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Imai Y. Poorly differentiated adenocarcinoma of the colon: subsite location and clinicopathologic features. Int J Colorectal Dis 2015; 30:187-96. [PMID: 25416528 DOI: 10.1007/s00384-014-2070-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/12/2014] [Indexed: 02/04/2023]
Abstract
PURPOSE Colorectal cancers of the proximal colon are characterized by good prognosis, microsatellite instability (MSI), and poor differentiation. MSI is associated with a favorable prognosis, but poorly differentiated adenocarcinomas (PDAs) have a poor prognosis. In this study, we aimed to investigate this inconsistency by analyzing the heterogeneity of PDAs. METHODS A total of 156 surgically resected PDAs were analyzed according to tumor subsite by morphological and immunohistochemical analyses. RESULTS Proximal PDAs (n = 86) were significantly associated with females, older age, cytokeratin (CK) 20 downregulation, aberrant MUC5AC expression, and MSI compared with distal PDAs (n = 70). Proximal PDAs tended to show a better overall survival rate than distal PDAs. PDAs with microsatellite stability (MSS) were suggested to progress from well- and moderately differentiated adenocarcinomas (WMDAs), but MSI PDAs typically not. MSI PDAs demonstrated a prognosis marginally better than MSS PDAs, but significantly worse than WMDAs (n = 170). Proximal MSS PDAs had a similar unfavorable prognosis but were significantly associated with females and aberrant MUC5AC expression compared with distal MSS PDAs. MSI may be predictive of prognosis only in proximal PDAs, because nearly all distal PDAs were MSS. In contrast, CK20 downregulation was significantly associated with better prognosis in both subsites. CONCLUSIONS Proximal PDAs had a better prognosis than distal PDAs due to a higher incidence of MSI PDAs, whose prognosis was significantly worse than WMDAs. Female and MUC5AC expression were characteristic of proximal PDAs independent of MSI. Subsite-specific features of PDAs may serve for subclassification and predicting prognosis.
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Affiliation(s)
- Yasuo Imai
- Department of Diagnostic Pathology, Ota Memorial Hospital, Fuji Heavy Industries Health Insurance Society, 455-1 Oshima, Ota, Gunma, 373-8585, Japan,
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Imai Y, Yamagishi H, Fukuda K, Ono Y, Inoue T, Ueda Y. Differential mucin phenotypes and their significance in a variation of colorectal carcinoma. World J Gastroenterol 2013; 19:3957-3968. [PMID: 23840140 PMCID: PMC3703182 DOI: 10.3748/wjg.v19.i25.3957] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2013] [Revised: 04/20/2013] [Accepted: 05/17/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate mucin expression profiles in colorectal carcinoma (CRC) histological subtypes with regard to clinicopathologic variables and prognosis.
METHODS: Mucin (MUC)2 and MUC5AC expressions were assessed by immunohistochemistry for a total of 250 CRC cases that underwent surgical resection. CRCs included 63 well-to-moderately differentiated adenocarcinomas (WMDAs), 91 poorly differentiated adenocarcinomas (PDAs), 81 mucinous adenocarcinoma (MUAs), and 15 signet-ring cell carcinomas (SRCCs). MUC2 and MUC5AC were scored as positive when ≥ 25% and ≥ 1% of cancer cells were stained positive, respectively. The human mutL homolog 1 and human mutS homolog 2 expressions were assessed by immunohistochemistry in PDAs to investigate mismatch-repair (MMR) status. Tumors that did not express either of these two were considered MMR-deficient. Results were analyzed for associations with clinicopathologic variables and the prognosis in individual histological CRC subtypes.
RESULTS: MUC2-positive and MUC5AC-positive WMDA percentages were 49.2% and 30.2%, respectively. In contrast, MUC2-positive and MUC5AC-positive PDA percentages were 9.5% and 51.6%, respectively. MUC2 levels tended to decrease and MUC5AC levels tended to increase from WMDA to PDA. In 21 tumors comprising both adenoma and adenocarcinoma components in a single tumor (4 WMDAs, 7 PDAs, and 10 MUAs), MUC2 was significantly downregulated in PDA and MUC5AC was downregulated in PDA and MUA in the adenoma-carcinoma sequence. These results suggested that MUC2 levels might be associated with malignant potential and that MUC5AC expression was an early event in tumorigenesis. Despite worse prognoses than WMDA, high MUC2 expression levels were maintained in MUA (95.1%) and SRCC (71.5%), which suggested a pathogenesis for these subtypes distinct from that of WMDA. No significant associations were found between MUC2 expression and any clinicopathologic variables in any histological subtype. MUC5AC expression in PDA was closely associated with right-sided location (P = 0.017), absence of nodal metastasis (P = 0.010), low tumor node metastasis stage (P = 0.010), and MMR deficiency (P = 0.003). MUC2 expression in WMDA was a marginal prognostic factor for recurrence/metastasis-free survival (RFS) by univariate Cox analysis (P = 0.077) but not by multivariate Cox analysis (P = 0.161). MUC5AC expression in PDA was a significant prognostic factor for RFS by univariate Cox analysis (P = 0.007) but not by multivariate Cox analysis (P = 0.104). Kaplan-Meier curves and log-rank tests revealed that MUC2 expression was marginally associated with a better WMDA prognosis [P = 0.064 for RFS and P = 0.172 for overall survival (OS)] but not for PDA. In contrast, MUC5AC expression was significantly and marginally associated with a better PDA prognosis in terms of RFS and OS, respectively (P = 0.004 for RFS and P = 0.100 for OS), but not for WMDA and MUA.
CONCLUSION: Mucin core protein expression profiles and clinical significance differ according to histological CRC subtypes. This may reflect different pathogeneses for these tumors.
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Souazé F, Bou-Hanna C, Kandel C, Leclair F, Devallière J, Charreau B, Bézieau S, Mosnier JF, Laboisse CL. Differential roles of Hath1, MUC2 and P27Kip1 in relation with gamma-secretase inhibition in human colonic carcinomas: a translational study. PLoS One 2013; 8:e55904. [PMID: 23409082 PMCID: PMC3569436 DOI: 10.1371/journal.pone.0055904] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 01/04/2013] [Indexed: 11/18/2022] Open
Abstract
Hath1, a bHLH transcription factor negatively regulated by the γ-secretase-dependent Notch pathway, is required for intestinal secretory cell differentiation. Our aim was fourfold: 1) determine whether Hath1 is able to alter the phenotype of colon cancer cells that are committed to a differentiated phenotype, 2) determine whether the Hath1-dependent alteration of differentiation is coupled to a restriction of anchorage-dependent growth, 3) decipher the respective roles of three putative tumor suppressor genes Hath1, MUC2 and P27kip1 in this coupling and, 4) examine how our findings translate to primary tumors. Human colon carcinoma cell lines that differentiate along a mucin secreting (MUC2/MUC5AC) and/or enterocytic (DPPIV) lineages were maintained on inserts with or without a γ-secretase inhibitor (DBZ). Then the cells were detached and their ability to survive/proliferate in the absence of substratum was assessed. γ-secretase inhibition led to a Hath1-mediated preferential induction of MUC2 over MUC5AC, without DPPIV modification, in association with a decrease in anchorage-independent growth. While P27kip1 silencing relieved the cells from the Hath1-induced decrease of anchorage-independent growth, MUC2 silencing did not modify this parameter. Hath1 ectopic expression in the Hath1 negative enterocytic Caco2 cells led to a decreased anchorage-independent growth in a P27kip1-independent manner. In cultured primary human colon carcinomas, Hath1 was up-regulated in 7 out of 10 tumors upon DBZ treatment. Parallel MUC2 up-regulation occurred in 4 (4/7) and P27kip1 in only 2 (2/7) tumors. Interestingly, the response patterns of primary tumors to DBZ fitted with the hierarchical model of divergent signalling derived from our findings on cell lines.
