Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8<sup>+</sup> Cells

Fridlender, Zvi G.; Kapoor, Veena; Buchlis, George; Cheng, Guanjun; Sun, Jing; Wang, Liang-Chuan S.; Singhal, Sunil; Snyder, Linda A.; Albelda, Steven Μ.

doi:10.1165/rcmb.2010-0080oc

Cited by 133 publications

(101 citation statements)

References 47 publications

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“…Our findings illustrate a regulatory role of MCP-1 on expression of CD8 and Foxp3 in colon cancer; MCP-1 deficiency increased expression of CD8 in the polyps and decreased expression of Foxp3 in the mucosal tissue and polyps. Our results are consistent with previously reported data showing that blockade of MCP-1 can result in activation of CTLs in a mouse model of lung cancer and a reduction in Tregs in TC1 tumor-bearing mice (12,13). These findings should be substantiated using fluorescence-activated cell sorting methodology to firmly establish a role of MCP-1 on immune regulation in the tumor microenvironment.…”

Section: Discussionsupporting

confidence: 93%

Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1

McClellan

Davis

Steiner

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

105

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Tumor-associated macrophages are associated with poor prognosis in certain cancers. Monocyte chemoattractant protein 1 (MCP-1) is thought to be the most important chemokine for recruitment of macrophages to the tumor microenvironment. However, its role on tumorigenesis in a genetic mouse model of colon cancer has not been explored. We examined the role of MCP-1 on tumor-associated macrophages, inflammation, and intestinal tumorigenesis. Male Apc Min/+, Apc Min/+/MCP-1−/− or wild-type mice were euthanized at 18 wk of age and intestines were analyzed for polyp burden, apoptosis, proliferation, β-catenin, macrophage number and phenotype, markers for cytotoxic T lymphocytes and regulatory T cells, and inflammatory mediators. MCP-1 deficiency decreased overall polyp number by 20% and specifically large polyp number by 45% ( P < 0.05). This was consistent with an increase in apoptotic cells ( P < 0.05), but there was no change detected in proliferation or β-catenin. MCP-1 deficiency decreased F4/80-positive cells in both the polyp tissue and surrounding intestinal tissue ( P < 0.05) as well as expression of markers associated with M1 (IL-12 and IL-23) and M2 macrophages (IL-13, CD206, TGF-β, and CCL17) ( P < 0.05). MCP-1 knockout was also associated with increased cytotoxic T lymphocytes and decreased regulatory T cells ( P < 0.05). In addition, MCP-1−/− offset the increased mRNA expression of IL-1β and IL-6 in intestinal tissue and IL-1β and TNF-α in polyp tissue ( P < 0.05), and prevented the decrease in SOCS1 expression ( P < 0.05). We demonstrate that MCP-1 is an important mediator of tumor growth and immune regulation that may serve as an important biomarker and/or therapeutic target in colon cancer.

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Section: Discussionsupporting

confidence: 93%

Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1

McClellan

Davis

Steiner

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

105

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“…Monoclonal antibodies against CCL2 have been administered in lung cancer immunotherapy models and have been identified to exhibit antitumor activity (34,35). The results of the present study confirm this the effect of targeting CCL2 by siRNA in DTX treatment.…”

Section: Discussionsupporting

confidence: 85%

“…Additionally, CCL2 is involved in DTX-induced chemoresistance in prostate cancer (32), and CCL2 inhibition augments DTX-induced inhibitory effects on the growth of prostate cancer (33). CCL2 blockades have also been demonstrated to inhibit tumor growth in lung cancer (34,35). However, the role of CCL2 in the sensitivity of lung cancer to DTX remains unclear.…”

Section: Introductionmentioning

confidence: 99%

CCL2 influences the sensitivity of lung cancer A549 cells to docetaxel

et al. 2018

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Abstract. Lung cancer is one of the most common malignant tumor types globally. Acquisition of chemoresistance in lung cancer cells is the primary cause of chemotherapy failure. Inflammatory chemokine C-C motif chemokine ligand 2 (CCL2) has been reported to be involved in the progression of cancer and drug resistance. However, its function in docetaxel (DTX) resistance of lung cancer remains unclear. In the present study, the mechanism underlying DTX-induced drug resistance was investigated. Reverse transcription-quantitative polymerase chain reaction and western blot analysis revealed that DTX treatment increased the mRNA and protein expression of CCL2 in lung cancer A549 cells. CCL2 was knocked down by small interfering RNA or was overexpressed by recombinant CCL2 lentivirus, and cell viability was determined. An MTT assay indicated that CCL2 downregulation decreased the viability of A549 cells and augmented the DTX-induced cytotoxicity, whereas CCL2 upregulation protected A549 cells from DTX-induced cytotoxicity. Additionally, it was revealed that CCL2 overexpression activated phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling and inhibited apoptosis-associated protein caspase-3 activation and B-cell lymphoma 2 (Bcl-2) phosphorylation at Ser 70 induced by DTX, and enhanced DTX-induced Bcl-2-associated death promoter phosphorylation at Ser 112 . PI3K/AKT inhibitor LY294002 restored DTX-induced caspase-3 activation and Bcl-2 phosphorylation, reversed the effect of CCL2 on the viability of A549 cells and enhanced DTX-induced cytotoxicity. These results demonstrated that chemoresistance may be mediated by cell stress responses involving CCL2 expression, suggesting that CCL2 may be a potential target for enhancing the therapeutic effect of DTX in lung cancer.

