MCP-1/CCL2 Mediated by Autocrine Loop of PDGF-BB Promotes Invasion of Lung Cancer Cell by Recruitment of Macrophages Via CCL2–CCR2 Axis

Ding, Mei; He, Shaojun; Yang, Jiong

doi:10.1089/jir.2018.0113

Cited by 30 publications

(19 citation statements)

References 32 publications

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“…Excessive production of CCL2 has been demonstrated in multiple cancer or precancerous lesions including oral lesions . Up to date, most studies have been focused on how CCL2 promotes cancer progression by recruiting inflammatory cells in lung cancer, colorectal cancer, breast cancer, and oral cancer . However, there is still a lack of evidence that the origin of local CCL2 in tumor microenvironment and its direct effect on tumor cells.…”

Section: Discussionmentioning

confidence: 99%

“…CCL2 and its main chemokine receptor CCR2 have been implicated in the pathogenesis of several different disease processes, including neurological disorders, autoimmune disease, obesity, atherosclerosis, and cancer . Significantly high expression of CCL2 has been detected in the epithelial region of many tumor types, including lung cancer, colorectal cancer, and breast cancer . CCL2 promotes tumor progression through multiple mechanisms including recruiting of CCR2‐positive mononuclear macrophages to secret of a variety of inflammatory factors and to promote angiogenesis.…”

Section: Introductionmentioning

confidence: 99%

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CCL2 promotes cell migration by inducing epithelial‐mesenchymal transition in oral squamous cell carcinoma

Ling

Yang

Chen

et al. 2019

J Oral Pathology Medicine

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Background Although a few studies suggested that the chemokine CCL2 might be involved in the development of oral squamous cell carcinoma (OSCC), the exact mechanism remains unclear. In this study, we aimed to determine the resource of CCL2 in lesions and explored a potential mechanism that CCL2 promotes tumor progression. The study was an effort to provide new insights into the pathological role of CCL2 in OSCC. Methods Specimens of OSCC and normal oral mucosa were stained using immunohistochemistry (IHC) to assess the CCL2 expression. Enzyme‐linked immunosorbent assay (ELISA) was used to detect the difference of CCL2 between OSCC and normal oral mucosa cell lines. In addition, we treated OSCC cells with exogenous rCCL2 combined with or without CCL2 neutralizing antibody and then determined the changes of in epithelial‐mesenchymal transition (EMT) markers and cell migration capacity using immunofluorescence, Western blotting, transwell migration, and wound healing assays. Results We have found that CCL2 expression was upregulated significantly in both lesions and cell culture supernatant of OSCC compared with controls. IHC staining demonstrated that CCL2 expression was primarily located in the cytoplasm and cell membrane of cells. We have also found that rCCL2 could effectively induce EMT through upregulating Snail in OSCC cells, which was demonstrated by the decrease of E‐cadherin and the increase of vimentin. In addition, we have found that CCL2 neutralizing antibody could block EMT induced by CCL2 in OSCC. Conclusions CCL2 secreted by cancer cells can promote cell migration by inducing EMT via paracrine or autocrine in OSCC.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

CCL2 promotes cell migration by inducing epithelial‐mesenchymal transition in oral squamous cell carcinoma

Ling

Yang

Chen

et al. 2019

J Oral Pathology Medicine

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“…In various cancers, the crosstalk of TAMs with tumor cells via the CCL2/CCR2 axis play multiple roles in cancer development, such as monocyte/macrophage recruitment at the tumor site (131), tumor progression, EMT, invasion, and metastasis (132). Experimental lung tumor models, in vitro TAMs-tumor cells, coculture models, and human lung cancer biopsies demonstrated that CCL2/CCR2 signaling is one of the central signaling pathways involved in lung cancer growth and metastasis (20,133,134). In the in vivo metastasis lung tumor model and human lung cancer biopsies, infiltration of TAMs was found to be increased by NFKB1-CCL2 signaling via an elevation in neddylation pathway (135).…”

Section: Chemokines Ccl2mentioning

confidence: 99%

Macrophage and Tumor Cell Cross-Talk Is Fundamental for Lung Tumor Progression: We Need to Talk

et al. 2020

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Regardless of the promising results of certain immune checkpoint blockers, current immunotherapeutics have met a bottleneck concerning response rate, toxicity, and resistance in lung cancer patients. Accumulating evidence forecasts that the crosstalk between tumor and immune cells takes center stage in cancer development by modulating tumor malignancy, immune cell infiltration, and immune evasion in the tumor microenvironment (TME). Cytokines and chemokines secreted by this crosstalk play a major role in cancer development, progression, and therapeutic management. An increased infiltration of Tumor-associated macrophages (TAMs) was observed in most of the human cancers, including lung cancer. In this review, we emphasize the role of cytokines and chemokines in TAM-tumor cell crosstalk in the lung TME. Given the role of cytokines and chemokines in immunomodulation, we propose that TAM-derived cytokines and chemokines govern the cancer-promoting immune responses in the TME and offer a new immunotherapeutic option for lung cancer treatment.