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Bara J, Forgue-Lafitte ME. Cytoplasmic MUC1 in PanIN-1. Clin Cancer Res 2008; 14:5306; author reply 5306-7. [PMID: 18698052 DOI: 10.1158/1078-0432.ccr-08-0402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Lidell ME, Bara J, Hansson GC. Mapping of the 45M1 epitope to the C-terminal cysteine-rich part of the human MUC5AC mucin. FEBS J 2007; 275:481-9. [DOI: 10.1111/j.1742-4658.2007.06215.x] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Forgue-Lafitte ME, Fabiani B, Levy PP, Maurin N, Fléjou JF, Bara J. Abnormal expression of M1/MUC5AC mucin in distal colon of patients with diverticulitis, ulcerative colitis and cancer. Int J Cancer 2007; 121:1543-9. [PMID: 17565737 DOI: 10.1002/ijc.22865] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
The abnormal expression of gastric M1/MUC5AC mucin in precancerous lesions and colon cancer evidenced by immunohistochemistry led us to check for its presence in the mucus obtained directly from patients undergoing surgery for cancerous (adenocarcinoma) or inflammatory (diverticulitis or ulcerative colitis) diseases. In parallel, the authors quantified aberrant crypt foci (ACF) and their immunolabelling by M1/MUC5AC in mucosae of cancer and diverticulitis patients. Immuno-Radio-Metric Assay of M1/MUC5AC mucin developed by the authors was used to detect M1/MUC5AC mucin in the colonic mucus scraped from surgical specimens. M1/MUC5AC mucin was detected in the mucus of 51/69 (74%) patients with colon adenocarcinoma, versus 7/27 (26%) patients with diverticulitis (threshold: 30 units of M1 mucin per mg protein, area under ROC curve: 0.80). M1/MUC5AC was present in significantly (p < 0.001) larger amounts in the mucus of cancer versus diverticulitis patients. All (10/10) patients with ulcerative colitis tested showed levels above the threshold and their mucosae were strongly labelled with the anti-M1/MUC5AC antibody by immunohistochemistry. Patients with cancer exhibited 3 fold more ACF than those with diverticulitis, but no significant difference was observed in the mean size and M1/MUC5AC expression pattern of ACF between these two groups. The expression of M1/MUC5AC was in correlation with their size. In macroscopically normal mucosa, ACF were the most important source of M1/MUC5AC mucin. Testing of M1/MUC5AC can enhance the detection of precancerous lesions and colon cancer.
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Yao T, Utsunomiya T, Oya M, Nishiyama K, Tsuneyoshi M. Extremely well-differentiated adenocarcinoma of the stomach: Clinicopathological and immunohistochemical features. World J Gastroenterol 2006; 12:2510-6. [PMID: 16688795 PMCID: PMC4087982 DOI: 10.3748/wjg.v12.i16.2510] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Minimal deviation carcinoma of the uterine cervix, otherwise known as extremely well-differentiated adenocarcinoma (EWDA), is characterized by its benign microscopic appearance in contrast to its aggressive behavior. In order to elucidate the clinicopathological features and biological behavior of the gastric counterpart of EWDA, we, using immunohistochemistry, analyzed nine lesions for the phenotypic expression, proliferative activity, and the expression of oncogene-associated products.
METHODS: Clinicopathological features, including pre-operative biopsy diagnosis, were reviewed. Using immunohitstochemistry, Ki-67 labeling index and expression of p53 and c-erbB-2 protein in the gastric lesions were detected.
RESULT: Locations in the middle or upper third of the stomach and polypoid macroscopic features are characteristic of EWDA of the stomach. Although 4 of the 9 lesions showed only focal lymphatic or venous invasion, lymph node metastasis was not present and none of the patients died of the lesions (mean follow-up period, 56 mo). All 9 cases of EWDA could be classified into gastric phenotype (5 lesions) and intestinal phenotype (4 lesions). The former resembled gastric foveolar epithelium, mucous neck cells or pyloric glands, but their papillary structures were frequently elongated and the tumor cells and their nuclei were slightly larger and more hyperchromatic compared to normal epithelium. The latter resembled intestinal metaplasia with minimal nulcear atypia and irregular glands; two of these lesions demonstrated complete intestinal phenotype, while two demonstrated incomplete intestinal phenotype. Ki-67 labeling index was low and none of the cases revealed over-expression of p53 and c-erbB-2 protein.
CONCLUSION: Unlike minimal deviation carcinoma of the cervix, these findings suggest that EWDA of the stomach is a lesion of low-grade malignancy. This favorable biological behavior is supported by the data of a low Ki-67 labeling index and a lack of p53 or c-erbB-2 protein over-expression. Because of its resemblance to normal gastric mucosa or mucosa with intestinal metaplasia, EWDA is often misdiagnosed. To prevent the misdiagnosis of such lesions, the clinical and pathologic characteristics should be taken into consideration.
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Affiliation(s)
- Takashi Yao
- Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Kocer B, McKolanis J, Soran A. Humoral immune response to MUC5AC in patients with colorectal polyps and colorectal carcinoma. BMC Gastroenterol 2006; 6:4. [PMID: 16409634 PMCID: PMC1363352 DOI: 10.1186/1471-230x-6-4] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2005] [Accepted: 01/12/2006] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND MUC5AC is a secreted mucin aberrantly expressed by colorectal polyps and carcinoma. It has been hypothesized that aberrant expression of MUC5AC in colorectal carcinoma tissues increased the overall survival of patients with colorectal carcinoma. The present study investigates the incidence of naturally occurring MUC5AC antibodies in the sera of normal individuals, patients with colonic polyps and patients with advanced colorectal carcinoma. A second aim was to determine the relationship of MUC5AC antibody with the prognosis of colorectal carcinoma. METHODS Free circulating MUC5AC antibodies were measured using an enzyme-linked immunosorbent assay with a synthetic peptide corresponding to an 8 aa. segment of MUC5AC tandem repeat region. Immunohistochemical analysis was completed to demonstrate MUC5AC expression in the polyp specimens. RESULTS MUC5AC antibodies were detected in 6 of 22 (27.3%) healthy subjects, 9 of 20 (45%) polyp patients, 18 of 30 (60%) patients with colorectal cancer. The presence of circulating free MUC5AC antibody levels was significantly correlated with expression of MUC5AC in polyp sections. Serum MUC5AC antibody positivity was higher in patients with colon located tumors, advanced stage and poorly differentiated tumors were found negatively affecting patient survival in our study. MUC5AC antibody positivity was higher in patients with poor prognostic parameters. Disease free survival and overall survival were shorter in this group of patients. In the multivariate analysis MUC5AC antibody positivity didn't find an independent prognostic factor on prognosis. CONCLUSION Decreased survival in colorectal carcinoma patients with MUC5AC antibody positivity may be due to a decrease in the MUC5AC expression in tumor tissues of surviving carcinoma patients.
