Anti-tumor activity and immune responses induced by human cancer-associated mucin core peptide

Objective: To investigate the immune responses induced by apomucin which is a mixture of mucin core peptide, in mice for elucidating the role of mucin core peptide in the modulation of cancers. Methods: Apomucin was isolated from human pancreatic cancer cell line SW1990. The mice were immunized with this apomucin (10μg/time×6) plus DETOX. Results: When immunized, all mice developed delayed-type hypersensitivity (DTH) after challenged with apomucin or synthetic peptide MUC-2 or MUC-3, while the mice immunized with apomucin alone did not develop DTH. No antibodies were detected by ELISA after immunization. When the spleen cells of vaccinated mice were cocultured with this apomucin (10–50μg/ml) and rhIL-2(50U/ml)in vitro, the proliferated lymphocytes showed cytotoxicity against human cancer cells, including colon cancer, gastric cancer, pancreatic cancer and leukemia as measured by Cr-51 release assay. Antibodies against MUC-2 and MUC-3 could block the cytotoxicity. Conclusion: It was identified that a vaccine combined of apomucin and immune adjuvant DETOX can induce cellular immune response and anti-tumor cytotoxicity in mice. This study was supported by National Natural Science Foundation of China No. 39570792.     

胃粘膜肠化与胃癌关系的粘液组织化学研究

本文应用粘液组织化学技术，对117例胄癌、62例慢性胃炎伴（肠化生）组织的粘液分泌进行观察。根据所含粘液不同，将胄癌分为肠型及胃型，将畅化分为大肠型及小肠型。肠型胃癌的肠化检出率显著高于胃型胃癌（P＜0．01）。大肠型肠化在肠型胃癌旁肠化检出率显著高于在胄型胄癌旁肠化及慢性胃炎伴肠化的检出率（P＜0．01）。肠型胃癌的发生与胄粘膜肠化，特别与大肠型肠化关系密切。因此，加强对大肠型肠化的密切随访．有利于胃癌的早期发现。     

A clinicopathologic study of mucinous adenocarcinoma of the stomach

Background. Mucinous adenocarcinoma of the stomach is a rare histologic type of gastric adenocarcinoma and its features are still controversial. We attempted to clarify the clinicopathologic characteristics of this histologic type. Methods. We reviewed the records of 112 patients with mucinous adenocarcinoma of the stomach (MUC) and 4160 patients with nonmucinous gastric adenocarcinoma (NMUC) for factors including age; sex; tumor location, size, and depth; lymph node metastasis; lymphatic or venous permeation; peritoneal dissemination; liver metastasis; and survival rate. We also investigated the relationship between cancer depth and lymph node metastasis. Statistical analysis included χ ² and Student's t -tests. Survival rates were calculated by the Kaplan-Meier method and analyzed by the log rank test. Results. MUC was found mostly in younger patients, in the lower part of the stomach and was of larger size, invading to or beyond the muscularis propria, positive for lymph node involvement, and associated with peritoneal dissemination. The overall 5-year survival rate in patients with MUC was lower than that in NMUC patients, because the MUC patients more frequently had advanced stage disease; however, the survival rates in the two groups did not differ significantly. As for the relationship between cancer depth and lymph node involvement, the frequency of lymph node metastasis increased when invasion reached the submucosa in patients with MUC compared with those with NMUC while the frequency of lymph node metastasis increased in the muscularis propria in patients with NMUC compared with those with NMUC. Conclusion. MUC was characteristically found in younger patients, at lower sites, at an advanced stage, and with peritoneal dissemination; MUC had a poor prognosis. Lymph node metastasis should be suspected when MUC invades to the submucosa or deeper. Received: March 14, 2001 / Accepted: June 18, 2001     

原发性肺腺癌的粘液组织化学研究

目的：研究原发性肺腺癌产生粘液物质的类型、性质及分布。方法：收集２２例原发性肺腺癌进行五种粘液组化染色，ＡＢｐＨ２．５，ＡＢｐＨ１．０，ＨＩＤ－ＡＢｐＨ２．５，ＡＢｐＨ２．５－ＰＡＳ，ＰＡＳ－Ｄ。结果：２２例均见粘液细胞型粘液，２１例邮被膜型粘液（两者主要为唾液酸粘液），１０例见到腺腔型粘液（硫酸粘液为主）。不同类型不同性质粘液可共存于同一肺腺癌中。结论：被膜型粘肺腺癌一种独立类型粘液，与粘液细胞     

