity, maintenance of tissue homeostasis, or tissue repair is discussed and the distinctions between tissue-protective and pro-tumorigenic inflammation are illuminated.

1,563 citations

Journal ArticleDOI
TL;DR: It is indicated that TAMs induce EMT program to enhance CRC migration, invasion, and CTC-mediated metastasis by regulating the JAK2/STAT3/miR-506-3p/FoxQ1 axis, which in turn leads to the production of CCL2 that promote macrophage recruitment, revealing a new cross-talk between immune cells and tumor cells in CRC microenvironment.
Abstract: Tumor-associated macrophages (TAMs) are major components of tumor microenvironment that frequently associated with tumor metastasis in human cancers. Circulating tumor cell (CTC), originating from primary tumor sites, is considered to be the precursors of tumor metastasis. However, the regulatory mechanism of TAMs in CTC-mediated tumor metastasis still remains unclear. Immunohistochemical staining was used to detect the macrophages infiltration (CD68 and CD163), epithelial–mesenchymal transition (EMT) markers (E-cadherin and Vimentin) expression in serial sections of human colorectal cancer (CRC) specimens. Then, the correlations between macrophages infiltration and clinicopathologic features, mesenchymal CTC ratio, and patients’ prognosis were analyzed. A co-culture assay in vitro was used to evaluate the role of TAMs on CRC EMT, migration and invasion, and ELISA, luciferase reporter assay and CHIP were performed to uncover the underlying mechanism. Furthermore, an in vivo model was carried out to confirm the effect of TAMs on mesenchymal CTC-mediated metastasis. Clinically, CD163+ TAMs infiltrated in invasive front was associated with EMT, mesenchymal CTC ratio, and poor prognosis in patients with CRC. CRC–conditioned macrophages regulated EMT program to enhance CRC cells migration and invasion by secreting IL6. TAMs-derived IL6 activated the JAK2/STAT3 pathway, and activated STAT3 transcriptionally inhibited the tumor suppressor miR-506-3p in CRC cells. miR-506-3p, a key miRNA regulating FoxQ1, was downregulated in CRC cells, resulting in increased FoxQ1 expression, which in turn led to the production of CCL2 that promoted macrophage recruitment. Inhibition of CCL2 or IL6 broke this loop and reduced macrophage migration and mesenchymal CTC-mediated metastasis, respectively. Our data indicates that TAMs induce EMT program to enhance CRC migration, invasion, and CTC-mediated metastasis by regulating the JAK2/STAT3/miR-506-3p/FoxQ1 axis, which in turn leads to the production of CCL2 that promote macrophage recruitment, revealing a new cross-talk between immune cells and tumor cells in CRC microenvironment.

362 citations


Cites background from "EMT and inflammation: inseparable a..."

  • ...Given that cytokine secretion represents the major functional response of macrophages, it was speculated that a signaling mechanism between TAMs and CRC cells exists that accounts at least in part for the previously described pro-tumorigenic activities [27]....

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Journal ArticleDOI
06 Sep 2018-Cell
TL;DR: These multipronged effects distinguish CIN as a central driver of tumor evolution and as a genomic source for the crosstalk between the tumor and its microenvironment, in the course of immune editing and evasion.

355 citations

Journal ArticleDOI
TL;DR: The role of hypoxia as a mechanism that drives the acquisition of tumor hallmarks that make certain cancers more aggressive is discussed and some combinations of therapies that inhibit the angiogenesis process and that may be a successful strategy for cancer patients are indicated.
Abstract: During carcinogenesis, advanced tumors are surrounded by both stromal and immune cells, which support tumor development. In addition, inflammation and angiogenesis are processes that play important roles in the development of cancer, from the initiation of carcinogenesis, tumor in situ and advanced stages of cancer. During acute inflammation, vascular hyperpermeability allows inflammatory mediators and immune response cells, including leukocytes and monocytes/macrophages, to infiltrate the site of damage. As a factor that regulates vascular permeability, vascular endothelial growth factor (VEGF) also plays a vital role as a multifunctional molecule and growth factor. Furthermore, stromal and immune cells secrete soluble factors that activate endothelial cells and favor their transmigration to eliminate the aggressive agent. In this review, we present a comprehensive view of both the relationship between chronic inflammation and angiogenesis during carcinogenesis and the participation of endothelial cells in the inflammatory process. In addition, the regulatory mechanisms that contribute to the endothelium returning to its basal permeability state after acute inflammation are discussed. Moreover, the manner in which immune cells participate in pathological angiogenesis release pro-angiogenic factors that contribute to early tumor vascularization, even before the angiogenic switch occurs, is also examined. Also, we discuss the role of hypoxia as a mechanism that drives the acquisition of tumor hallmarks that make certain cancers more aggressive. Finally, some combinations of therapies that inhibit the angiogenesis process and that may be a successful strategy for cancer patients are indicated.

169 citations


Cites background from "EMT and inflammation: inseparable a..."

  • ...This set of immune cells and the molecules they secrete then activate the PI3K and NF-κB signaling pathways for promoting the EMT and vasculogenic mimicry (81, 82)....

