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Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer.
Means AL, Freeman TJ, Zhu J, Woodbury LG, Marincola-Smith P, Wu C, Meyer AR, Weaver CJ, Padmanabhan C, An H, Zi J, Wessinger BC, Chaturvedi R, Brown TD, Deane NG, Coffey RJ, Wilson KT, Smith JJ, Sawyers CL, Goldenring JR, Novitskiy SV, Washington MK, Shi C, Beauchamp RD
(2018) Cell Mol Gastroenterol Hepatol 6: 257-276
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Carcinoma, Cell Line, Cell Line, Tumor, Colitis, Colorectal Neoplasms, Dextran Sulfate, Humans, Inflammation, Intestinal Mucosa, Mice, Mice, Inbred C57BL, Mice, Transgenic, Smad4 Protein, Transforming Growth Factor beta1
Show Abstract · Added September 12, 2018
Background & Aims - Chronic inflammation is a predisposing condition for colorectal cancer. Many studies to date have focused on proinflammatory signaling pathways in the colon. Understanding the mechanisms that suppress inflammation, particularly in epithelial cells, is critical for developing therapeutic interventions. Here, we explored the roles of transforming growth factor β (TGFβ) family signaling through SMAD4 in colonic epithelial cells.
Methods - The gene was deleted specifically in adult murine intestinal epithelium. Colitis was induced by 3 rounds of dextran sodium sulfate in drinking water, after which mice were observed for up to 3 months. Nontransformed mouse colonocyte cell lines and colonoid cultures and human colorectal cancer cell lines were analyzed for responses to TGFβ1 and bone morphogenetic protein 2.
Results - Dextran sodium sulfate treatment was sufficient to drive carcinogenesis in mice lacking colonic expression, with resulting tumors bearing striking resemblance to human colitis-associated carcinoma. Loss of SMAD4 protein was observed in 48% of human colitis-associated carcinoma samples as compared with 19% of sporadic colorectal carcinomas. Loss of increased the expression of inflammatory mediators within nontransformed mouse colon epithelial cells in vivo. In vitro analysis of mouse and human colonic epithelial cell lines and organoids indicated that much of this regulation was cell autonomous. Furthermore, TGFβ signaling inhibited the epithelial inflammatory response to proinflammatory cytokines.
Conclusions - TGFβ suppresses the expression of proinflammatory genes in the colon epithelium, and loss of its downstream mediator, SMAD4, is sufficient to initiate inflammation-driven colon cancer. Transcript profiling: GSE100082.
1 Communities
1 Members
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16 MeSH Terms
Distinct Immunomodulatory Effects of Spermine Oxidase in Colitis Induced by Epithelial Injury or Infection.
Gobert AP, Al-Greene NT, Singh K, Coburn LA, Sierra JC, Verriere TG, Luis PB, Schneider C, Asim M, Allaman MM, Barry DP, Cleveland JL, Destefano Shields CE, Casero RA, Washington MK, Piazuelo MB, Wilson KT
(2018) Front Immunol 9: 1242
MeSH Terms: Animals, Citrobacter rodentium, Colitis, Cytokines, Dextran Sulfate, Disease Models, Animal, Gene Deletion, Immunity, Mucosal, Immunomodulation, Intestinal Mucosa, Male, Mice, Mice, Knockout, Oxidoreductases Acting on CH-NH Group Donors, Spermidine, Spermine
Show Abstract · Added June 23, 2018
Polyamines have been implicated in numerous biological processes, including inflammation and carcinogenesis. Homeostatic regulation leads to interconversion of the polyamines putrescine and the downstream metabolites spermidine and spermine. The enzyme spermine oxidase (SMOX), which back-converts spermine to spermidine, contributes to regulation of polyamine levels, but can also have other effects. We have implicated SMOX in gastric inflammation and carcinogenesis due to infection by the pathogen . In addition, we reported that SMOX can be upregulated in humans with inflammatory bowel disease. Herein, we utilized -deficient mice to examine the role of SMOX in two murine colitis models, infection and dextran sulfate sodium (DSS)-induced epithelial injury. In -infected wild-type (WT) mice, there were marked increases in colon weight/length and histologic injury, with mucosal hyperplasia and inflammatory cell infiltration; these changes were ameliorated in mice. In contrast, with DSS, mice exhibited substantial mortality, and increased body weight loss, colon weight/length, and histologic damage. In -infected WT mice, there were increased colonic levels of the chemokines CCL2, CCL3, CCL4, CXCL1, CXCL2, and CXCL10, and the cytokines IL-6, TNF-α, CSF3, IFN-γ, and IL-17; each were downregulated in mice. In DSS colitis, increased levels of IL-6, CSF3, and IL-17 were further increased in mice. In both models, putrescine and spermidine were increased in WT mice; in mice, the main effect was decreased spermidine and spermidine/spermine ratio. With , polyamine levels correlated with histologic injury, while with DSS, spermidine was inversely correlated with injury. Our studies indicate that SMOX has immunomodulatory effects in experimental colitis polyamine flux. Thus, SMOX contributes to the immunopathogenesis of infection, but is protective in DSS colitis, indicating the divergent effects of spermidine.