Role of mucins in the skin during benign and malignant conditions

Skin-related diseases comprise a major health challenge to the practicing physician, and constitute a significant psychological, social and financial burden to the society. Further, skin cancer, especially non-melanoma skin cancer is currently the leading type of malignancy in the Western world. Given the huge burden of skin diseases, there is growing emphasis on understanding their pathophysiology, and towards their early detection. Mucins are high-molecular weight O- and N-linked glycoproteins that have emerged in recent years as important molecules in maintaining health and in promoting or protecting against inflammation and cancer. They have also begun to emerge as highly specific diagnostic and prognostic markers and novel therapeutic targets in several malignant disorders. However, their role in cutaneous pathologies has remained largely obscured. The present review provides the expression patterns and proposed role of mucins in the healthy skin and various benign and malignant skin diseases. The review has immense clinical significance as the availability of highly specific reagents including monoclonal antibodies against mucins makes them extremely attractive targets for specific diagnosis and/or immunotherapy of benign and malignant cutaneous diseases.     

胃癌组织形态,粘液类型及CEA表达和肿瘤异质性的研究

应用粘液组化及免疫组化方法对104例胃癌的异质性进行了研究。结果表明：胃癌的组织形态、粘液类型、CEA分布及生物学行为等均存在着异质性，总的可概括为分化水平和功能水平两大方面。提示在肿瘤诊治过程中，判断肿瘤病理类型、生物学行为及对治疗的敏感性均应考虑到肿瘤的异质性。     

垂体腺瘤中黏蛋白1的表达与肿瘤侵袭性的关系

目的 探讨垂体腺瘤中黏蛋白1（MUC1）的表达与肿瘤侵袭性的关系.方法 采用免疫组织化学法检测26例侵袭性垂体腺瘤和29例非侵袭性垂体腺瘤患者肿瘤组织中MUC1的表达.结果 侵袭性垂体腺瘤组织中MUC1高表达,阳性率为76.92％（20/26）;非侵袭性垂体腺瘤组织中MUC1为弱阳性表达或不表达,阳性率为27.57％（8/29）,两者差异有统计学意义（x2=13.35,P＜ 0.01）.功能性垂体腺瘤组织中MUC1阳性率为44.82％（13/35）,非功能垂体腺瘤中MUC1阳性表达率为75.00％（15/20）,两者差异无统计学意义（x2=6.13,P＞ 0.01）.结论 MUC1在侵袭性垂体腺瘤组织中的表达及分布特点可作为垂体腺瘤侵袭性的辅助鉴别诊断指标,有可能作为垂体腺瘤免疫治疗的靶抗原.     

黏蛋白1与多发性骨髓瘤免疫治疗的研究进展

 多发性骨髓瘤（MM）是一种目前不可被治愈的恶性浆细胞肿瘤。免疫治疗在消除MM微小残留病、降低复发、提高患者总生存率方面有重要作用,受到人们越来越多的重视。黏蛋白1（MUC1）为MM相关抗原,以其为靶点的免疫治疗具有良好的应用前景,其中部分MUC1疫苗已经进入临床试验,并报道有临床反应。该文讨论MUC1及其作为MM免疫治疗靶点的最新研究进展。     

Expression of Sulfomucins in Normal Mucosae, Colorectal Adenocarcinomas and Metastases