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Journal ArticleDOI
TL;DR: miR-195-5p may play a vital role in regulating NOTCH2-mediated tumor cell EMT, thereby affecting IL-4-related M2-like TAM polarization in CRC.
Abstract: Tumor microenvironment (TME) is a complex environment containing tumor cells, tumor-associated macrophages (TAMs), interstitial cells, and non-cellular components. Epithelial–mesenchymal transition (EMT), as a major actor in cancer tumorigenicity and metastasis, was involved in the interaction between TAMs and tumor cells. However, the potential mechanisms of EMT and how EMT-programmed tumor cells affect M2-like TAMs still need further exploration. An integrated analysis of nine CRC miRNA expression datasets was performed. Functional assays, including the EdU, clone formation, wound healing, and transwell assays, were used to determine the anticancer role of miR-195-5p in human CRC progression. Furthermore, RNA immunoprecipitation, RNA decay, and dual-luciferase reporter assays were used to determine the mechanism of miR-195-p CRC progression. Then co-culture, migration, and ELISA assays were applied to determine the role of miR-195-5p in macrophage recruitment and alternative polarization. Xenograft mouse models were used to determine the role of miR-195-5p in CRC tumorigenicity and TAM polarization in vivo. An integrated analysis confirmed that miR-195-5p was significantly downregulated in CRC tissues, and patients with a low level of miR-195-5p had significantly shortened overall survival as revealed by the TCGA-COAD dataset. Altered miR-195-5p in colon cancer cells led to distinct changes of proliferation, migration, invasion, and EMT. Mechanistically, miR-195-5p regulated NOTCH2 expression in a post-transcriptional manner by directly binding to 3′-UTR of the Notch2 mRNA. Subsequently, miR-195-5p/NOTCH2 suppressed GATA3-mediated IL-4 secretion in CRC cells and ultimately inhibited M2-like TAM polarization. miR-195-5p may play a vital role in regulating NOTCH2-mediated tumor cell EMT, thereby affecting IL-4-related M2-like TAM polarization in CRC.

150 citations


Cites background from "EMT and inflammation: inseparable a..."

  • ...Epithelial–mesenchymal transition (EMT), as a major actor modulating tumor metastasis [2, 3], may be involved in the interaction between the tumor cells and tumor microenviron-...

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References
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Journal ArticleDOI
TL;DR: This review will discuss the biological processes and the structure and function of CCL2, one of the key chemokines that regulate migration and infiltration of monocytes/macrophages.
Abstract: Chemokines constitute a family of chemoattractant cytokines and are subdivided into four families on the basis of the number and spacing of the conserved cysteine residues in the N-terminus of the protein. Chemokines play a major role in selectively recruiting monocytes, neutrophils, and lymphocytes, as well as in inducing chemotaxis through the activation of G-protein-coupled receptors. Monocyte chemoattractant protein-1 (MCP-1/CCL2) is one of the key chemokines that regulate migration and infiltration of monocytes/macrophages. Both CCL2 and its receptor CCR2 have been demonstrated to be induced and involved in various diseases. Migration of monocytes from the blood stream across the vascular endothelium is required for routine immunological surveillance of tissues, as well as in response to inflammation. This review will discuss these biological processes and the structure and function of CCL2.

3,050 citations


"EMT and inflammation: inseparable a..." refers background in this paper

  • ...CCL2 expression in cancer correlates with TAM density (Deshmane et al., 2009)....

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Journal ArticleDOI
TL;DR: It is shown that most human tumors constitutively express IDO, and that expression of IDO by immunogenic mouse tumor cells prevents their rejection by preimmunized mice, suggesting that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor.
Abstract: T lymphocytes undergo proliferation arrest when exposed to tryptophan shortage, which can be provoked by indoleamine 2,3-dioxygenase (IDO), an enzyme that is expressed in placenta and catalyzes tryptophan degradation. Here we show that most human tumors constitutively express IDO. We also observed that expression of IDO by immunogenic mouse tumor cells prevents their rejection by preimmunized mice. This effect is accompanied by a lack of accumulation of specific T cells at the tumor site and can be partly reverted by systemic treatment of mice with an inhibitor of IDO, in the absence of noticeable toxicity. These results suggest that the efficacy of therapeutic vaccination of cancer patients might be improved by concomitant administration of an IDO inhibitor.

2,140 citations


"EMT and inflammation: inseparable a..." refers background in this paper

  • ...Indoleamine 2,3 dioxygenase (IDO) is mainly a tumor cell-derived, inflammation-induced, immunosuppressive factor (Muller et al., 2008; Uyttenhove et al., 2003) that promotes tumor progression....