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“…It is known that MCP-1 secreted from tumor cells is an important determinant in the pathogenesis of human lung cancers. Previous studies have also demonstrated that blockade of MCP-1, as mediated by neutralizing antibodies, in several animal models of non-small cell lung cancer significantly slowed the growth of primary tumors (37,38). These results, thus, supported the notion that FMS could not only suppress the LLC1 cell growth but also attenuate relative inflammation levels in vivo.…”

Section: Fuc-enriched F3 Polysaccharide Fraction Induced Antibodies Rsupporting

confidence: 64%

Immunization of fucose-containing polysaccharides from Reishi mushroom induces antibodies to tumor-associated Globo H-series epitopes

Liao

Liang

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Carbohydrate-based vaccines have shown therapeutic efficacy for infectious disease and cancer. The mushroom Ganoderma lucidum (Reishi) containing complex polysaccharides has been used as antitumor supplement, but the mechanism of immune response has rarely been studied. Here, we show that the mice immunized with a L-fucose (Fuc)-enriched Reishi polysaccharide fraction (designated as FMS) induce antibodies against murine Lewis lung carcinoma cells, with increased antibody-mediated cytotoxicity and reduced production of tumor-associated inflammatory mediators (in particular, monocyte chemoattractant protein-1). The mice showed a significant increase in the peritoneal B1 B-cell population, suggesting FMS-mediated anti-glycan IgM production. Furthermore, the glycan microarray analysis of FMS-induced antisera displayed a high specificity toward tumor-associated glycans, with the antigenic structure located in the nonreducing termini (i.e., Fucα1-2Galβ1-3GalNAc-R, where Gal, GalNAc, and R represent, respectively, Dgalactose, D-N-acetyl galactosamine, and reducing end), typically found in Globo H and related tumor antigens. The composition of FMS contains mainly the backbone of 1,4-mannan and 1,6-α-galactan and through the Fucα1-2Gal, Fucα1-3/4Man, Fucα1-4Xyl, and Fucα1-2Fuc linkages (where Man and Xyl represent D-mannose and D-xylose, respectively), underlying the molecular basis of the FMSinduced IgM antibodies against tumor-specific glycans. mushroom polysaccharide | antitumor activity | anti-Globo H antibody V arious forms of herbal medicine polysaccharides have become valuable as health supplements worldwide (1, 2), suggesting that administration of such polysaccharides may improve innate immunity in vivo. The underlying molecular mechanisms, however, still remain ambiguous. Aberrant terminal fucosylation as well as sialylation in tumor-associated glycans is one of several glycosylation events important in cancer progression (3, 4), and such unusual glycans have recently been used for the development of anticancer vaccines (5-7). As an example, the Globo H-based glycoconjugate vaccines are currently undergoing large-scale clinical trials and have shown promise in therapeutic treatment (8, 9). Studies on the immune response to pathogenic microorganisms (such as Haemophilus influenza type B and Streptococcus pneumonia) have demonstrated that polysaccharides containing repeating antigenic units are generally T cell-independent (TI) (10, 11). Furthermore, recent findings revealed that specific B-cell subsets could establish memory for providing specific Ig synthesis in response to TI-associated polysaccharides (12)(13)(14). In an attempt to understand the biological significance of polysaccharides derived from natural sources, we previously isolated and characterized a crude extract fraction of water-soluble and L-fucose (Fuc)-containing polysaccharides (F3) from Ganoderma lucidum (Reishi) (a mushroom that has been long used as a herb medicine) (15). F3 has since been shown essential for regulation of cytokine network...

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Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8⁺ Cells

Cited by 133 publications

References 47 publications

Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1

Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1

CCL2 influences the sensitivity of lung cancer A549 cells to docetaxel

Immunization of fucose-containing polysaccharides from Reishi mushroom induces antibodies to tumor-associated Globo H-series epitopes

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Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8+ Cells

Cited by 133 publications

References 47 publications

Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1

Linking tumor-associated macrophages, inflammation, and intestinal tumorigenesis: role of MCP-1

CCL2 influences the sensitivity of lung cancer A549 cells to docetaxel

Immunization of fucose-containing polysaccharides from Reishi mushroom induces antibodies to tumor-associated Globo H-series epitopes

Contact Info

Product

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About

Monocyte Chemoattractant Protein–1 Blockade Inhibits Lung Cancer Tumor Growth by Altering Macrophage Phenotype and Activating CD8⁺ Cells