We have examined the expression of specific mucin antigens in tissue sections from 92 cases of colorectal carcinoma, using sulfomucin-specific monoclonal antibody (MAb) 91.9H. The expression of sulfomucins was high in normal mucosae and much lower in primary colorectal carcinoma, in metastatic lesions in lymph nodes or in liver. The intracellular localization of sulfomucins was also different among these tissues. In normal mucosae, MAb 91.9H binding was seen in the supranuclear area, presumably Golgi complexes, the luminal surface, and secretory products. In primary colorectal carcinomas and in their metastatic lesions, MAb 91.9H was preferentially localized in the cell surface and substances attached to the luminal surface of glandular structures. Analysis of the lysates of normal and tumor tissues showed that very-high-molecular-weight components contained the antigenic epitopes. The intensity of MAb 91.9H binding was lower in tumors at advanced stages than in tumors at early stages. These high-molecular-weight components were apparently reactive with MAb FH6 specific for sialyl-Le^x (s-Le^x) structures. Histological specimens with low levels of MAb 91.9H reactivity often exhibited relatively high levels of MAb FH6 reactivity. These two mucins may have reversed expression during carcinogenesis and carcinoma progression, and this change may be related to metastatic potential.     

胃粘膜肠化、异型增生和胃癌组织粘液组化及PCNA表达的相关分析

本文对３４例胃粘膜肠化、３２例异型增生、２２例胃癌行粘液化及ＰＣＮＡ免疫组化研究。结果表明：唾酸粘液阳性与肠化、异型增生、胃癌呈负相关，而硫酸粘液阳性呈正相关。ＰＣＮＡ阳性、肠化与异型增生及胃癌差异有显著意义（Ｐ＜０．０５），而异型增生与胃癌差异无显著意义（Ｐ＞０．０５）。唾酸粘液阳性者，ＰＣＮＡ阳性率为２６．３％，而硫酸粘液阳性者为９２．０％，两者有非常显著差异（Ｐ＜０．０１）。     

MUC3诱导抗肿瘤免疫反应的实验研究

目的　探讨肿瘤粘液糖蛋白的核心多肽ＭＵＣ３诱导的抗肿瘤免疫反应。方法　测定多肽ＭＵＣ３ 免疫后小鼠的皮肤迟发性超敏反应（ＤＴＨ）和脾淋巴细胞的体外细胞毒反应。结果　ＭＵＣ３可以诱导小鼠的ＤＴＨ反应;体外脾淋巴细胞对ＭＵＣ３表达阳性的粘液腺癌细胞系,如人胰腺癌细胞株ＳＷ１９９０、人胃癌细胞株ＫＡＴＯ３都具有强的细胞毒作用,ＭＵＣ３的抗体Ｍ３Ｐ可以抑制体外鼠脾细胞的细胞毒作用。结论　ＭＵＣ３作为一类重要的肿瘤相关抗原,可以诱导小鼠的细胞免疫反应,并可能作为一有效的免疫原用于提高抗肿瘤免疫反应。     

Cronkhite-Canada syndrome complicated with huge intramucosal gastric cancer

Cronkhite-Canada syndrome (CCS) is a rare nonhereditary disorder with gastrointestinal polyposis and associated ectodermal changes. This report documents a 59-year-old Japanese man with CCS who underwent a total gastrectomy for gastric tumors. The resected specimen showed a huge gastric adenocarcinoma with numerous polyps throughout the stomach. The cancer was pathologically limited to within the mucosa and its histological structure resembled that of hyperplasia in CCS polyps, which led us to suppose that the carcinoma had arisen from hyperplastic CCS polyps. These results urged us to study the phenotypic expression of mucins, which revealed MUC2(−) and MUC5AC(+) and supported the diagnosis of the tumor as a gastric-type well-differentiate adenocarcinoma. A literature search revealed that 32 gastric carcinomas which developed in patients with CCS were mostly limited to within the submucosa in spite of their huge sizes, and such cancer development in CCS polyposis is therefore not considered to be unusual.     

