Inflammatory mediators in breast cancer: Coordinated expression of TNFα & IL-1β with CCL2 & CCL5 and effects on epithelial-to-mesenchymal transition

Abstract

BackgroundThe inflammatory chemokines CCL2 (MCP-1) & CCL5 (RANTES) and the inflammatory cytokines TNFα & IL-1β 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, TNFα and IL-1β 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, TNFα and IL-1β 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 TNFα & IL-1β 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 TNFα & IL-1β expression. These results suggest progression-related roles for TNFα and IL-1β in breast cancer, as indeed indicated by the following: (1) Tumors of the IDC-with-relapse group had significantly higher persistence of TNFα and IL-1β compared to tumors of DCIS or IDC-no-relapse; (2) Continuous stimulation of the tumor cells by TNFα (and to some extent IL-1β) has led to EMT in the tumor cells; (3) Combined analyses with relevant clinical parameters suggested that IL-1β acts jointly with other pro-malignancy factors to promote disease relapse.ConclusionsOur findings suggest that the coordinated expression of CCL2 & CCL5 and TNFα & IL-1β may be important for disease course, and that TNFα & IL-1β 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.

PKCλ/ι signaling promotes triple-negative breast cancer growth and metastasis

“…All these cytokines have been implicated in breast cancer progression previously. [46][47][48] To test the effect of these cytokines on PKCl/i activation, we treated MDA-MB-231 cells with different cytokines and tested phosphorylation of PKCl/i. Intriguingly, we found that both TGFb1 and IL1b, individually and in combination, induced PKCl/i phosphorylation in MDA-MB-231 cells (Figure 6a and Supplementary Figure S8a).…”

Pilot Study on “Pericytic Mimicry” and Potential Embryonic/Stem Cell Properties of Angiotropic Melanoma Cells Interacting with the Abluminal Vascular Surface

“…Interestingly, from the coculture of EC and MC versus simultaneously MC alone and EC alone, 17 genes from the 27 known differentially expressed genes were linked to migratory and/or embryonic/cancer stem cell properties: nine overexpressed genes: CCL2, ICAM1, SELE, IL6, TRAF1, SERPINB2, CXCL6, PDGFB and EVX1, and eight underexpressed genes: CFDP1, BLID, RGNEF, MALT1, RANBP9, UPF1, PLAA and ZXDC. More specifically, these genes have demonstrated properties linked to (i) cancer cell migration: CCL2 [26,27], ICAM1 [28], IL6 [29], RGNEF [30] and RANBP9 [31]; (ii) cancer progression and metastasis: CCL2 [26,27,32], ICAM1 [33,34], SELE [35,36], TRAF1 [37], IL6 [29], SERPINB2 [38], CXCL6 [39], BLID [40], MALT1 [41], UPF1 [42], PLAA [43], RGNEF [44], ZXDC [45]; (iii) EMT: CCL2 [46] and IL6 [29] ; and (iv) embryonic and/or cancer stem cell properties: CCL2 [46][47][48] , PDGFB [49] , EVX1 [50], CFDP1 [51] and RANBP9 [52] . Furthermore, the 15 most significantly enriched functional groups analyzed by IPA included: development, cell movement, cancer, and embryonic development.…”

CCL5 as a potential immunotherapeutic target in triple-negative breast cancer

“…The expression of CCL2 and CCL5 in the IDC-with-relapse group was associated with further elevated expression of IL1b and TNF-a. 35 In human breast tumor cells, CCL5-containing vesicles on microtubules traffic from the endoplasmic reticulum to the post-Golgi stage before CCL5 is released, and this process is controlled by the stiffness of the actin cytoskeleton in a manner dependent on the (43)TRKN(46) sequence of the 40 s loop of CCL5.…”