Plasma Chemokine CCL2 and Its Receptor CCR2 Concentrations as Diagnostic Biomarkers for Breast Cancer Patients

Abstract

The aim of this study was to investigate plasma levels and applicability of CCL2, CCR2, and tumor marker CA 15-3 in breast cancer (BC) patients and in relation to the control groups: patients with benign breast tumor and healthy subjects. Plasma levels of tested parameters were determined by enzyme-linked immunosorbent assay (ELISA) and CA 15-3 by Chemiluminescent Microparticle Immunoassay (CMIA). The median levels of CCL2 in entire group of BC were significantly higher compared to the control groups, similarly as median levels of CA 15-3. CCR2 is a negative marker whose levels were significantly lower in BC group compared to healthy women. The concentration of CCL2 in BC increases with advancing tumor stage, while a median level of CCR2 decreases with advancing stage. CCL2 showed the highest value of sensitivity (SE) (64.95%) in entire BC group and also in early stages of disease. The highest specificity (SP) was obtained by CA 15-3 (85.71%). The area under the ROC curve (AUC) of CCR2 (0.7304) was the largest of all the tested parameters (slightly lower than CA 15-3) in the entire BC group, but a maximum range was obtained for the combination of all tested parameters with CA 15-3 (0.8271). In early stages of BC the highest AUC of all tested parameters was observed in CCL2 or CCR2 (stage I: 0.6604 and 0.6564; respectively; stage II: 0.7768, respectively, for CCR2). The findings of this study suggest that there may be applicability of CCL2, CCR2 in diagnosis of BC patients, particularly in conjunction with CA 15-3.

Serum levels of the chemokine CCL2 are elevated in malignant pleural mesothelioma patients

“…C-C motif chemokine ligand 2 (CCL2), also known as monocyte chemotactic protein-1 (MCP-1), is expressed in most human cancers [35][36][37], and plays a key role in the recruitment of macrophages and MDSCs [35,36,[38][39][40]. In general agreement with the findings that tumors accumulate macrophages and MDSCs that have pro-tumorigenic properties and express CCL2 and that CCL2 expression in tumor tissue is associated with advanced tumor stage and worse prognosis, there are several studies that report elevated levels of CCL2 in the serum of cancer patients and/or an association between elevated serum CCL2 and poor prognosis [41][42][43][44][45][46][47][48][49][50][51]. Other studies, however, found either no association between the serum CCL2 levels of cancer patients and clinical variables or that lower serum CCL2 levels were associated with poor prognosis or that higher serum CCL2 levels were associated with favorable prognosis [52][53][54][55][56][57][58][59][60].…”

More Than Just Attractive: How CCL2 Influences Myeloid Cell Behavior Beyond Chemotaxis

“…CCL2 expression is inducible, triggered upon exposure to inflammatory stimuli, such as interleukin-1, interleukin-4, interleukin-6 (IL-1, IL-4, and IL-6), tumor necrosis factor α (TNFα), transforming growth factor β (TGFβ), lipopolysaccharide (LPS), interferon γ (IFNγ), plateletderived growth factor (PDGF), vascular endothelial growth factor (VEGF), macrophage colonystimulating factor (M-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) (29)(30)(31)(32)(33). It is found in the circulation, where it has been suggested as a diagnostic biomarker of breast cancer and prostate cancer (34,35), as well as in tissues (www.proteinatlas.org) (36), where it attracts leukocytes to sites of infection or injury to mediate defense and repair.…”

“…THP-1 derived macrophages (M2 differentiated with PMA) Coculture with MCF10A tumor cells Cytokine array, RT-PCR (12) m BMDMs (differentiated in L-cell CM) LPS, IFNγ+LPS RT-PCR (13) RAW264.7 (macrophage cell line) LPS RT-PCR (14) m synovial macrophages (adherent fraction of synovial cells) Tenascin-C, osteopontin RT-PCR (15) m PEMs (adherent fraction) Coculture with MDA-MB 231 tumor cells RT-PCR (16) m PEMs (M2 differentiated with M-CSF) 4T1 cancer-cell-derived GM-CSF Northern blot (17) m microglial cells Fragment of amyloid β-protein Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) Northern blot (18) h female reproductive tract DCs (positive selection from endometrium tissue) Human immunodeficiency virus Multiplex assay (19) h DCs (from PBMCs, differentiated with IL-4 and GM-CSF) Dengue virus RT-PCR (20) h DCs (from PBMCs, differentiated with IL-4 and GM-CSF) TLR3, TLR4, and TLR8 agonists ELISA (21) h lung mast cells (isolated by elutriation) rhSCF Northern blot (22) HMC-1 (mast cell line) rhSCF ELISA (22) LAD 2 (mast cell line) Complement factor C3a or C5a ELISA (23) HMC-1 (mast cell line) fMLP (bacterial-derived peptide) RNase protection assay (24) h neutrophils LPS, IFNγ, LPS+IFNγ, IFNγ+TLR2 ligands (LTA or Pam3CSK4), TNFα, TNFα+IFNγ ELISA (25) h neutrophils PMA, LPS, PAM3CSK4 (TLR2 ligand), FSL-1 (bacterial derived TLR2/6 agonist) ELISA (26) RBL-2H3 (rat basophil cell line) fMLP or C3a or C5a ELISA (27) h eosinophils CB+C5a, CB+fMLP, CB+PAF, GM-CSF, Ionomycin, PMA, IL-5+CB+C5a, IL-5+CB+PAF, CB+C5a, IL-5+C5a, IL-5+C5a+CB ELISA (28) This table provides an exemplary overview of the different types of myeloid cells and their ability to secrete CCL2. The stimulant and the readout are provided.…”

Chemokine Ligand 13 (CXCL13) in Neuroborreliosis and Neurosyphilis as Selected Spirochetal Neurological Diseases: A Review of Its Diagnostic Significance

“…Their primary function is to stimulate leukocyte movement and control their migration from the blood to tissues. It has also been proven that chemokines are involved in the activation of adhesion molecules, and regulation of angiogenesis, embryogenesis, organogenesis, and apoptosis [14,15]. Chemokines can be divided into constitutive (lymphoid) and inducible, which are upregulated at sites of inflammation [16,17].…”