Time trends for small gastric cancer in Japan

Background. Gastric cancer rates in Japan have been declining since the 1970s. The rate of differentiated carcinomas has decreased and that of undifferentiated carcinomas has increased. However, little is known about the time trends of small gastric cancer. The aim of this study was to investigate the trends of small gastric cancer over time in Japan. Methods. We reviewed cases of small gastric cancer (less than 20 mm in diameter) in two groups of patients who entered the age range of 55-to-67 years 14 years apart: patients in cohort 1 (n = 66) were born between 1899 and 1912, and those in cohort 2 (n = 66) were born between 1926 and 1936. Between-group comparisons were made for macroscopic, microscopic, and histochemical findings. Mucin histochemical analysis was used to investigate gastric and nongastric phenotypes. Helicobacter pylori was also investigated by immunohistochemistry. Results. There were significant decreases in the incidence of elevated carcinoma (20% in cohort 1 vs 6% in cohort 2; P < 0.05) and papillary adenocarcinoma (11% vs 2%; P < 0.05). The incidence of flat carcinomas was significantly increased (3% vs 15%; P < 0.05). The incidence of tumors surrounded by fundic gland mucosa increased (20% vs 29%), whereas that of tumors surrounded by intestinal metaplastic mucosa decreased (52% vs 41%). The rate of H. pylori infection in mucosa surrounding tumors was the same in both groups (35%). The incidence of tubular adenocarcinoma with gastric-type mucin was higher in cohort 2 (64%) than in cohort 1 (51%). Conclusion. The rate of tubular adenocarcinomas containing gastric type mucin has increased over time. These tumors had a tendency to develop in the fundic gland mucosa and to show less intestinal metaplasia. The H. pylori infection rate was unrelated to this time trend. In advanced gastric cancer, the differentiated carcinoma rate has decreased; however, in small gastric cancer, the rate of tubular adenocarcinoma containing gastric type mucin has increased. This suggests that tubular adenocarcinoma with gastric type mucin changes into poorly differentiated adenocarcinoma as tumors grow to advanced stages. Received: April 24, 2000 / Accepted: August 1, 2000     

QUALITATIVE STUDY OF SIALOMUCINS CHANGES DURING N－METHYL－N－NITROSOUREA－INDUCED C OLONIC CARCINOGENESIS IN MICE

ＱＵＡＬＩＴＡＴＩＶＥＳＴＵＤＹＯＦＳＩＡＬＯＭＵＣＩＮＳＣＨＡＮＧＥＳＤＵＲＩＮＧＮ－ＭＥＴＨＹＬ－Ｎ－ＮＩＴＲＯＳＯＵＲＥＡ－ＩＮＤＵＣＥＤＣＯＬＯＮＩＣＣＡＲＣＩＮＯＧＥＮＥＳＩＳＩＮＭＩＣＥＷａｎｇＱｉａｎｇ王强；ＷａｎｇＹｕａｎｈｅ王元和；...     

胃肠道印戒细胞癌超微结构分型

通过对３８例胃肠道印戒细胞癌进行超微细胞结构观察，发现印戒细胞癌可有三种类型，即粘液型、微囊型和糖原型。结合粘液组化染色，作者对印戒细胞癌的细胞起源以及癌细胞不同形态表现的原因和意义进行了探讨，认为印戒细胞癌起源于具有多潜能分化的干细胞，癌细胞超微结构形态特征的变化是其畸形分化或功能代谢不同的具体表现。     

Prognostic relevance of tn expression in Breast Cancer

Background  Abnormal glycosylation patterns have been recognized as a feature of carcinoma-associated mucins. The expression of the Tn antigen in breast cancer tissue was investigated to assess its prognostic relevance. Methods  Formalin-fixed, paraffin-embedded materials from 219 patients with breast cancer were used. Immunohistochemical staining of the Tn antigen was retrospectively investigated and a lesion staining 10% or more was considered positive. Results  Tn antigen expression was present in 99 (45%) of 219 lesions. There were no correlations between Tn antigen expression and mean patient age, nodal status, estrogen receptor status, or menopausal status, but there was a slightly significant association between Tn and tumor size. Patients negative for the Tn antigen had a significantly better survival rate than those who were positive. Multivariate analysis also indicated that Tn expression correlated significantly with overall survival in addition to nodal status and tumor size. Conclusions  Tn expression was a significant prognostic factor in breast cancer, but the significance was lost on multivariate analysis. The biological implication of Tn expression in breast cancer needs further investigation.     

