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

• Main Authors: Yaeli Lebel-Haziv, Tsipi Meshel, Gali Soria, Adva Yeheskel, Elad Mamon, Adit Ben-Baruch
• Format: Article
• Language: English
• Published: Elsevier 2014-09-01
• Series: Neoplasia: An International Journal for Oncology Research
• Online Access: http://www.sciencedirect.com/science/article/pii/S1476558614001109

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).