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Affiliation(s)
- Belma Kocer
- Research Fellow, Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - John McKolanis
- Senior Research Associate Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
| | - Atilla Soran
- Professor of Surgery, Magee-Womens Hospital of UPMC, 300 Halket St, Suite 2601, Pittsburgh, PA 15213, USA
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Aihara R, Ajioka Y, Watanabe H, Shiroshita H, Akazawa K, Kuwano H. Incidence and distribution of hybrid goblet cells in complete type intestinal metaplasia of the stomach. Pathol Res Pract 2005; 201:11-9. [PMID: 15807306 DOI: 10.1016/j.prp.2004.09.014] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Previous reports suggest that hybrid goblet cells (HGCs) sharing both gastric and intestinal mucin phenotypes are rarely observed in complete intestinal metaplasia (cIM) of the stomach. However, we have made a different observation. Thus, we compared the incidence and distribution of HGCs within the tubules of gastric cIM and the duodenum in order to define the significance of HGCs. Fifteen antral sections and 16 fundic sections from tissue with cIM and gastric cancer, as well as 19 sections from duodenal tissue with cancer of the Papilla of Vater, were stained for human gastric mucin (HGM), Con A, MUC2, CD10, and Ki-67. Multivariate analysis showed that antral location, a distance of 5mm or less from the tumor margin, and the presence of underlying pyloric glands were significant predictive factors for tubules containing >50% HGCs as part of their goblet cell population. The incidence of tubules with HGCs differed significantly in tissue samples from the antrum, body and duodenum. HGCs did not stain for Ki-67 and were not surrounded by gastric foveolar-type epithelium within the tubules of cIM foci. These findings indicate that alterations in the proportion of HGCs may occur under some circumstances, and that HGCs are not precursors to gastric foveolar-type cells in the stomach and duodenum.
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Affiliation(s)
- Ryuusuke Aihara
- Division of Molecular and Diagnostic Pathology, Graduate School of Medical and Dental Science, Niigata University, 1-757 Asahimachi-dori Ichibancho, Niigata-city 951-8510, Japan.
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Amano Y, Ishihara S, Kushiyama Y, Yuki T, Takahashi Y, Chinuki D, Miyake T, Miyaoka Y, Rumi MAK, Ishimura N, Adachi K, Kinoshita Y. Barrett's oesophagus with predominant intestinal metaplasia correlates with superficial cyclo-oxygenase-2 expression, increased proliferation and reduced apoptosis: changes that are partially reversed by non-steroidal anti-inflammatory drugs usage. Aliment Pharmacol Ther 2004; 20:793-802. [PMID: 15379840 DOI: 10.1111/j.1365-2036.2004.02195.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Cyclo-oxygenase-2 expression has been reported to play an important role in the metaplasia-dysplasia-carcinoma sequence in Barrett's oesophagus. However, the existence of cyclo-oxygenase-2 expressing cells in Barrett's epithelium is still uncertain. AIM To identify the cells that express cyclo-oxygenase-2 protein and to investigate the relationship between cyclo-oxygenase-2 expression and mucin-phenotype of Barrett's epithelium. METHODS Sections from 466 biopsy samples of Barrett's epithelium from 358 non-medicated patients were immunohistochemically examined for the cyclo-oxygenase-2 expression, mucin-phenotype, cell proliferation and apoptosis. RESULTS Cyclo-oxygenase-2 expression was detected in 71.0% of Barrett's epithelium biopsy samples. In Barrett's epithelium with the gastric predominant mucin-phenotype, cyclo-oxygenase-2 expression was mainly found in stromal and deep epithelial cells, whereas in intestinal predominant mucin-phenotype, it was mostly in superficial epithelial cell. A significant elevation of proliferating cell nuclear antigen index and suppression of apoptotic index was observed in Barrett's epithelium with superficial epithelial cyclo-oxygenase-2 expression. Neither such elevation of proliferating cell nuclear antigen index nor the suppression of apoptotic index could be found in chronic non-steroidal anti-inflammatory drugs users. CONCLUSIONS Barrett's epithelium with intestinal mucin and superficial epithelial cyclo-oxygenase-2 expression possess a higher proliferation potential, but this risk may be thwarted by non-steroidal anti-inflammatory drugs administration.
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Affiliation(s)
- Y Amano
- Division of Gastrointestinal Endoscopy, Shimane University Hospital, Shimane, Japan.
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Nollet S, Escande F, Buisine MP, Forgue-Lafitte ME, Kirkham P, Okada Y, Bara J. Mapping of SOMU1 and M1 Epitopes on the Apomucin Encoded by the 5′ End of the MUC5AC Gene. ACTA ACUST UNITED AC 2004; 23:93-9. [PMID: 15165482 DOI: 10.1089/153685904774129694] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
We have developed 11 monoclonal antibodies (MAbs) against human gastric mucin, (1-13M1, 2-11M1, 2-12M1, 9-13M1, 58M1, 19M1, 21M1, 45M1, 463M, 589M, 62M1), which specifically stained by immunohistochemisty both the human gastric surface mucosa and colon adenoma. Among them, five (19M1, 21M1, 463M, 589M, 62M1) immunoreacted with the peptide encoded by the 3' region of the MUC5AC gene (Nollet et al: Int J Cancer 2002;99:336-343). In this study, we identified in the 5' region of this gene the nucleotide fragments encoding peptides immunoreacting with three other anti-M1 MAbs (1-13M1, 2-11M1 and 9-13M1), as well as the SOMU1 MAb (Sotozono et al: J Immunol Methods 1996;192:187-196). 1-13M1 MAb immunoreacts with peptides, including the Cys 2 and Cys 4 domains. The SOMU1 MAb recognized the Cys 5 domain, and the MAbs 2-11M1 and 9-13M1 the globular D1/D2 and D3 domains, respectively. Using serial sections of the mucosae adjacent to colon adenocarcinomas and colon adenomas, we observed that the anti-M1 and anti-SOMU1 MAbs displayed the same immunostaining patterns. The three anti-M1 MAbs (2-12M1, 58M1, and 45M1) did not react with the products of the MUC5AC gene tested until now. The MUC5AC apomucin is now well characterized by MAbs immunoreacting against seven different epitopes belonging to the different main cystein globular domains of this macromolecule. Such antibodies are useful tools for studying the biosynthesis, polymerization, and degradation of mucin.
