The Versatile World of Inflammatory Chemokines in Cancer

Leibovich-Rivkin, Tal; Lebel-Haziv, Yaeli; Lerrer, Shalom; Weitzenfeld, Polina; Ben‐Baruch, Adit

doi:10.1007/978-94-007-6217-6_6

Cited by 3 publications

(2 citation statements)

References 259 publications

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“…In parallel to the above, we determined the effects of the combined stimulation by TNF α + Estrogen + EGF on the ability of the tumor cells to acquire additional promalignancy functions. Doing a “per cell” analysis, we found that the stimulation of the tumor cells by TNF α + Estrogen + EGF has given rise to potent elevation in the release of the inflammatory chemokines CXCL8 ( Figure 8(b1) ) and CCL2 ( Figure 8(b2) ), which have been well characterized as strong tumor-promoting factors by virtue of their potent angiogenic activities and recruitment of tumor-supporting leukocytes to the tumors [ 76 – 81 ]. In addition, in response to the combined stimulation by TNF α + Estrogen + EGF, the tumor cells have acquired the ability to produce high levels of functional matrix metalloproteinase 9 (MMP9; Figure 8(c) ), a key enzyme in degradation of the extracellular matrix (ECM) during local invasion end extravasation of the tumor cells [ 82 ].…”

Section: Resultsmentioning

confidence: 99%

Progression of Luminal Breast Tumors Is Promoted by Ménage à Trois between the Inflammatory Cytokine TNFαand the Hormonal and Growth-Supporting Arms of the Tumor Microenvironment

Weitzenfeld

Meron

Leibovich-Rivkin

et al. 2013

Mediators of Inflammation

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Breast cancer progression is strongly linked to inflammatory processes, aggravating disease course. The impacts of the inflammatory cytokine TNFα on breast malignancy are not fully substantiated, and they may be affected by cooperativity between TNFα and other protumoral mediators. Here, we show that together with representatives of other important arms of the tumor microenvironment, estrogen (hormonal) and EGF (growth-supporting), TNFα potently induced metastasis-related properties and functions in luminal breast tumor cells, representing the most common type of breast cancer. Jointly, TNFα + Estrogen + EGF had a stronger effect on breast cancer cells than each element alone, leading to the following: (1) extensive cell spreading and formation of FAK/paxillin-enriched cellular protrusions; (2) elevated proportion of tumor cells coexpressing high levels of CD44 and β1 and VLA6; (3) EMT and cell migration; (4) resistance to chemotherapy; (5) release of protumoral factors (CXCL8, CCL2, MMPs). Importantly, the tumor cells used in this study are known to be nonmetastatic under all conditions; nevertheless, they have acquired high metastasizing abilities in vivo in mice, following a brief stimulation by TNFα + Estrogen + EGF. These dramatic findings indicate that TNFα can turn into a strong prometastatic factor, suggesting a paradigm shift in which clinically approved inhibitors of TNFα would be applied in breast cancer therapy.

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Section: Resultsmentioning

confidence: 99%

Progression of Luminal Breast Tumors Is Promoted by Ménage à Trois between the Inflammatory Cytokine TNFαand the Hormonal and Growth-Supporting Arms of the Tumor Microenvironment

Weitzenfeld

Meron

Leibovich-Rivkin

et al. 2013

Mediators of Inflammation

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“…CCL21 encodes a C-C chemokine that is mainly presented in lymphoid tissue and serves an important role in dendritic cell recruitment and lymphoid neogenesis ( 31 ). In addition, NF-κB signaling is a major link between cancer and inflammation, which is triggered by proinflammatory cytokines such as CCL21 ( 32 , 33 ); several previous studies have indicated that the activation of NF-κB signaling is related to GC oncogenesis ( 34 – 36 ). In addition, miR-338 was highly associated with GC through the inhibition the GC cell proliferation ( 37 ), which is similar with the present data.…”

Section: Discussionmentioning

confidence: 99%

Identifying heterogeneous subtypes of gastric cancer and subtype‑specific subpaths of microRNA‑target pathways

