Cyr61 promotes CD204 expression and the migration of macrophages via MEK/ERK pathway in esophageal squamous cell carcinoma

Abstract

Tumor-associated macrophages (TAMs) are known to be involved in the progression of various human malignancies. We previously demonstrated that CD204 was a useful marker for TAMs contributing to the angiogenesis, progression, and prognosis of human esophageal squamous cell carcinoma (ESCC). We also showed that conditioned media of ESCC cell lines induced CD204 expression in THP-1 human monocytic leukemia cells. Here, we performed a cDNA microarray analysis between THP-1 cells stimulated with TPA (macrophage [MΦ]-like THP-1 cells) treated with and without conditioned medium of ESCC cell line to clarify the molecular characteristics of TAMs in ESCC. From the microarray data, we discovered that Cyr61 was induced in CD204-positive-differentiated THP-1 cells (TAM-like THP-1 cells). In the ESCC microenvironment, not only cancer cells but also TAMs expressed Cyr61. Interestingly, the expression levels of Cyr61 showed a significant positive correlation with the number of CD204-positive macrophages in ESCCs by immunohistochemistry. Recombinant human Cyr61 (rhCyr61) promoted cell migration and induced the expression of CD204 along with the activation of the MEK/ERK pathway in MΦ-like THP-1 cells. Pretreatment with a MEK1/2 inhibitor significantly inhibited not only the Cyr61-mediated migration but also the CD204 expression in the MΦ-like THP-1 cells. These results suggest that Cyr61 may contribute to the expression of CD204 and the promotion of cell migration via the MEK/ERK pathway in TAMs in the ESCC microenvironment.

CCN1/CYR61-mediated meticulous patrolling by Ly6C low monocytes fuels vascular inflammation

“…Neither murine PBMCs nor endothelial cells released CCN1 on a short-term basis, although endothelial cell-derived CCN1 coats the surface of these cells in the steady state and 18-h treatment with TNF-α and bafilomycin A1 stimulated CCN1 release by human PBMCs (18). These results are in accordance with the chemoattractant properties of CCN1 for monocytes/macrophages in the early phase of inflammation, whereas PBMC-derived CCN1 locally immobilize recruited leukocytes in the invaded tissue after extravasation at later time points (18,19,(50)(51)(52)(53).…”

“…Interestingly, increased soluble CCN1 levels are observed in synovial fluid from rheumatoid arthritis patients (15) and in the serum of SLE patients (64). Hence, the chemoattractant properties of CCN1 for human and murine monocytes and macrophages (15,16,18,19) strongly implicates CCN1 in the numerous pathologies in which TLR7 activity plays an important role.…”

“…First described in cardiovascular development and carcinogenesis, CCN1 now is recognized as a mediator in leukocyte migration and inflammatory processes (15,16) and in the development of the thymus (17). CCN1 exhibits chemoattractant properties for human and murine inflammatory monocytes by promoting their adhesion and migration through integrin CD11b and the cell-surface heparin sulfate proteoglycan syndecan-4 (15,16,(18)(19)(20)(21). CCN1 treatment of murine macrophages induces transcriptional changes characteristic of M1 polarization including the up-regulation of proinflammatory cytokines, such as TNF-α, IL-1β, or IL-6 (21).…”

Role of tumor‐associated macrophages in human malignancies: friend or foe?

“…For example, the matricellular protein cysteine-rich angiogenic inducer 61, which is enriched in tissues of esophageal squamous cell carcinoma, is believed to induce CD204 expression in infiltrated macrophages. 144 The molecular functions of CD163 and CD204 themselves are also suggested directly influence the function of M2-TAMs. CD163 is a membrane protein belonging to the scavenger receptor cysteine-rich domain family and acts as an endocytic receptor for a hemoglobin-haptoglobin (Hb-Hp) complex.…”

miR-1291 targets mucin 1 inhibiting cell proliferation and invasion to promote cell apoptosis in esophageal squamous cell carcinoma

“…Therefore, it is a formidable task to study and explore novel biomarkers or therapeutic targets for ESCC patients. Recently some research findings have indicated that the initiation and development of ESCC involved the mutation of numerous oncogenes and anti-oncogenes, and thus were characterized by the synergetic effect of multiple genes, factors and steps (5,6), yet more effort is still needed to study the genetic and molecular changes underlying the development of ESCC.…”