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Affiliation(s)
- S Nollet
- Mucin Immunochemistry laboratory, INSERM U-482, Paris, France
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Koike M, Inada K, Nakanishi H, Matsuura A, Nakamura S, Tatematsu M. Cellular differentiation status of epithelial polyps of the colorectum: the gastric foveolar cell-type in hyperplastic polyps. Histopathology 2003; 42:357-64. [PMID: 12653947 DOI: 10.1046/j.1365-2559.2003.01562.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS The 'metaplastic' polyp of the colorectum, a synonym for the hyperplastic polyp, was named based only on features of the crypt epithelium. It is considered non-neoplastic, but the precise cellular differentiation status remains to be proven. METHODS AND RESULTS Forty-eight hyperplastic polyps, 12 serrated adenomas, 45 tubular adenomas and five juvenile polyps were studied for their phenotypic expression using gastric (foveolar or pyloric gland cell), small intestinal (goblet cell), and colonic (goblet cell) cellular markers by immunohistochemical and mucin histochemical techniques. Gastric foveolar cell-type differentiation was significantly expressed in hyperplastic polyps, while colonic differentiation was also consistently preserved. Neither gastric pyloric-type nor small intestinal differentiation was observed. The same cell differentiation status as hyperplastic polyps was observed in serrated adenomas but not in tubular adenomas or juvenile polyps. CONCLUSIONS A large proportion of hyperplastic polyps are composed of hybrid epithelium, with bidirectional differentiation to both gastric foveolar and colonic epithelial cells in the same crypt. Therefore hyperplastic polyps might be interpreted as the outcome of abnormal cell differentiation of stem cells. The same phenotypic expression suggests that hyperplastic polyps and serrated adenomas share the same cell lineage.
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Affiliation(s)
- M Koike
- Division of Oncological Pathology, Aichi Cancer Centre Research Institute, Nagoya, Japan
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Yao T, Takata M, Tustsumi S, Nishiyama KI, Taguchi KI, Nagai E, Tsuneyoshi M. Phenotypic expression of gastrointestinal differentiation markers in colorectal adenocarcinomas with liver metastasis. Pathology 2002; 34:556-60. [PMID: 12555994 DOI: 10.1080/0031302021000035965-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
AIM The purpose of the present study was to clarify the correlation between phenotypic expression of gastrointestinal differentiation markers and colorectal cancer behaviour, particularly invasion and hepatic metastasis. METHODS Thirty-one cases of advanced colorectal adenocarcinoma (CRC) with liver metastasis were selected. Phenotypic patterns were evaluated immunohistochemically by means of antibodies to CD10, MUC2, and human gastric mucin (HGM). RESULTS The incidence of MUC2 (45.2%) and HGM (16.1%) expression in CRCs with liver metastasis did not differ from non-metastatic CRCs. In contrast, the incidence of CD10 expression was significantly higher in CRCs with liver metastasis (58.1%) than in control CRCs (21.7%). Phenotypic expression in the liver metastasis carcinomas was similar to that of the primary lesions. CONCLUSIONS The findings suggest that cases of CRC with CD10 expression are at increased risk of liver metastasis. Even if there is no liver metastasis at laparotomy for CRC, careful follow-up is recommended for CRCs with CD10 expression.
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Affiliation(s)
- Takashi Yao
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Baldus SE, Mönig SP, Arkenau V, Hanisch FG, Schneider PM, Thiele J, Hölscher AH, Dienes HP. Correlation of MUC5AC immunoreactivity with histopathological subtypes and prognosis of gastric carcinoma. Ann Surg Oncol 2002; 9:887-93. [PMID: 12417511 DOI: 10.1007/bf02557526] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
BACKGROUND MUC5AC represents a mucin peptide core expressed in normal gastric epithelia. Its presence in gastric carcinomas was previously described as a characteristic of gastric differentiation. METHODS MUC5AC reactivity was investigated by immunohistochemistry and correlated with clinicopathological variables in a large series (n = 200) of gastric carcinomas. RESULTS A statistically significant association between MUC5AC positivity and parameters of cancer progression (pTNM staging and grading) could not be observed. However, MUC5AC exhibited correlations with certain subtypes of histopathological differentiation. A significant reduction of MUC5AC expression was evident in mucinous and undifferentiated carcinomas according to the World Health Organization classification, as well as in type III cancers according to the Goseki classification system. Furthermore, reduced MUC5AC reactivity (confined to up to 35% of the tumor area) was significantly correlated with an unfavorable prognosis of all patients in univariate and multivariate analysis. The same association could be observed in the subgroup of pTNM stage I patients (n = 60). CONCLUSIONS A significant reduction of gastric differentiation as reflected by MUC5AC immunoreactivity represents a marker of worse survival probability in gastric cancer. Finally, reduced MUC5AC positivity defines a high-risk subgroup of pTNM stage I patients.
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Affiliation(s)
- Stephan E Baldus
- Institute of Pathology and Center of Biochemistry, Medical Faculty, University of Cologne, Cologne, Germany.
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Yao T, Kajiwara M, Kuroiwa S, Iwashita A, Oya M, Kabashima A, Tsuneyoshi M. Malignant transformation of gastric hyperplastic polyps: alteration of phenotypes, proliferative activity, and p53 expression. Hum Pathol 2002; 33:1016-22. [PMID: 12395375 DOI: 10.1053/hupa.2002.126874] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The aim of this study was to clarify the mechanism of malignant transformation of gastric hyperplastic polyps, focusing on phenotypic expression, cell proliferation, and p53 overexpression. Twenty-two lesions of gastric hyperplastic polyps with neoplastic foci were selected for this study. The phenotypes were divided into 3 types (G, gastric; incomp I, incomplete intestinal; and comp I, complete intestinal), according to immunohistochemical stains (human gastric mucin [HGM], MUC2, and CD10). The cell proliferative activity by Ki-67 and overexpression of p53 protein were also examined. Eleven of these lesions contained carcinoma components (CA, category 5 by the Vienna classification), 6 of which were accompanied by low-grade dysplasia (LGD, category 3) and 4 of which were accompanied by high-grade dysplasia (HGD, category 4). Another 2 were composed only of HGD, and the remaining 9 were composed of both LGD and HGD components. As a result, 15 LGD, 15 HGD, and 11 CA components were recognized. The 15 LGD components were classified as 1 G type and 14 incomp I type. All hyperplastic components expressed HGM, 5 (22.7%) of which were accompanied by focal intestinal metaplasia demonstrated by MUC2 expression, whereas intestinalization frequently occurred in neoplastic components (93% of LGD, 53% of HGD, and 64% of CA components). The labeling index was 22.2% in hyperplastic, 42.2% in LGD, 55.7% in HGD, and 53.9% in CA components. p53 protein overexpression was recognized in none of hyperplastic, in 40% of the LGD, in 60% of the HGD, and in 45% of the CA components. These results suggest the importance of the dysplasia-carcinoma sequence in malignant transformation of hyperplastic polyps. Interestingly, intestinalization frequently occurs during neoplastic transformation, although it is not common in the surrounding hyperplastic components.