Bai

Zhang

2017

Mol Med Report

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The present study aimed to classify gastric cancer (GC) into subtypes and to screen the subtype-specific genes, their targeted microRNAs (miRNAs) and enriched pathways to explore the putative mechanism of each GC subtypes. The GSE13861 data set was downloaded from the Gene Expression Omnibus and used to screen differential expression genes (DEGs) in GC samples based on the detection of imbalanced differential signal algorithm. The specific genes in each subtype were identified with the cut-off criterion of U>0.04, pathway enrichment analysis was performed and the subtype-specific subpaths of miRNA-target pathway were determined. A total of 1,263 DEGs were identified in the primary gastric adenocarcinoma (PGD) samples, which were subsequently divided into four subtypes, according to the hierarchy cluster analysis. Identification of the subpaths of each subtype indicated that the subpath related to subtype 1 was miRNA (miR)-202/calcium voltage-gated channel subunit α1 (CACNA1E)/type II diabetes mellitus. The nuclear factor-κB signaling pathway was the most significantly specific pathway and subpath identified for subtype 2, which was regulated by miR-338-targeted suppression of C-C motif chemokine ligand 21 (CCL21). For subtype 3, significant related pathways included ubiquitin-mediated proteolysis and proteasome, and the important subpath was miR-146B/proteasome 26S subunit, non-ATPase 3 (PSMD3)/proteasome; focal adhesion was the significant pathway indicated for subtype 4, and the subpaths were miR-34A/vinculin (VCL)/focal adhesion and miR-34C/VCL/focal adhesion. In addition, Helicobacter pylori infection was higher in GC subtype 1 than in other subtypes. Specific genes, such as CACNA1E, CCL21, PSMD3 and VCL, may be used as potential feature genes to identify different subtypes of GC, and their associated subpaths may partially explain the pathogenetic mechanism of each GC subtype.

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Breast Cancer: Coordinated Regulation of CCL2 Secretion by Intracellular Glycosaminoglycans and Chemokine Motifs

et al. 2014

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The chemokine CCL2 (MCP-1) has been identified as a prominent tumor-promoting factor in breast cancer. The major source for CCL2 is in the tumor cells; thus, identifying the mechanisms regulating CCL2 release by these cells may enable the future design of modalities inhibiting CCL2 secretion and consequently reduce tumorigenicity. Using cells deficient in expression of glycosaminoglycans (GAGs) and short hairpin RNAs reducing heparan sulfate (HS) and chondroitin sulfate (CS) expression, we found that intracellular HS and CS (= GAGs) partly controlled the trafficking of CCL2 from the Golgi toward secretion. Next, we determined the secretion levels of GFP-CCL2-WT and GFP-CCL2-variants mutated in GAG-binding domains and/or in the 40s loop of CCL2 (45TIVA48). We have identified partial roles for R18+K19, H66, and the 45TIVA48 motif in regulating CCL2 secretion. We have also demonstrated that in the absence of R24 or R18+K19 +45TIVA48, the secretion of CCL2 by breast tumor cells was almost abolished. Analyses of the intracellular localization of GFP-CCL2-mutants in the Golgi or the endoplasmic reticulum revealed particular intracellular processes in which these CCL2 sequences controlled its intracellular trafficking and secretion. The R24, 45TIVA48 and R18+K19 +45TIVA48 domains controlled CCL2 secretion also in other cell types. We propose that targeting these chemokine regions may lead to reduced secretion of CCL2 by breast cancer cells (and potentially also by other malignant cells). Such a modality may limit tumor growth and metastasis, presumably without affecting general immune activities (as discussed below).

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The Versatile World of Inflammatory Chemokines in Cancer

Cited by 3 publications

References 259 publications

Progression of Luminal Breast Tumors Is Promoted by Ménage à Trois between the Inflammatory Cytokine TNFαand the Hormonal and Growth-Supporting Arms of the Tumor Microenvironment

Progression of Luminal Breast Tumors Is Promoted by Ménage à Trois between the Inflammatory Cytokine TNFαand the Hormonal and Growth-Supporting Arms of the Tumor Microenvironment

Identifying heterogeneous subtypes of gastric cancer and subtype‑specific subpaths of microRNA‑target pathways

Breast Cancer: Coordinated Regulation of CCL2 Secretion by Intracellular Glycosaminoglycans and Chemokine Motifs

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