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“…CCL2 inhibitors have been tested in various tumors, tumor cells and xenograft models with CCL2 lowering effects brought about by losartan (63) anlotinib (64) imatinib (65) zoledronic acid (66) oroxylin A (67) aspirin (68) natural compounds in coffee (kahweol acetate, cafestol) (69) or conophylline from Ervatamia microphylla (70) which can reduce invasive inflammatory tumor infiltration. The mechanism of action for CCL2 reducing agents may center around the modification of upstream or downstream targets such as PLEK2/EGRF (71) HER2-EGF/HRG, PI3K-NF-kB axis (27) SRC, PKC (58) the neddylation pathway (72) or the well-known mitogen-activated protein kinases and phosphatidylinositol 3-kinase/Akt cell signaling pathways (73). While others have reported apigenin to have an effect on NF-kappaB/Snail pathway (74), pSTAT3, pERK or PI3K/pAkt (75), our previous studies suggest the effects of TNFα in TNBC cell lines, as it relates to CCL2 are driven through the higher expression of IKBK epsilon (31).…”

Section: Discussionmentioning

confidence: 99%

Effect of apigenin on whole transcriptome profile of TNFα‑activated MDA‑MB‑468 triple negative breast cancer cells

et al. 2020

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The lack of hormone receptors in triple negative breast cancer (TNBC) is associated with the inefficacy of anti-estrogen chemotherapies, leaving fewer options for patient treatment and higher mortality rates. Additionally, as with numerous types of inflammatory breast cancer, infiltration of tumor associated macrophages and other leukocyte sub-populations within the tumor inevitably lead to aggressive, chemo-resistant, metastatic and invasive types of cancer which escape immune surveillance. These processes are orchestrated by the release of potent cytokines, including TNFα, IL-6 and CCL2 from the stroma, tumor and immune cells within the tumor microenvironment. The present study evaluated apigenin modulating effects on the pro-inflammatory activating action of TNFα in TNBC MDA-MB-468 cells, derived from an African American woman. Initially, cell viability was determined to establish an optimal sub-lethal dose of TNFα and apigenin in MDA-MB-468 cells. Subsequently, various treatments effects were evaluated using whole transcriptomic analysis of mRNA and long intergenic non-coding RNA with Affymetrix HuGene-2.1-st human microarrays. Gene level differential expression analysis was conducted on 48,226 genes where TNFα caused significant upregulation of 53 transcripts and downregulation of 11 transcripts. The largest upward differential shift was for CCL2 [+61.86 fold change (FC); false discovery rate (FDR), P<0.0001]; which was down regulated by apigenin (to +10.71 FC vs. Control; FDR P-value <0.001), equivalent to an 83% reduction. Several TNFα deferentially upregulated transcripts were reduced by apigenin, including CXCL10, C3, PGLYRP4, IL22RA2, KMO, IL7R, ROS1, CFB, IKBKe, SLITRK6 (a checkpoint target) and MMP13. Confirmation of CCL2 experimentally induced transcript alterations was corroborated at the protein level by ELISA assays. The high level of CCL2 transcript in the cell line was comparable to that in our previous studies in MDA-MB-231 cells. The differential effects of TNFα were corroborated by ELISA, where the data revealed a >10-fold higher releasing rate of CCL2 in MDA-MB-468 cells compared with in MDA-MB-231 cells, both of which were attenuated by apigenin. The data obtained in the present study demonstrated a high level of CCL2 in MDA-MB-468 cells and a possible therapeutic role for apigenin in downregulating TNFα-mediated processes in these TNBC cells.

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MCP-1/CCL2 Mediated by Autocrine Loop of PDGF-BB Promotes Invasion of Lung Cancer Cell by Recruitment of Macrophages Via CCL2–CCR2 Axis

Cited by 30 publications

References 32 publications

CCL2 promotes cell migration by inducing epithelial‐mesenchymal transition in oral squamous cell carcinoma

CCL2 promotes cell migration by inducing epithelial‐mesenchymal transition in oral squamous cell carcinoma

Macrophage and Tumor Cell Cross-Talk Is Fundamental for Lung Tumor Progression: We Need to Talk

Effect of apigenin on whole transcriptome profile of TNFα‑activated MDA‑MB‑468 triple negative breast cancer cells

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