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2 Members
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16 MeSH Terms
BVES is required for maintenance of colonic epithelial integrity in experimental colitis by modifying intestinal permeability.
Choksi YA, Reddy VK, Singh K, Barrett CW, Short SP, Parang B, Keating CE, Thompson JJ, Verriere TG, Brown RE, Piazuelo MB, Bader DM, Washington MK, Mittal MK, Brand T, Gobert AP, Coburn LA, Wilson KT, Williams CS
(2018) Mucosal Immunol 11: 1363-1374
MeSH Terms: Adult, Animals, Caco-2 Cells, Cell Line, Cell Line, Tumor, Citrobacter rodentium, Coculture Techniques, Colitis, Ulcerative, Colon, Dextran Sulfate, Epithelial Cells, Escherichia coli, Female, HEK293 Cells, Humans, Intestinal Absorption, Intestinal Mucosa, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Middle Aged, Permeability, RNA, Messenger, Signal Transduction, Tight Junctions
Show Abstract · Added June 23, 2018
Blood vessel epicardial substance (BVES), or POPDC1, is a tight junction-associated transmembrane protein that modulates epithelial-to-mesenchymal transition (EMT) via junctional signaling pathways. There have been no in vivo studies investigating the role of BVES in colitis. We hypothesized that BVES is critical for maintaining colonic epithelial integrity. At baseline, Bves mouse colons demonstrate increased crypt height, elevated proliferation, decreased apoptosis, altered intestinal lineage allocation, and dysregulation of tight junctions with functional deficits in permeability and altered intestinal immunity. Bves mice inoculated with Citrobacter rodentium had greater colonic injury, increased colonic and mesenteric lymph node bacterial colonization, and altered immune responses after infection. We propose that increased bacterial colonization and translocation result in amplified immune responses and worsened injury. Similarly, dextran sodium sulfate (DSS) treatment resulted in greater histologic injury in Bves mice. Two different human cell lines (Caco2 and HEK293Ts) co-cultured with enteropathogenic E. coli showed increased attaching/effacing lesions in the absence of BVES. Finally, BVES mRNA levels were reduced in human ulcerative colitis (UC) biopsy specimens. Collectively, these studies suggest that BVES plays a protective role both in ulcerative and infectious colitis and identify BVES as a critical protector of colonic mucosal integrity.
0 Communities
3 Members
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26 MeSH Terms
Ornithine Decarboxylase in Macrophages Exacerbates Colitis and Promotes Colitis-Associated Colon Carcinogenesis by Impairing M1 Immune Responses.
