Increased expression of MUC1 in advanced pancreatic cancer

Hinoda, Yuji; Ikematsu, Yoshito; Horinochi, Michiko; Sato, Shuji; Yamamoto, Kotaro T.; Nakano, Tomoko; Fukui, Minoru; Suehiro, Yutaka; Hamanaka, Yuichiro; Nishikawa, Yoshiro; Kida, Hideo; Waki, Shinji; Oka, M.; Imai, Kohzoh; Yonezawa, Suguru

doi:10.1007/s00535-003-1224-6

Cited by 88 publications

(63 citation statements)

References 24 publications

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“…Several reports have investigated MUC1 or MUC2. Overexpression of MUC1 in pancreatic cancer is associated with poor prognosis (31), and there is disputed evidence that tumors associated with MUC1 directly influence the response of immunocytes. For example, MUC1 inhibits the function of effector cells such as natural killer cells, lymphokine-activated killer cells, and cytotoxic T-cells.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

Hoshi

Sawada

Uchida³

et al. 2011

Int J Oncol

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“…Current theory holds that MUC1 is involved in configuring the cell surface properties of epithelial cells, associating with receptors for growth factors and differentiation factors at the cell surface, and signaling or modifying signal transduction in the cell in response to different cell surface conditions (adhesion, cellular polarity, and cellular neighborhood) or stimulation with growth or differentiation factors (9). Moreover, overexpression of MUC1 in pancreatic cancer is associated with poor prognosis (10,11). Thus, suppressing expression of MUC1 in pancreatic tumor cells would be predicted to affect different aspects of the malignant and metastatic properties of cancer, including proliferation, invasion, metastasis, or differentiation status.…”

Section: Discussionmentioning

confidence: 99%

RNA Interference Suppression of MUC1 Reduces the Growth Rate and Metastatic Phenotype of Human Pancreatic Cancer Cells

Tsutsumida

Swanson

Singh

et al. 2006

Clinical Cancer Research

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104

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MUC1is a highly glycosylated, type I transmembrane protein expressed by normal ductal epithelial cells of the pancreas, breast, lung, and gastrointestinal tract, and overexpressed in many cases of adenocarcinoma.We down-regulated MUC1expression by RNA interference and investigated the effects on malignant and metastatic potential of a human pancreatic cancer cell line, S2-013. MUC1-suppressed clones, S2-013.MTII.C1and S2-013.MTII.C2, were established by targeting a sequence 3,151 bp from the initiation codon and characterized in vitro for proliferation, invasion, and adhesion. We evaluated the effects of MUC1 suppression in vivo on tumor growth and metastatic properties following implantation into the cecum or pancreas of athymic mice. MUC1-suppressed clones showed significantly decreased proliferation in vitro and in vivo. Global gene expression was evaluated by oligonucleotide microarray analysis. Surprisingly, genes predicted to increase doubling times (cyclin B1 and cyclin D3) were overexpressed in MUC1-suppressed clones. There were alterations in expression of several genes that may affect the malignant properties of pancreatic cancer. Adhesion of MUC1-suppressed cells in vitro to type IV collagen and fibronectin was slightly increased, and adhesion was slightly decreased to type I collagen and laminin. Results of implantation to cecum and pancreas showed significant reduction of metastasis to lymph nodes, lung, or peritoneal sites compared with S2-013.gfp-neo control cells. These results support the hypothesis that MUC1 contributes significantly to growth and metastasis, and that down-regulation of MUC1 protein expression decreases the metastatic potential of pancreatic adenocarcinoma.In spite of recent efforts to improve prevention, screening, and therapy, pancreatic cancer has a poor prognosis: a 5-year survival rate of f3% and a median survival of <6 months (1). The poor prognosis is a consequence of metastatic disease that results from a lack of early detection and effective treatment. MUC1 is a polymorphic, highly glycosylated, type I transmembrane protein expressed by ductal epithelial cells of secretory organs, including the pancreas, breast, lung, and gastrointestinal tract (2), which is overexpressed and aberrantly glycosylated in most cases of adenocarcinoma. Previously, we investigated the role of MUC1 in invasion and metastasis by heterotopic implantation of tumor fragments onto the cecum of nude mice (3). Overexpressing full-length MUC1 in the pancreatic tumor cell line, S2-013, which expresses low levels of endogenous MUC1 and is spontaneously metastatic in the nude mouse model, altered the propensity for these cells to metastasize to lymph nodes and lungs.Overexpressing two mutant forms of MUC1, tandem repeat deleted [MUC1(CTR)] or cytoplasmic tail deleted (MUC1F.CT3), eliminated the phenotype and restored to control levels the degree of metastasis to lymph nodes and lung. DNA microarray analyses on clonal populations of these cells revealed very few differences in gene expression p...

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“…One of such biomarkers, sialylated MUC-1 mucin, which is expressed preferentially in pancreatic cancer cells (82) and was correlated with tumor aggressiveness and patient survival (83), has been proposed and used as a potential antigen in a pilot, feasibility trial of vaccination in patients with pancreas and biliary cancer (84). Interestingly, mesothelin, one of the pancreas-related proteins recently discovered and discussed before, has been shown to be a potentially relevant immunologic target (85).…”

Section: Immunologic Markersmentioning

confidence: 99%

Molecular biomarkers: their increasing role in the diagnosis, characterization, and therapy guidance in pancreatic cancer

Jimeno

Hidalgo

2006

Molecular Cancer Therapeutics

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The rapidly expanding knowledge of the pathogenesis of pancreatic cancer at the molecular level is providing new targets for disease characterization, early diagnosis, and drug discovery and development. Gene mutation analysis has provided insight on the pathogenesis and progression from preinvasive lesions to invasive cancer. Gene and protein expression profiling has advanced our understanding of pancreatic ductal adenocarcinoma identifying genes that are highly expressed in pancreatic cancers, providing more insight into the clinicopathologic features of pancreatic cancer, and revealing novel features related to the process of tissue invasion by these tumors. The increasing knowledge of the pathway activation profile in pancreatic cancer is yielding new targets but also new markers to select patients and guide and predict therapy efficacy. The discovery of genetic factors of which the presence predisposes pancreatic cancer to successful targeting, such as the association of BRCA2/Fanconi anemia genes defects and sensitivity to mitomycin C, will eventually lead to a more individualized treatment approach. In summary, several decades of intensive research have originated multiple factors or biomarkers that are likely to be helpful in the diagnosis, characterization, and therapy selection of pancreatic cancer patients. A deep understanding of the relative relevance of each biomarker will be key to efficiently diagnose this disease and direct our patients towards the drugs more likely to be of benefit based on their particular profile. The development of new preclinical models is of paramount importance to achieve these goals. [Mol Cancer Ther 2006;5(4):787 -96]

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Increased expression of MUC1 in advanced pancreatic cancer

Abstract: Our data suggest that the expression of MUC1 may be related to the progression of pancreatic cancer.

Cited by 88 publications

References 24 publications

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

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

RNA Interference Suppression of MUC1 Reduces the Growth Rate and Metastatic Phenotype of Human Pancreatic Cancer Cells

Molecular biomarkers: their increasing role in the diagnosis, characterization, and therapy guidance in pancreatic cancer

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