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Journal ArticleDOI
01 Feb 2013-Science
TL;DR: A role for EMT in the blood-borne dissemination of human breast cancer is supported as both single cells and multicellular clusters, expressing known EMT regulators, including transforming growth factor (TGF)–β pathway components and the FOXC1 transcription factor.
Abstract: Epithelial-mesenchymal transition (EMT) of adherent epithelial cells to a migratory mesenchymal state has been implicated in tumor metastasis in preclinical models. To investigate its role in human cancer, we characterized EMT in circulating tumor cells (CTCs) from breast cancer patients. Rare primary tumor cells simultaneously expressed mesenchymal and epithelial markers, but mesenchymal cells were highly enriched in CTCs. Serial CTC monitoring in 11 patients suggested an association of mesenchymal CTCs with disease progression. In an index patient, reversible shifts between these cell fates accompanied each cycle of response to therapy and disease progression. Mesenchymal CTCs occurred as both single cells and multicellular clusters, expressing known EMT regulators, including transforming growth factor (TGF)–β pathway components and the FOXC1 transcription factor. These data support a role for EMT in the blood-borne dissemination of human breast cancer.

2,071 citations


"EMT and inflammation: inseparable a..." refers background in this paper

  • ...Similarly, many publications have illustrated the prometastatic effects of EMT program activation in cancer cells (Bates and Mercurio, 2005; Fassina et al., 2012; Spaderna et al., 2006; Yu et al., 2013)....

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Journal ArticleDOI
26 Nov 2015-Nature
TL;DR: This study functionally probes the role of EMT in PDAC by generating mouse models of PDAC with deletion of Snail or Twist, two key transcription factors responsible for EMT, and highlights the importance of combining EMT inhibition with chemotherapy for the treatment of pancreatic cancer.
Abstract: Diagnosis of pancreatic ductal adenocarcinoma (PDAC) is associated with a dismal prognosis despite current best therapies; therefore new treatment strategies are urgently required. Numerous studies have suggested that epithelial-to-mesenchymal transition (EMT) contributes to early-stage dissemination of cancer cells and is pivotal for invasion and metastasis of PDAC. EMT is associated with phenotypic conversion of epithelial cells into mesenchymal-like cells in cell culture conditions, although such defined mesenchymal conversion (with spindle-shaped morphology) of epithelial cells in vivo is rare, with quasi-mesenchymal phenotypes occasionally observed in the tumour (partial EMT). Most studies exploring the functional role of EMT in tumours have depended on cell-culture-induced loss-of-function and gain-of-function experiments involving EMT-inducing transcription factors such as Twist, Snail and Zeb1 (refs 2, 3, 7-10). Therefore, the functional contribution of EMT to invasion and metastasis remains unclear, and genetically engineered mouse models to address a causal connection are lacking. Here we functionally probe the role of EMT in PDAC by generating mouse models of PDAC with deletion of Snail or Twist, two key transcription factors responsible for EMT. EMT suppression in the primary tumour does not alter the emergence of invasive PDAC, systemic dissemination or metastasis. Suppression of EMT leads to an increase in cancer cell proliferation with enhanced expression of nucleoside transporters in tumours, contributing to enhanced sensitivity to gemcitabine treatment and increased overall survival of mice. Collectively, our study suggests that Snail- or Twist-induced EMT is not rate-limiting for invasion and metastasis, but highlights the importance of combining EMT inhibition with chemotherapy for the treatment of pancreatic cancer.

1,622 citations


"EMT and inflammation: inseparable a..." refers background in this paper

  • ...Although two recent studies (Fischer et al., 2015; Zheng et al., 2015) have revived the debate about the universal requirement of EMT in the metastasis process, the current dogma is that EMT processes might be involved in the initial steps of the metastatic cascade, including tumor invasion, intravasation, and micrometastases formation....

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  • ...Although two recent studies (Fischer et al., 2015; Zheng et al., 2015) have revived the debate about the universal requirement of EMT in the metastasis process, the current dogma is that EMT processes might be involved in the initial steps of the metastatic cascade, including tumor invasion,…...

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Journal ArticleDOI
26 Nov 2015-Nature
TL;DR: The potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, for breast cancer treatment is suggested, using a mesenchymal-specific Cre-mediated fluorescent marker switch system in spontaneous breast-to-lung metastasis models.
Abstract: The role of epithelial-to-mesenchymal transition (EMT) in metastasis is a longstanding source of debate, largely owing to an inability to monitor transient and reversible EMT phenotypes in vivo. Here we establish an EMT lineage-tracing system to monitor this process in mice, using a mesenchymal-specific Cre-mediated fluorescent marker switch system in spontaneous breast-to-lung metastasis models. We show that within a predominantly epithelial primary tumour, a small proportion of tumour cells undergo EMT. Notably, lung metastases mainly consist of non-EMT tumour cells that maintain their epithelial phenotype. Inhibiting EMT by overexpressing the microRNA miR-200 does not affect lung metastasis development. However, EMT cells significantly contribute to recurrent lung metastasis formation after chemotherapy. These cells survived cyclophosphamide treatment owing to reduced proliferation, apoptotic tolerance and increased expression of chemoresistance-related genes. Overexpression of miR-200 abrogated this resistance. This study suggests the potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, for breast cancer treatment.

1,488 citations


"EMT and inflammation: inseparable a..." refers background in this paper

  • ...Although two recent studies (Fischer et al., 2015; Zheng et al., 2015) have revived the debate about the universal requirement of EMT in the metastasis process, the current dogma is that EMT processes might be involved in the initial steps of the metastatic cascade, including tumor invasion,…...

    [...]