Singh K, Coburn LA, Asim M, Barry DP, Allaman MM, Shi C, Washington MK, Luis PB, Schneider C, Delgado AG, Piazuelo MB, Cleveland JL, Gobert AP, Wilson KT
(2018) Cancer Res 78: 4303-4315
MeSH Terms: Animals, Azoxymethane, Carcinogenesis, Colitis, Ulcerative, Colon, Colonic Neoplasms, Cytokines, Dextran Sulfate, Inflammation, Macrophage Activation, Macrophages, Male, Mice, Ornithine Decarboxylase, Transcription, Genetic, Up-Regulation
Show Abstract · Added June 15, 2018
Ornithine decarboxylase (ODC) is the rate-limiting enzyme for polyamine biosynthesis and restricts M1 macrophage activation in gastrointestinal (GI) infections. However, the role of macrophage ODC in colonic epithelial-driven inflammation is unknown. Here, we investigate cell-specific effects of ODC in colitis and colitis-associated carcinogenesis (CAC). Human colonic macrophages expressed increased ODC levels in active ulcerative colitis and Crohn's disease, colitis-associated dysplasia, and CAC. Mice lacking in myeloid cells ( mice) that were treated with dextran sulfate sodium (DSS) exhibited improved survival, body weight, and colon length and reduced histologic injury versus control mice. In contrast, GI epithelial-specific knockout had no effect on clinical parameters. Despite reduced histologic damage, colitis tissues of mice had increased levels of multiple proinflammatory cytokines and chemokines and enhanced expression of M1, but not M2 markers. In the azoxymethane-DSS model of CAC, mice had reduced tumor number, burden, and high-grade dysplasia. Tumors from mice had increased M1, but not M2 macrophages. Increased levels of histone 3, lysine 9 acetylation, a marker of open chromatin, were manifest in tumor macrophages of mice, consistent with our findings that macrophage ODC affects histone modifications that upregulate M1 gene transcription during GI infections. These findings support the concept that macrophage ODC augments epithelial injury-associated colitis and CAC by impairing the M1 responses that stimulate epithelial repair, antimicrobial defense, and antitumoral immunity. They also suggest that macrophage ODC is an important target for colon cancer chemoprevention. Ornithine decarboxylase contributes to the pathogenesis of colitis and associated carcinogenesis by impairing M1 macrophage responses needed for antitumoral immunity; targeting ODC in macrophages may represent a new strategy for chemoprevention. .
©2018 American Association for Cancer Research.
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2 Members
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16 MeSH Terms
BVES regulates c-Myc stability via PP2A and suppresses colitis-induced tumourigenesis.
Parang B, Kaz AM, Barrett CW, Short SP, Ning W, Keating CE, Mittal MK, Naik RD, Washington MK, Revetta FL, Smith JJ, Chen X, Wilson KT, Brand T, Bader DM, Tansey WP, Chen R, Brentnall TA, Grady WM, Williams CS
(2017) Gut 66: 852-862
MeSH Terms: Animals, Biomarkers, Tumor, Caco-2 Cells, Carcinogenesis, Cell Adhesion Molecules, Colitis, Colitis, Ulcerative, Colon, Colonic Neoplasms, DNA Methylation, Dextran Sulfate, Down-Regulation, Female, Gene Expression Profiling, HEK293 Cells, Humans, Male, Membrane Proteins, Mice, Mice, Knockout, Muscle Proteins, Promoter Regions, Genetic, Protein Phosphatase 2, Proto-Oncogene Proteins c-myc, RNA, Messenger, Wnt Signaling Pathway
Show Abstract · Added April 15, 2017
OBJECTIVE - Blood vessel epicardial substance (BVES) is a tight junction-associated protein that regulates epithelial-mesenchymal states and is underexpressed in epithelial malignancy. However, the functional impact of BVES loss on tumourigenesis is unknown. Here we define the in vivo role of BVES in colitis-associated cancer (CAC), its cellular function and its relevance to patients with IBD.
DESIGN - We determined promoter methylation status using an Infinium HumanMethylation450 array screen of patients with UC with and without CAC. We also measured mRNA levels in a tissue microarray consisting of normal colons and CAC samples. and wild-type mice (controls) were administered azoxymethane (AOM) and dextran sodium sulfate (DSS) to induce tumour formation. Last, we used a yeast two-hybrid screen to identify BVES interactors and performed mechanistic studies in multiple cell lines to define how BVES reduces c-Myc levels.