Gastric-type well-differentiated adenocarcinoma and pyloric gland adenoma of the stomach

Since 1985, when gastric-type well-differentiated adenocarcinomas were demonstrated in hyperplastic polyps of the stomach, we have studied phenotypic expression in gastrointestinal epithelial lesions. The recent discovery of MUC genes coding core proteins of mucin has improved research on the phenotypic expression of gastrointestinal neoplasms. The disease entity of gastric-type well-differentiated adenocarcinoma has recently been accepted, especially in Japan and Europe. This entity has often become a clinicopathological subject of discussion, because its biological behavior is possibly highly malignant, in spite of the difficulty in making endoscopic and histopathological diagnoses. Even under these circumstances, the term “gastric adenoma” usually means flat adenoma of the intestinal type. Gastric-type adenomas have been regarded as exceptional until recently. Although gastric-type adenomas could theoretically be classified into foveolar type and pyloric-gland type, foveolar-type adenoma is, in practice, difficult to distinguish from gastric-foveolar-type adenocarcinoma. In 2003, we first reported systematic clinicopathological analyses of pyloric gland adenoma, demonstrating its unstable and precancerous nature. In this article, we review and discuss the clinicopathological and molecular pathological aspects of gastric-type well-differentiated adenocarcinomas and pyloric gland adenomas, mainly based on our published and unpublished data.     

Adjuvant chemotherapy improves overall survival after TME surgery in mucinous carcinoma of the rectum

Introduction

Mucinous tumours of the rectum are characterised by an abundance of extracellular mucin within the tumour complex. They are known to have a poor prognosis compared to non-mucinous adenocarcinomas. The effect of adjuvant chemotherapy on the survival outcomes of patients with mucinous cancer remains unclear. This study evaluated the 5-year overall survival of patients with mucinous rectal cancer following optimal TME surgery to determine whether adjuvant chemotherapy conferred a survival benefit.

Methods

An analysis of a prospectively-maintained database was conducted of patients presenting with mucinous rectal cancer between 2000 and 2010. Patients with mucinous tumours were identified from final pathology reports of the surgical resection specimens. The primary outcome was 5-year overall survival; univariate and multivariate analysis was performed using Cox proportional hazards regression models.

Results

A total of 191 patients were included for analysis with mean age of presentation 64.6 years (36–88 ± 11). On the fully adjusted multivariate model, EMVI status (HR 1.853, 95% CI 1.081–3.175) and not being given adjuvant chemotherapy (HR 2.888, 95% CI 1.801–4.633) were significant for disease recurrence. The 5-year overall survival for patients that had undergone adjuvant chemotherapy was 66.1% compared with 35.2% (Mantel Cox log-rank test – p < 0.0001).

Conclusion

This study demonstrates that adjuvant chemotherapy is an independent factor for improvement in overall survival in patients with mucinous adenocarcinoma. Therefore, patients who have undergone TME surgery for mucinous carcinoma of the rectum should be offered adjuvant chemotherapy even in the absence of other high-risk features for poor outcomes.     

Irinotecan-induced mucositis is associated with changes in intestinal mucins

Purpose  Mucositis is a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy and radiotherapy. Irinotecan is used to treat a variety of solid tumours, through the inhibition of DNA topoisomerase I and is linked with severe mucositis and diarrhoea. Mucus production appears to be increased, which may contribute to the development of diarrhoea. Methods  Dark agouti rats were treated with irinotecan, and tissues collected at several time points up to 72 h. Goblet cells and mucin secretion were investigated, as well as mucin expression (Muc2 and Muc4) and kruppel-like factor (Klf) 4 using immunohistochemistry in the gastrointestinal tract. Both goblet cells and cells positive for Muc expression were counted, and analysed statistically using the Mann–Whitney U test with Bonferroni correction. Results  Goblet cells decreased significantly after irinotecan treatment. However, mucin secretion increased. Mucin expression changed significantly after treatment. Muc2 and Muc4 decreased significantly in the villi of the jejunum after treatment, Muc2 and Muc4 decreased significantly in the crypts. Muc2 decreased significantly in the colon. Conclusions  Irinotecan causes an increase in mucin secretion and a net decrease in mucin-producing goblet cells, and the expression of Muc2 and Muc4 in the gastrointestinal tract is altered following treatment. Increased mucin secretion is likely to be related to altered mucin expression, and may contribute to chemotherapy-induced diarrhoea.