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Breast cancer: coordinated regulation of CCL2 secretion by intracellular glycosaminoglycans and chemokine motifs.

ABSTRACT: 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 ((45)TIVA(48)). We have identified partial roles for R18+K19, H66, and the (45)TIVA(48) motif in regulating CCL2 secretion. We have also demonstrated that in the absence of R24 or R18+K19+(45)TIVA(48), 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, (45)TIVA(48) and R18+K19+(45)TIVA(48) 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).

SUBMITTER: Lebel-Haziv Y

PROVIDER: S-EPMC4234876 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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Breast cancer: coordinated regulation of CCL2 secretion by intracellular glycosaminoglycans and chemokine motifs.

Lebel-Haziv Yaeli Y Meshel Tsipi T Soria Gali G Yeheskel Adva A Mamon Elad E Ben-Baruch Adit A

Neoplasia (New York, N.Y.) 20140901 9

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 ...[more]

PMID: 25246273

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Project description:BackgroundThe inflammatory chemokines CCL2 (MCP-1) & CCL5 (RANTES) and the inflammatory cytokines TNF? & IL-1? were shown to contribute to breast cancer development and metastasis. In this study, we wished to determine whether there are associations between these factors along stages of breast cancer progression, and to identify the possible implications of these factors to disease course.MethodsThe expression of CCL2, CCL5, TNF? and IL-1? was determined by immunohistochemistry in patients diagnosed with: (1) Benign breast disorders (=healthy individuals); (2) Ductal Carcinoma In Situ (DCIS); (3) Invasive Ducal Carcinoma without relapse (IDC-no-relapse); (4) IDC-with-relapse. Based on the results obtained, breast tumor cells were stimulated by the inflammatory cytokines, and epithelial-to-mesenchymal transition (EMT) was determined by flow cytometry, confocal analyses and adhesion, migration and invasion experiments.ResultsCCL2, CCL5, TNF? and IL-1? were expressed at very low incidence in normal breast epithelial cells, but their incidence was significantly elevated in tumor cells of the three groups of cancer patients. Significant associations were found between CCL2 & CCL5 and TNF? & IL-1? in the tumor cells in DCIS and IDC-no-relapse patients. In the IDC-with-relapse group, the expression of CCL2 & CCL5 was accompanied by further elevated incidence of TNF? & IL-1? expression. These results suggest progression-related roles for TNF? and IL-1? in breast cancer, as indeed indicated by the following: (1) Tumors of the IDC-with-relapse group had significantly higher persistence of TNF? and IL-1? compared to tumors of DCIS or IDC-no-relapse; (2) Continuous stimulation of the tumor cells by TNF? (and to some extent IL-1?) has led to EMT in the tumor cells; (3) Combined analyses with relevant clinical parameters suggested that IL-1? acts jointly with other pro-malignancy factors to promote disease relapse.ConclusionsOur findings suggest that the coordinated expression of CCL2 & CCL5 and TNF? & IL-1? may be important for disease course, and that TNF? & IL-1? may promote disease relapse. Further in vitro and in vivo studies are needed for determination of the joint powers of the four factors in breast cancer, as well as analyses of their combined targeting in breast cancer.

Dataset Information

Breast cancer: coordinated regulation of CCL2 secretion by intracellular glycosaminoglycans and chemokine motifs.

Publications

Breast cancer: coordinated regulation of CCL2 secretion by intracellular glycosaminoglycans and chemokine motifs.

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