RESULTS - mRNA was reduced in tumours from patients with CAC via promoter hypermethylation. Importantly, promoter hypermethylation was concurrently present in distant non-malignant-appearing mucosa. As seen in human patients, was underexpressed in experimental inflammatory carcinogenesis, and mice had increased tumour multiplicity and degree of dysplasia after AOM/DSS administration. Molecular analysis of tumours revealed Wnt activation and increased c-Myc levels. Mechanistically, we identified a new signalling pathway whereby BVES interacts with PR61α, a protein phosphatase 2A regulatory subunit, to mediate c-Myc destruction.
CONCLUSION - Loss of BVES promotes inflammatory tumourigenesis through dysregulation of Wnt signalling and the oncogene c-Myc. promoter methylation status may serve as a CAC biomarker.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.
0 Communities
4 Members
0 Resources
26 MeSH Terms
EGFR-mediated macrophage activation promotes colitis-associated tumorigenesis.
Hardbower DM, Coburn LA, Asim M, Singh K, Sierra JC, Barry DP, Gobert AP, Piazuelo MB, Washington MK, Wilson KT
(2017) Oncogene 36: 3807-3819
MeSH Terms: Animals, Carcinogenesis, Colitis, Colon, Colonic Neoplasms, Dextran Sulfate, ErbB Receptors, Humans, Immunity, Innate, Macrophage Activation, Macrophages, Male, Mice, Inbred C57BL, Mice, Transgenic, Neovascularization, Pathologic, Precancerous Conditions, Signal Transduction
Show Abstract · Added March 12, 2017
Epidermal growth factor receptor (EGFR) signaling is a known mediator of colorectal carcinogenesis. Studies have focused on the role of EGFR signaling in epithelial cells, although the exact nature of the role of EGFR in colorectal carcinogenesis remains a topic of debate. Here, we present evidence that EGFR signaling in myeloid cells, specifically macrophages, is critical for colon tumorigenesis in the azoxymethane-dextran sodium sulfate (AOM-DSS) model of colitis-associated carcinogenesis (CAC). In a human tissue microarray, colonic macrophages demonstrated robust EGFR activation in the pre-cancerous stages of colitis and dysplasia. Utilizing the AOM-DSS model, mice with a myeloid-specific deletion of Egfr had significantly decreased tumor multiplicity and burden, protection from high-grade dysplasia and significantly reduced colitis. Intriguingly, mice with gastrointestinal epithelial cell-specific Egfr deletion demonstrated no differences in tumorigenesis in the AOM-DSS model. The alterations in tumorigenesis in myeloid-specific Egfr knockout mice were accompanied by decreased macrophage, neutrophil and T-cell infiltration. Pro-tumorigenic M2 macrophage activation was diminished in myeloid-specific Egfr-deficient mice, as marked by decreased Arg1 and Il10 mRNA expression and decreased interleukin (IL)-4, IL10 and IL-13 protein levels. Surprisingly, diminished M1 macrophage activation was also detectable, as marked by significantly reduced Nos2 and Il1b mRNA levels and decreased interferon (IFN)-γ, tumor necrosis factor (TNF)-α and IL-1β protein levels. The alterations in M1 and M2 macrophage activation were confirmed in bone marrow-derived macrophages from mice with the myeloid-specific Egfr knockout. The combined effect of restrained M1 and M2 macrophage activation resulted in decreased production of pro-angiogenic factors, CXCL1 and vascular endothelial growth factor (VEGF), and reduced CD31 blood vessels, which likely contributed to protection from tumorigenesis. These data reveal that EGFR signaling in macrophages, but not in colonic epithelial cells, has a significant role in CAC. EGFR signaling in macrophages may prove to be an effective biomarker of CAC or target for chemoprevention in patients with inflammatory bowel disease.
0 Communities
3 Members
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17 MeSH Terms
The human intestinal microbiota of constipated-predominant irritable bowel syndrome patients exhibits anti-inflammatory properties.
