Induction of cyclooxygenase-2 in monocyte/macrophage by mucins secreted from colon cancer cells

Inaba, Takaaki; Sano, Hajime; Kawahito, Yutaka; Hla, Timothy; Akita, Kaoru; Toda, Munetoyo; Yamashina, Ikuo; Inoue, Mizue; Nakada, Hiroshi

doi:10.1073/pnas.0435410100

Cited by 64 publications

(53 citation statements)

References 31 publications

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“…Also, soluble MUC1 induces apoptosis of activated T cells and inhibits the proliferation of natural killer cells and cytotoxic T-cells (32,33). MUC2 has been reported to bind to a scavenger receptor of monocytes/macrophages and leads to the overproduction of PGE2, which suppresses immunocytes through COX2 (34,35). In this study, the growth of MUC5AC-knockdown cells was inhibited in not only xenografted tumors but also a lung metastasis mode (Table I).…”

Section: Discussionmentioning

confidence: 55%

Tumor-associated MUC5AC stimulates in vivo tumorigenicity of human pancreatic cancer

Hoshi

Sawada

Uchida³

et al. 2011

Int J Oncol

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Abstract. MUC5AC, a high molecular weight glycoprotein, is overexpressed in the ductal region of human pancreatic cancer but is not detectable in the normal pancreas, suggesting its association with disease development. In the present study, we investigated the in vitro and in vivo effects of MUC5AC knockdown by short interfering RNA (siRNA) in the MUC5AC-overexpressing SW1990 and BxPC3 human pancreatic cancer cell lines in order to clarify its function. Significant decreases in the expression levels of MUC5AC mRNA and protein were observed in SW1990 and BxPC3 cells that had been stably transfected with a MUC5AC siRNA expression vector (SW1990/si-MUC5AC and BxPC3/si-MUC5AC cells) compared to those in cells transfected with an si-mock vector (SW1990/si-mock and BxPC3/si-mock cells). In in vitro studies, neither type of MUC5AC-knockdown cell showed any difference in cell survival, proliferation, or morphology from the si-mock cells or parental cells. However, in vivo xenograft studies demonstrated that MUC5AC knockdown significantly reduced the tumorigenicity and suppressed the tumor growth of si-MUC5AC cells compared to those of the si-mock cells. Immunohistochemical analysis revealed that CD45R/B220 + and Gr-1 + cells had infiltrated into the tumor tissue of the SW1990/si-MUC5AC cells. Furthermore, cancer-associated antigen specific antibodies were detected at high levels in the sera from the SW1990/si-MUC5AC cell-bearing mice. These results suggest that tumorassociated MUC5AC expressed on the surface of pancreatic cancer cells supports the escape of pancreatic cancer cells from immunosurveillance. The present findings highlight a new dimension of MUC5AC as a functional immunosuppressive agent and its important role in pancreatic cancer progression.

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Section: Discussionmentioning

confidence: 55%

Tumor-associated MUC5AC stimulates in vivo tumorigenicity of human pancreatic cancer

Hoshi

Sawada

Uchida³

et al. 2011

Int J Oncol

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“…Possible natural ligands include glycoprotein hormones, microbes, sulfated glycolipids, and glycosaminoglycans that bear various sulfate residues (56). 4 Lewis X and 3-SO 4 -LeA (but not 6-SO 4 -Lewis X or 6-SO 4 -LeA), as well as polyanionic ligands such as acetyl-LDL, poly(I), fucoidan, and lipopolysaccharide (57).…”

Section: Resultsmentioning

confidence: 99%

Multiple Hepatic Receptors Cooperate to Eliminate Secretory Mucins Aberrantly Entering the Bloodstream: Are Circulating Cancer Mucins the “Tip of the Iceberg”?

Wahrenbrock

Varki

2006

Cancer Research

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Hollow organs lined by columnar epithelial cells normally secrete mucins and their proteolytic fragments vectorially into the lumen. These heterogeneously O-glycosylated molecules are known to aberrantly enter the bloodstream in the setting of epithelial carcinomas and possibly during injury or inflammation. We have recently shown that carcinoma mucin fragments can trigger the rapid formation of platelet-rich microthrombi in vivo. Thus, mechanisms to clear such aberrantly secreted mucins must exist. Indeed, we found that i.v. injected carcinoma mucin fragments had an f1 minute half-life in mice, which was primarily due to rapid clearance by hepatic reticuloendothelial cells. Inhibition of known glycan-recognizing hepatic clearance receptors showed involvement of multiple partially overlapping clearance systems. Studies of genetically deficient mice and incomplete competition between different mucins confirmed this result. Thus, multiple hepatic clearance receptors cooperate to eliminate secretory mucins entering the circulation, limiting potential pathology. This may also explain why mucin-type clustered O-glycosylation is rare on plasma proteins. Notably, small subsets of injected carcinoma mucins remained unrecognized by clearance systems, had a much longer half-life, and carried highly sialylated O-glycans. Similar circulating mucins were found in tumor-bearing mice despite lack of saturation of hepatic clearance mechanisms. Thus, circulating cancer mucins currently used as clinical diagnostic markers likely represent only the clearance-resistant ''tip of the iceberg.'' Such aberrantly circulating mucins could play pathologic roles not only in cancer but also during injury or inflammation of hollow organs and in liver disease. (Cancer Res 2006; 66(4): 2433-41)

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“…For example cancer cellderived mucins lead to the induction of the tumor-promoter COX2 in stromal cells [61]. The engagement of ECM receptors, e.g.…”

Section: The Extracellular Matrixmentioning

confidence: 99%

A Digest on the Role of the Tumor Microenvironment in Gastrointestinal Cancers

Augsten

Hägglöf

Peña

et al. 2010

Cancer Microenvironment

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Experimental studies and analyses of clinical material have convincingly demonstrated that tumor formation and progression occurs through a concerted action of malignant cells and the surrounding microenvironment of the tumor stroma. The tumor microenvironment is comprised of various cell types like fibroblasts, immune cells, vascular cells and bone-marrow-derived cells embedded in the extracellular matrix. This review, focusing on recent findings in the context of gastrointestinal tumors, introduces the different stromal cell types and delineates their contributions to cancer initiation, growth and metastasis. By selected examples we also present how the tumor microenvironment is emerging as a promising target for therapeutic intervention.

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Induction of cyclooxygenase-2 in monocyte/macrophage by mucins secreted from colon cancer cells

Cited by 64 publications

References 31 publications

Tumor-associated MUC5AC stimulates in vivo tumorigenicity of human pancreatic cancer

Tumor-associated MUC5AC stimulates in vivo tumorigenicity of human pancreatic cancer

Multiple Hepatic Receptors Cooperate to Eliminate Secretory Mucins Aberrantly Entering the Bloodstream: Are Circulating Cancer Mucins the “Tip of the Iceberg”?

A Digest on the Role of the Tumor Microenvironment in Gastrointestinal Cancers

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