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Affiliation(s)
- Takashi Yao
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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16
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Kocer B, Soran A, Erdogan S, Karabeyoglu M, Yildirim O, Eroglu A, Bozkurt B, Cengiz O. Expression of MUC5AC in colorectal carcinoma and relationship with prognosis. Pathol Int 2002; 52:470-7. [PMID: 12167106 DOI: 10.1046/j.1440-1827.2002.01369.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Overexpression and alterations in the glycosylation of gastric mucins have been described in colorectal carcinoma. The purpose of our study was to confirm aberrant expression of MUC5AC in colorectal carcinoma, to investigate relationships between clinicopathological parameters and MUC5AC expression, and to determine if MUC5AC expression may be a prognostic factor for colorectal carcinoma. Immunohistochemical staining using an antibody against MUC5AC tandem repeat epitopes was performed on colorectal tumor specimens (n = 41), their metastatic tumors in regional lymph nodes (n = 21) and normal colonic mucosa (n = 41). We also documented clinicopathological parameters such as the age and sex of the patient, location, size, Dukes stage, histological type and grade of the tumor, pre-sence and number of metastatic lymph nodes, lymphatic, venous and perineural invasion, presence of preoperative and postoperative metastatic tumors and tumor recurrence. MUC5AC was expressed in 34.1% of tumor samples, 24.4% of normal colonic mucosa samples and 19% of lymph node metastases. MUC5AC showed ectopic expression in colorectal carcinoma and was also expressed strongly in mucinous carcinoma (60%). The number of tumors that expressed MUC5AC was lower in patients older than 60 years, in rectum-localized tumors and in patients who had evidence of recurrence and/or metastasis in the postoperative period. The patients with MUC5AC-negative tumors had a lower incidence of being disease free and of overall survival. In conclusion, the patients with MUC5AC-negative tumors had poor clinicopathological parameters and showed worse survival than patients with MUC5AC-positive tumors. Absence of MUC5AC expression in tumors can be a prognostic factor for more aggressive colorectal carcinoma.
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Affiliation(s)
- Belma Kocer
- Department of Second General Surgery, Ankara Numune Teaching and Research Hospital, Ankara, Turkey.
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17
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Yao T, Tsutsumi S, Akaiwa Y, Takata M, Nishiyama K, Kabashima A, Tsuneyoshi M. Phenotypic expression of colorectal adenocarcinomas with reference to tumor development and biological behavior. Jpn J Cancer Res 2001; 92:755-61. [PMID: 11473726 PMCID: PMC5926785 DOI: 10.1111/j.1349-7006.2001.tb01158.x] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The purpose of this study is to clarify the correlation between cell differentiation and tumor development, including tumor aggressiveness and biological behavior. Eighty-three cases of advanced colorectal adenocarcinoma were randomly selected. Using immunohistochemical staining with antibodies to CD10, MUC2 and human gastric mucin (HGM), the colorectal adenocarcinomas could be classified into five types (18 small intestinal, 27 large intestinal, 2 gastric, 9 mixed and 27 unclassified). Each type had characteristic features. The small-intestinal type showed a relatively lower incidence of lymphatic permeation and higher venous invasion. The large-intestinal type showed a low incidence of venous invasion and lymph node metastasis. The mixed type revealed female and right-side-dominant distribution, large tumor size, high incidence of mucinous carcinoma, and low incidence of venous invasion. Gastric type was seen in only two cases (2%), which exhibited high histologic grade, lymphatic permeation and lymph node metastasis with no venous invasion. Such phenotypic classifications are considered to be useful not only for evaluation of the biological behavior of the carcinoma, but also for analysis of tumorigenesis.
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Affiliation(s)
- T Yao
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka 812-8582, Japan
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18
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Glickman JN, Wang H, Das KM, Goyal RK, Spechler SJ, Antonioli D, Odze RD. Phenotype of Barrett's esophagus and intestinal metaplasia of the distal esophagus and gastroesophageal junction: an immunohistochemical study of cytokeratins 7 and 20, Das-1 and 45 MI. Am J Surg Pathol 2001; 25:87-94. [PMID: 11145256 DOI: 10.1097/00000478-200101000-00010] [Citation(s) in RCA: 112] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
The pathogenesis of short segment Barrett's esophagus (SSBE) and intestinal metaplasia (IM) of the gastroesophageal junction (IMGEJ) are poorly understood. Also, these conditions are difficult to distinguish from one another based solely on endoscopic and pathologic criteria. Therefore, the aim of this study was to evaluate the immunophenotypic features of SSBE and IMGEJ and to compare the results with lesions of known etiologies: long segment BE (LSBE) caused by reflux disease and Helicobacter pylori-induced IM of the gastric antrum (IMGA). Routinely processed mucosal biopsy specimens from 11 patients with LSBE, 17 with SSBE, 10 with IMGEJ, 16 with IMGA, 17 with a normal nonmetaplastic GEJ, and 7 patients with a normal gastric antrum were immunohistochemically stained with monoclonal antibodies to: Das1, an antibody shown to react specifically with colonic goblet cells; 45M1, an antibody that recognizes the M1 gastric mucin antigen; and cytokeratin (CK) 7 and 20, antibodies that have previously been reported to show specific staining patterns in BE versus IMGA. Also evaluated was nonintestinalized mucinous epithelium from LSBE, SSBE, and also the normal GEJ and gastric antrum. LSBE, SSBE, and IMGEJ showed similar prevalences of Das1 (91% versus 88% versus 100%) and 45M1 reactivity (100% versus 100% versus 100%), and a similar pattern of CK7/20 reactivity (diffuse strong CK7 staining of the surface and crypt epithelium, and strong surface and superficial crypt CK20 staining) (91% versus 94% versus 90%). In contrast, although 45M1 reactivity in IMGA (93%) was similar to that of the other three groups, IMGA showed a significantly lower prevalence of Das positivity (13%, p < 0.001), and only a 14% prevalence of the CK7/20 staining pattern that was predominant in the other three groups (p < 0.001). Das1, 45M1, and CK7/20 staining were similar in nonintestinalized "cardia-type" mucinous epithelium from LSBE, SSBE, and the GEJ, but all were distinct from the normal gastric antrum. In summary, the immunophenotypic features of SSBE and IMGEJ are similar and closely resemble those seen in classic LSBE, but are distinct from IMGA. This may indicate that IM in LSBE, SSBE and at the GEJ have similar biologic properties. Based on our data, SSBE and IMGEJ cannot be distinguished on the basis of their immunophenotype.
