Combined status of MUC1 mucin and surfactant apoprotein A expression can predict the outcome of patients with small‐size lung adenocarcinoma

Tsutsumida, Hideaki; Goto, Masamichi; Kitajima, Shinichi; Kubota, Ichiro; Hirotsu, Yasunobu; Yonezawa, Suguru

doi:10.1111/j.1365-2559.2004.01797.x

Cited by 44 publications

(39 citation statements)

References 41 publications

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“…Nonetheless, these animals showed significantly improved survival compared with animals challenged with tumors in which MUC1 was not suppressed. This is consistent with clinical findings, which suggest that increased tumor growth rates (18 -20) or MUC1 expression (21,22) are associated with poor prognosis in many types of cancers.…”

Section: Discussionsupporting

confidence: 81%

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

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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Section: Discussionsupporting

confidence: 81%

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

104

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“…9 Jiang et al 18 reported that a deletion in the surfactant apoprotein A gene contributed to a poor prognosis in stage IA lung cancer; in the current study, the micropapillary pattern area always showed high MUC1 expression and loss of surfactant apoprotein A was predictive of a poor prognosis in cases with a micropapillary pattern.…”

Section: Discussionmentioning

confidence: 70%

“…9 Therefore, we investigated MUC1 and surfactant apoprotein A expression in the micropapillary pattern area and performed statistical analysis using the Kaplan-Meier method for the 21 micropapillary pattern-positive cases. Typical immunohistochemical findings are shown in Figure 5.…”

Section: Surfactant Apoprotein a Expression And Outcomementioning

confidence: 99%

A micropapillary pattern is predictive of a poor prognosis in lung adenocarcinoma, and reduced surfactant apoprotein A expression in the micropapillary pattern is an excellent indicator of a poor prognosis

et al. 2007

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A micropapillary pattern is defined as papillary tufts without a fibrovascular core and is known to be a factor that indicates a poor prognosis in numerous cancers. However, their role in lung adenocarcinoma has not been investigated widely. In 185 cases of small-size lung adenocarcinoma (r3 cm), cases with a micropapillary pattern ratio of more than 1% (analyzed by NIH image) were defined as micropapillary pattern positive. Correlations between the micropapillary pattern and clinicopathological factors were investigated and immunohistochemical expression of mucin and various antigens was examined in regions with and without micropapillary patterns. Micropapillary pattern-positive tumors (micropapillary pattern ratio Z1%) were observed in 11.4% of cases (21/185) and the micropapillary pattern ratio correlated with TNM stage (P ¼ 0.0002), lymphatic invasion (P ¼ 0.0002) and lymph node metastasis (P ¼ 0.03). Disease-free interval (Po0.0002) and survival (P ¼ 0.027) were significantly shorter for micropapillary pattern-positive patients, and micropapillary pattern-positive stage IA cases also had a significantly shorter disease-free interval (Po0.0001). MUC1 was expressed strongly across the surface of the micropapillary structure, whereas MUC4 tended to show lower expression in the micropapillary pattern. It was noteworthy that the disease-free interval in patients with high surfactant apoprotein A expression was significantly better than in patients with low surfactant apoprotein A expression (P ¼ 0.03), and no recurrence or death occurred in patients with high surfactant apoprotein A expression. Our results show that the micropapillary pattern ratio correlates with lymphatic invasion and lymph node metastasis, and that a high micropapillary pattern ratio leads to a poor prognosis. High MUC1 expression on the surface is an important characteristic of a micropapillary pattern, and reduced surfactant apoprotein A expression in the micropapillary pattern may be an excellent indicator for poor prognosis in small-size lung adenocarcinoma.

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“…Evidence suggests that this overexpression was not due to a gene amplification event, but to an as yet unknown mechanism. MUC1 overexpression is associated with poor prognosis in breast (Rakha et al, 2005) and lung adenocarcinoma (Tsutsumida et al, 2004); however, its influence in the prognosis of mesothelioma has not been reported.…”

Section: Discussionmentioning

confidence: 95%

Overexpression and altered glycosylation of MUC1 in malignant mesothelioma

et al. 2008

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Current interest in the MUC1/EMA mucin relates to its role in malignancy, and its potential as a therapeutic target. MUC1/EMA expression has been observed in the majority of epithelioid mesotheliomas. However, little is known of the characteristics of MUC1/ EMA in mesothelioma. Herein, we studied the cell surface and soluble expression of the MUC1/EMA glycoprotein, and determined the mRNA and genomic expression profiles in mesothelioma. We found that the anti-MUC1 antibody, E29, was the most diagnostically useful of seven antibody clones examined with a sensitivity of 84% (16 out of 19 cases) and no false positive results. MUC1 mRNA expression was significantly higher in mesothelioma samples than in benign mesothelial cells. No amplification of the MUC1 gene was observed by FISH. Seven of 9 mesothelioma samples expressed MUC1-secreted mRNA isoform in addition to the archetypal MUC1/transmembrane form. CA15.3 (soluble MUC1) levels were significantly higher in the serum of mesothelioma patients than in healthy controls but were not significantly different to levels in patients with benign asbestos-related disease. CA15-3 in effusions could differentiate malignant from benign effusions but were not specific for mesothelioma. Thus, as in other cancers, alterations in MUC1 biology occur in mesothelioma and these results suggest that specific MUC1 characteristics may be useful for mesothelioma diagnosis and should also be investigated as a potential therapeutic target.

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Combined status of MUC1 mucin and surfactant apoprotein A expression can predict the outcome of patients with small‐size lung adenocarcinoma

Abstract: A high MUC1/SP-A ratio is strongly associated with a poor outcome in patients with small-size lung adenocarcinoma.

Cited by 44 publications

References 41 publications

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

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

A micropapillary pattern is predictive of a poor prognosis in lung adenocarcinoma, and reduced surfactant apoprotein A expression in the micropapillary pattern is an excellent indicator of a poor prognosis

Overexpression and altered glycosylation of MUC1 in malignant mesothelioma

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