Gobert AP, Sagrestani G, Delmas E, Wilson KT, Verriere TG, Dapoigny M, Del'homme C, Bernalier-Donadille A
(2016) Sci Rep 6: 39399
MeSH Terms: Animals, Anti-Inflammatory Agents, Colitis, Cytokines, Dextran Sulfate, Dysbiosis, Gastrointestinal Microbiome, Humans, Inflammation, Intestines, Irritable Bowel Syndrome, Mice, Mice, Inbred C57BL, Microbiota, Rats
Show Abstract · Added December 17, 2016
The intestinal microbiota of patients with constipated-predominant irritable bowel syndrome (C-IBS) displays chronic dysbiosis. Our aim was to determine whether this microbial imbalance instigates perturbation of the host intestinal mucosal immune response, using a model of human microbiota-associated rats (HMAR) and dextran sulfate sodium (DSS)-induced experimental colitis. The analysis of the microbiota composition revealed a decrease of the relative abundance of Bacteroides, Roseburia-Eubacterium rectale and Bifidobacterium and an increase of Enterobacteriaceae, Desulfovibrio sp., and mainly Akkermansia muciniphila in C-IBS patients compared to healthy individuals. The bacterial diversity of the gut microbiota of healthy individuals or C-IBS patients was maintained in corresponding HMAR. Animals harboring a C-IBS microbiota had reduced DSS colitis with a decreased expression of pro-inflammatory cytokines from innate, Th1, and Th17 responses. The pre-treatment of conventional C57BL/6 mice or HMAR with A. muciniphila, but not with Escherichia coli, prior exposure to DSS also resulted in a reduction of colitis severity, highlighting that the anti-inflammatory effect of the gut microbiota of C-IBS patients is mediated, in part, by A. muciniphila. This work highlights a novel aspect of the crosstalk between the gut microbiota of C-IBS patients and host intestinal homeostasis.
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1 Members
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15 MeSH Terms
Neonatal colonization of mice with LGG promotes intestinal development and decreases susceptibility to colitis in adulthood.
Yan F, Liu L, Cao H, Moore DJ, Washington MK, Wang B, Peek RM, Acra SA, Polk DB
(2017) Mucosal Immunol 10: 117-127
MeSH Terms: Animals, Animals, Newborn, Cell Proliferation, Cells, Cultured, Colitis, Dextran Sulfate, Disease Models, Animal, Female, Gastrointestinal Microbiome, Humans, Immunoglobulin A, Intestinal Mucosa, Intestines, Lactobacillus rhamnosus, Mice, Mice, Inbred C57BL, Pregnancy, Probiotics, Symbiosis, Tight Junctions
Show Abstract · Added April 26, 2016
Development of the intestinal microbiota during early life serves as a key regulatory stage in establishing the host-microbial relationship. This symbiotic relationship contributes to developing host immunity and maintaining health throughout the life span. This study was to develop an approach to colonize conventionally raised mice with a model probiotic bacterium, Lactobacillus rhamnosus GG (LGG), and to determine the effects of LGG colonization on intestinal development and prevention of colitis in adulthood. LGG colonization in conventionally raised was established by administering LGG to pregnant mice starting at gestational day 18 and pups at postnatal days 1- 5. LGG colonization promoted bodyweight gain and increased diversity and richness of the colonic mucosa-associated microbiota before weaning. Intestinal epithelial cell proliferation, differentiation, tight junction formation, and mucosal IgA production were all significantly enhanced in LGG-colonized mice. Adult mice colonized with LGG showed increased IgA production and decreased susceptibility to intestinal injury and inflammation induced in the dextran sodium sulfate model of colitis. Thus, neonatal colonization of mice with LGG enhances intestinal functional maturation and IgA production and confers lifelong health consequences on protection from intestinal injury and inflammation. This strategy might be applied for benefiting health in the host.
0 Communities
2 Members
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20 MeSH Terms
Bilirubin prevents acute DSS-induced colitis by inhibiting leukocyte infiltration and suppressing upregulation of inducible nitric oxide synthase.