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Affiliation(s)
- J N Glickman
- Department of Pathology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA
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19
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Yao T, Nishiyama KI, Oya M, Kouzuki T, Kajiwara M, Tsuneyoshi M. Multiple 'serrated adenocarcinomas' of the colon with a cell lineage common to metaplastic polyp and serrated adenoma. Case report of a new subtype of colonic adenocarcinoma with gastric differentiation. J Pathol 2000; 190:444-9. [PMID: 10699993 DOI: 10.1002/(sici)1096-9896(200003)190:4<444::aid-path520>3.0.co;2-o] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
A 70-year-old woman underwent right hemicolectomy and six carcinomas were recognized in the resected colon. These carcinomas were considered to be of a cell lineage common to serrated adenoma (SA) and hyperplastic (metaplastic) polyp (H/MP), because of the occurrence of multiple SAs and H/MPs around the carcinomas, as well as the co-existence of SA and H/MP areas within the carcinomas. These carcinomas had the following common histological and immunohistochemical features: a serrated structure resembling SA; a lace-like structure; infiltrative growth within the muscularis propria, with dedifferentiation at the invasive front; and immunohistochemical expression of pS2 and human gastric mucin. Based on these features, a new subtype of carcinoma is proposed, with a cell lineage common to SA and H/MP. It would also seem that p53 is involved in the serrated adenoma-carcinoma sequence.
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Affiliation(s)
- T Yao
- Second Department of Pathology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
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20
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Kushima R, Manabe R, Hattori T, Borchard F. Histogenesis of gastric foveolar metaplasia following duodenal ulcer: a definite reparative lineage of Brunner's gland. Histopathology 1999; 35:38-43. [PMID: 10383712 DOI: 10.1046/j.1365-2559.1999.00681.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
AIMS We aimed to clarify the histogenesis of gastric metaplasia in the duodenal mucosa, particularly in association with a reparative lineage of Brunner's glands. METHODS AND RESULTS Using immunohistochemical methods with recently developed antimucin monoclonal antibodies (mAbs) that distinguish foveolar and deep mucins of the gastric type, as well as mAb MIB-1, the histogenesis of gastric metaplasia was investigated in the duodenal wall of 20 surgically resected specimens. In duodenal ulcers extending into Brunner's glands with destruction of the muscularis mucosae, proliferating cells positive for MIB-1 were scattered in Brunner's glands. Interestingly, a group of proliferating cells was often seen next to the ulcerated surface. These cells were also positive for M1 (gastric-foveolar type mucin) but negative for M2 (deep gastric and Brunner glands' mucin). In regenerating ducts through granulation tissue, the proliferating cell zone was elongated, above which foveolar-type cells positive for M1 but negative for M2 were detected, indicating that the G-zone is newly established in Brunner's glands at the floor of an ulcer to produce gastric-foveolar cells. Subsequently, an organoid growth of the normal stomach mucosa is completed in the duodenum. CONCLUSIONS This study indicates a possible histogenetic pathway of gastric metaplasia in close association with a reparative lineage of Brunner's glands, suggesting that the occurrence of the gastric-foveolar type epi-thelium is not a simple expansion of Brunner's duct but a true metaplasia.
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Affiliation(s)
- R Kushima
- Department of Pathology, Shiga University of Medical Science, Ohtsu, Japan
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21
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Yao T, Kouzuki T, Kajiwara M, Matsui N, Oya M, Tsuneyoshi M. 'Serrated' adenoma of the colorectum, with reference to its gastric differentiation and its malignant potential. J Pathol 1999; 187:511-7. [PMID: 10398114 DOI: 10.1002/(sici)1096-9896(199904)187:5<511::aid-path308>3.0.co;2-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Serrated adenoma of the colorectum was a newly proposed entity in 1990, characterized by epithelial neoplasia combining the architectural features of a hyperplastic (metaplastic) polyp with the cytological features of an adenoma. Its histogenesis and natural history still remain unclear. Forty-six serrated adenomas were obtained from 46 patients. The clinicopathological features were summarized. Paraffin-embedded blocks from 34 serrated adenomas were available for immunohistochemical studies using pS2, human gastric mucin, and p53 protein. Eighteen hyperplastic (metaplastic) polyps, 16 tubular adenomas, and 12 early-stage adenocarcinomas were randomly selected as control groups for immunohistochemical analysis. The patients' ages ranged from 32 to 86 (average 61.4) years. Males were more frequently affected than females. Serrated adenomas were predominantly present in the left-side of the colon and in the rectum (72 per cent). Their sizes ranged from 3 to 26 mm (average 9. 2mm). Six lesions (13 per cent) contained foci of high-grade dysplasia. These adenomas were significantly larger (12.7 mm) than those containing no high-grade dysplasia (8.6mm). pS2 and human gastric mucin were expressed significantly more frequently in both hyperplastic (metaplastic) polyps and serrated adenomas than in tubular adenomas or adenocarcinomas. p53-positive cells were present in 18 of the 29 pure serrated adenomas (62 per cent) and in one of the five areas of low-grade dysplasia in serrated adenomas with high-grade dysplasia (20 per cent), most of which revealed a sporadic distribution. Only five of the 29 serated adenomas with no high-grade dysplasia (17 per cent) were regarded as demonstrating p53 overexpression. On the other hand, three of the five areas of high-grade dysplasia in serrated adenomas (60 per cent) revealed diffuse positivity (3+) for p53 protein. The serrated adenoma, which possibly shows gastric differentiation, is considered to be an independent histological entity among the various phenotypes of colorectal adenomas. Serrated adenoma would seem to be a precursor of carcinoma, its potential for malignant transformation being similar to that of the traditional tubular adenoma. It would also seem that p53 is involved in the serrated adenoma-carcinoma sequence.
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Affiliation(s)
- T Yao
- Second Department of Pathology, Faculty of Medicine, Kyushu University, Fukuoka, Japan
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22
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Bartman AE, Sanderson SJ, Ewing SL, Niehans GA, Wiehr CL, Evans MK, Ho SB. Aberrant expression of MUC5AC and MUC6 gastric mucin genes in colorectal polyps. Int J Cancer 1999; 80:210-8. [PMID: 9935202 DOI: 10.1002/(sici)1097-0215(19990118)80:2<210::aid-ijc9>3.0.co;2-u] [Citation(s) in RCA: 82] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Altered mucin glycosylation and the de novo appearance of gastric mucin antigens have been described in colonic adenomas. The purpose of our study was to determine if expression of the gastric mucin genes MUC5AC and MUC6 occurs in colorectal adenomas and whether this correlates with histopathologic criteria of malignant potential. Immunohistochemical staining using antibodies against MUC5AC and MUC6 tandem repeat synthetic peptides was performed on specimens of normal colon mucosa (n = 26), hyperplastic polyps (n = 9) and adenomatous polyps (n = 111). Mucin mRNA levels were determined using RNase protection assays using riboprobes corresponding to unique non-repetitive sequences. MUC5AC and MUC6 staining were rarely detected and of low intensity in normal colon and hyperplastic polyps. The number of immunoreactive polyps and intensity of MUC5AC and MUC6 staining were greatest in larger adenomas of moderate villous histology and dysplasia. MUC5AC and MUC6 staining tended to decrease in highly villous polyps with severe dysplasia. Increased MUC5AC mRNA levels were found in 26/45 of adenomas tested compared with 0/9 normal colon specimens. MUC6 mRNA levels were found in 20/45 of adenomas compared with 1/9 normal colon specimens. MUC5AC and MUC6 mRNA were present more frequently and at higher levels in polyps with intermediate stages of size, villous histology and dysplasia. We conclude that aberrant expression of MUC5AC and MUC6 mucin genes is likely responsible for an expanded repertoire of mucin antigen expression in colorectal neoplasia.
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Affiliation(s)
- A E Bartman
- Department of Medicine, Veterans Affairs Medical Center and the University of Minnesota, Minneapolis, USA
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23
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Wu LB, Kushima R, Borchard F, Molsberger G, Hattori T. Intramucosal carcinomas of the stomach: phenotypic expression and loss of heterozygosity at microsatellites linked to the APC gene. Pathol Res Pract 1998; 194:405-11. [PMID: 9689649 DOI: 10.1016/s0344-0338(98)80031-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Evaluation of the role of somatic genetic alterations in cancer development is best performed by examining small tumors in the earlier stages of carcinogenesis. We examined the relationship between allelic deletions of 4 microsatellites linked to the adenomatous polyposis coli (APC) gene and differential histogenetical phenotypes in 34 intramucosal carcinomas of the stomach, of which, structurally, 24 cases were the gland-forming type (so-called "intestinal type") and 10 were the diffuse type. Using mucin and immunohistochemical staining techniques specific for gastric- and intestinal-type mucins, the phenotype of each tumor was histogenetically classified as exclusively gastric, predominantly gastric, predominantly intestinal or exclusively intestinal. There was generally a free combination between structural types and phenotypic mucin expression. Allelic deletions were detected in 6 carcinomas of the exclusively intestinal phenotype. The incidence of allelic deletions was significantly higher in the predominantly and exclusively intestinal phenotypes (6/16, 37.5%) than in the predominantly and exclusively gastric phenotypes (0/18) (p = 0.0060, Fisher's test). Taking the high frequency of allelic deletions in 5q in invasive stomach carcinomas, the present study suggests that genetic alteration in this region is a very early event in stomach carcinomas with intestinal differentiation but a relatively late event in those with gastric differentiation.
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Affiliation(s)
- L B Wu
- Department of Pathology, Shiga University of Medical Science, Ohtsu, Japan
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24
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Ota H, Katsuyama T, Nakajima S, El-Zimaity H, Kim JG, Graham DY, Genta RM. Intestinal metaplasia with adherent Helicobacter pylori: a hybrid epithelium with both gastric and intestinal features. Hum Pathol 1998; 29:846-50. [PMID: 9712427 DOI: 10.1016/s0046-8177(98)90455-5] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Helicobacter pylori seem to avoid areas of intestinal metaplasia in the gastric mucosa, but attachment of these bacteria to epithelium with the appearance of incomplete intestinal metaplasia has been documented. To characterize the nature of the epithelium to which H pylori was attached, we carried out an immunohistochemical study using monoclonal antibodies against gastric surface mucous cell mucins (M1), blood group-related carbohydrates antigens (Le(a), sialyl Le(a), Le(b), type 1H, and type 2H) and sialyl Tn antigen. The results of this study suggest that these areas of H pylori attachment represent a hybrid epithelium whose cells share characteristics of both gastric surface mucous cells and intestinal metaplastic cells. Whether all areas of incomplete intestinal metaplasia represent an intermediate stage between the normal gastric epithelium and the fully developed complete type of metaplasia remains to be determined.
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Affiliation(s)
- H Ota
- Department of Medicine, Veterans Affairs Medical Center and Baylor College of Medicine, Houston, TX, USA
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25
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Bara J, Chastre E, Mahiou J, Singh RL, Forgue-Lafitte ME, Hollande E, Godeau F. Gastric M1 mucin, an early oncofetal marker of colon carcinogenesis, is encoded by the MUC5AC gene. Int J Cancer 1998; 75:767-73. [PMID: 9495247 DOI: 10.1002/(sici)1097-0215(19980302)75:5<767::aid-ijc17>3.0.co;2-3] [Citation(s) in RCA: 91] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Gastric M1 mucin and the MUC5AC gene show a similar oncofetal expression in the colon. Our aim was to determine whether M1 mucin is the product of the MUC5AC gene. A recombinant baculovirus encoding the C-terminal portion of the MUC5AC gene as a fusion protein was isolated and the immunoreactivity of the recombinant mucin (rM) toward M1 antibodies studied. Chicken antibodies also were raised against purified rM. Besides its reactivity with L56/C, a serum recognizing the bacterially expressed MUC5AC gene product, rM was endowed with M1 immunoreactivity: (i) rM-expressing cells were stained specifically with anti-M1 serum and with the monoclonal antibody (MAb) 21M1, defining the M1-f epitope; (ii) both L56/C and anti-M1 antibodies recognized the same bands in immunoblots of rM-containing cell extracts; (iii) the 21M1 antibody reacted with rM in an immunoradiometric assay. Among the 7 M1 epitopes, M1-f was the only one encoded by the 3' portion of the MUC5AC gene. It was the only epitope detected in a native mucin M1-derived 170 kDa bromelain proteolytic fragment. Furthermore, the staining patterns of human tissues obtained with either anti-rM chicken antibodies or anti-M1 antibodies were identical. We conclude that M1 immunoreactivity is encoded at least in part by the MUC5AC gene.
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Affiliation(s)
- J Bara
- INSERM U-55, Equipe Cancérogenèse et Différenciation de l'Epithélium Gastrointestinal, Hôpital Saint-Antoine, Paris, France.
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26
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Kushima R, Borchard F, Hattori T. A new aspect of gastric metaplasia in Crohn's disease: bidirectional (foveolar and pyloric) differentiation in so-called 'pyloric metaplasia' in the ileum. Pathol Int 1997; 47:416-9. [PMID: 9211531 DOI: 10.1111/j.1440-1827.1997.tb04517.x] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Mucus-secreting cells found at the site of ileac ulceration in Crohn's disease have been described as 'pyloric metaplasia'. Using mucin-histochemical methods and immunohistochemical stainings for Ki-67 antigen and foveolar-type mucin (M1) of the stomach, the characteristics of this type of metaplasia were studied in surgically resected ileac specimens from two Japanese patients with Crohn's disease. Not only pyloric-type cells but also foveolar-type cells were demonstrated; often displaying an organoid growth of the normal stomach mucosa. Stem cells of the ileac crypt may differentiate potentially to intestinal-, pyloric- and also to foveolar-type cells. The term 'pyloric metaplasia' is not appropriate and 'gastric metaplasia' should be used when describing this type of metaplasia.