Zucker SD, Vogel ME, Kindel TL, Smith DL, Idelman G, Avissar U, Kakarlapudi G, Masnovi ME
(2015) Am J Physiol Gastrointest Liver Physiol 309: G841-54
MeSH Terms: Animals, Bilirubin, Cell Movement, Colitis, Colon, Cytotoxins, Dextran Sulfate, Interleukin-5, Intestinal Mucosa, Leukocytes, Male, Mice, Mice, Inbred C57BL, Nitric Oxide Synthase Type II, Protective Agents, Up-Regulation, Vascular Cell Adhesion Molecule-1
Show Abstract · Added April 27, 2017
Bilirubin is thought to exert anti-inflammatory effects by inhibiting vascular cell adhesion molecule-1 (VCAM-1)-dependent leukocyte migration and by suppressing the expression of inducible nitric oxide synthase (iNOS). As VCAM-1 and iNOS are important mediators of tissue injury in the dextran sodium sulfate (DSS) murine model of inflammatory colitis, we examined whether bilirubin prevents colonic injury in DSS-treated mice. Male C57BL/6 mice were administered 2.5% DSS in the drinking water for 7 days, while simultaneously receiving intraperitoneal injections of bilirubin (30 mg/kg) or potassium phosphate vehicle. Disease activity was monitored, peripheral blood counts and serum nitrate levels were determined, and intestinal specimens were analyzed for histological injury, leukocyte infiltration, and iNOS expression. The effect of bilirubin on IL-5 production by HSB-2 cells and on Jurkat cell transendothelial migration also was determined. DSS-treated mice that simultaneously received bilirubin lost less body weight, had lower serum nitrate levels, and exhibited reduced disease severity than vehicle-treated animals. Concordantly, histopathological analyses revealed that bilirubin-treated mice manifested significantly less colonic injury, including reduced infiltration of eosinophils, lymphocytes, and monocytes, and diminished iNOS expression. Bilirubin administration also was associated with decreased eosinophil and monocyte infiltration into the small intestine, with a corresponding increase in peripheral blood eosinophilia. Bilirubin prevented Jurkat migration but did not alter IL-5 production. In conclusion, bilirubin prevents DSS-induced colitis by inhibiting the migration of leukocytes across the vascular endothelium and by suppressing iNOS expression.
Copyright © 2015 the American Physiological Society.
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1 Members
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17 MeSH Terms
Peroxisome proliferator-activated receptor δ promotes colonic inflammation and tumor growth.
Wang D, Fu L, Ning W, Guo L, Sun X, Dey SK, Chaturvedi R, Wilson KT, DuBois RN
(2014) Proc Natl Acad Sci U S A 111: 7084-9
MeSH Terms: Adenoma, Animals, Cell Communication, Cell Line, Tumor, Colitis, Colorectal Neoplasms, Cyclooxygenase 2, Dextran Sulfate, Dietary Fats, Dinoprostone, Epithelial Cells, Humans, Macrophages, Male, Mice, Mice, Knockout, Monocytes, Receptors, Cytoplasmic and Nuclear
Show Abstract · Added May 27, 2014
Although epidemiologic and experimental evidence strongly implicates chronic inflammation and dietary fats as risk factors for cancer, the mechanisms underlying their contribution to carcinogenesis are poorly understood. Here we present genetic evidence demonstrating that deletion of peroxisome proliferator-activated receptor δ (PPARδ) attenuates colonic inflammation and colitis-associated adenoma formation/growth. Importantly, PPARδ is required for dextran sodium sulfate induction of proinflammatory mediators, including chemokines, cytokines, COX-2, and prostaglandin E2 (PGE2), in vivo. We further show that activation of PPARδ induces COX-2 expression in colonic epithelial cells. COX-2-derived PGE2 stimulates macrophages to produce proinflammatory chemokines and cytokines that are responsible for recruitment of leukocytes from the circulation to local sites of inflammation. Our results suggest that PPARδ promotes colonic inflammation and colitis-associated tumor growth via the COX-2-derived PGE2 signaling axis that mediates cross-talk between tumor epithelial cells and macrophages.
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2 Members
0 Resources
18 MeSH Terms