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27
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Kushima R, Remmele W, Stolte M, Borchard F. Pyloric gland type adenoma of the gallbladder with squamoid spindle cell metaplasia. Pathol Res Pract 1996; 192:963-9; discussion 970-1. [PMID: 8950764 DOI: 10.1016/s0344-0338(96)80081-1] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
This study documents a pyloric gland type adenoma of the gallbladder with prominent spindle cell metaplasia arising in a 61 year-old woman. A pedunculated polyp, 1.5 x 1.0 x 1.0 cm, was histologically diagnosed as a tubular adenoma. Most glandular structures showed positivity for a monoclonal antibody M2 (2B5) which indicates a differentiation to pylotic gland type. The spindle cell component displayed no apparent epithelial structures but stained mostly positive for pancytokeratin and cytokeratin (CK) 18, and focally for CK 5 + 6, CKs 7 and 19, whereas CKs 8, 13, 20, and non-epithelial markers could not be demonstrated. This suggests that the spindle cells were immature epithelial cells differentiating towards squamous and/or glandular cells. Even in spindle cell areas, the nuclear atypia was mild, and proliferating cells positive for MIB-1 (Ki-67) antigen were infrequently seen. This unique phenomenon, of which only three cases have been previously reported, is considered to represent benign squamoid spindle cell metaplasia.
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Affiliation(s)
- R Kushima
- Department of Pathology, Shiga University of Medical Science, Otsu, Japan
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28
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Kushima R, Müller W, Stolte M, Borchard F. Differential p53 protein expression in stomach adenomas of gastric and intestinal phenotypes: possible sequences of p53 alteration in stomach carcinogenesis. Virchows Arch 1996; 428:223-7. [PMID: 8764930 DOI: 10.1007/bf00196694] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
In a comparative study, the expression of p53 protein was investigated in intestinal- and gastric-type adenomas of the stomach. The former is a conventional type, which is well known to be a premalignant lesion of the stomach, but the latter is a rare, more recently noted entity. Of 28 intestinal-type adenomas, 17 (60.7%) contained more than 5% of p53 immunoreactive cells. In these adenomas, the extent of positivity for p53 protein was significantly higher in high-grade dysplasia than in low-grade dysplasia (P < 0.05), suggesting that p53 alteration plays a part in the dysplastic progression of intestinal-type adenomas. Among 18 gastric-type adenomas in which most of the tumour cells displayed gastric-type mucin, substantial expression of p53 protein was found only in the 3 tumours with high-grade dysplasia. Thus, the incidence of p53 expression was significantly higher in intestinal-type adenomas than in gastric-type adenomas (P < 0.01). These results suggest that p53 gene alteration is an earlier event in the gastric carcinogenetic sequence with the intestinal phenotype than in that with the gastric phenotype.
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Affiliation(s)
- R Kushima
- Institute of Pathology, Heinrich Heine University of Düsseldorf, Germany
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29
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Kushima R, von Hinüber G, Lessel W, Stolte M, Borchard F. Sebaceous gland metaplasia in cardiac-type mucosa of the oesophago-gastric junction. Virchows Arch 1996; 428:297-9. [PMID: 8764940 DOI: 10.1007/bf00196704] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
The first case of sebaceous gland metaplasia arising in cardiac-type mucosa of the oesophago-gastric junction of 71-year-old man is reported. Within cardiac glands, small nests composed of clear cells closely resembling sebaceous glands of the skin were found. Immunohistochemically, the cell nests stained positively for a monoclonal antibody 115D8 against milk-fat globule membrane (MAM-6). These cells were sometimes covered by cylindrical cells positive for foveolar-type mucin of the stomach (MI), and basal marginal cells of these nests expressed high molecular weight cytokeratins (34BE12). This study documents a new type of metaplasia of the gastric mucosa.
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Affiliation(s)
- R Kushima
- Institute of Pathology, Heinrich Heine University, Düsseldorf, Germany
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30
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Montserrat C, Hollande E, Guy-Crotte O, Figarella C. Direct double antibody sandwich immunoassay of mucin M1 epitopes in human mucus secreting pancreatic cell lines. Clin Chim Acta 1995; 243:43-52. [PMID: 8747513 DOI: 10.1016/0009-8981(95)06153-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
A direct sandwich enzyme immunoassay using two monoclonal antibodies was developed in order to quantify mucin M1 antigens produced by two pancreatic adenocarcinoma cell lines: CAPAN-1 and CFPAC-1. As a solid phase, the wells of a microtiter plate were coated with a first monoclonal antibody, 1-13 M1 and the biotinylated monoclonal conjugate 9-13 M1 was used as the second antibody. The assay was optimized with streptavidin-peroxidase. The detection limit of the assay is 1.6 ng/ml. This ELISA is highly specific, sensitive, reproducible and quickly performed. It will permit the comparison of mucin exocytosis by the two cell lines in response to secretagogue agents and may help in the study of the pathogenesis of mucus hypersecretion such as cystic fibrosis.
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Affiliation(s)
- C Montserrat
- Groupe de Recherche sur les Glandes Exocrines, Faculté de Médecine, Marseille, France
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31
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Rothacker D, Knolle J, Stiller D, Borchard F. Primary retroperitoneal mucinous cystadenomas with gastric epithelial differentiation. Pathol Res Pract 1993; 189:1195-204. [PMID: 8183741 DOI: 10.1016/s0344-0338(11)80844-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
We present two rare cases of retroperitoneal mucinous cystadenomas (RMC) by clinical data, light microscopy, electron microscopy, histochemistry, and immunohistochemistry. Both tumors occurred in women. We excluded attachment to any organ. Additional immunohistochemical examinations were performed for comparison in 10 cases of ovarian mucinous cystadenomas (OMC). Both RMC showed no significant immunohistochemical differences from the OMC. Ultrastructurally and histologically the RMC resemble OMC reported in the literature. Immunohistologically, we proved gastric epithelial differentiation by using one monoclonal antibody (2B5) recognizing gastric mucin and one polyclonal antibody against pepsinogen II (PG II). In spite of this, the histogenesis of RMC in the presented cases in the end remains uncertain.
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Affiliation(s)
- D Rothacker
- Center of Pathology, Heinrich-Heine-University Düsseldorf, Germany
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Pinczower GD, Gianello RD, Williams RP, Preston BN, Preston H, Linnane AW. Monoclonal antibody 4D3 detects small intestinal mucin antigen (SIMA)--glycoprotein in the serum of patients with colorectal cancer. Int J Cancer 1993; 54:391-6. [PMID: 8509213 DOI: 10.1002/ijc.2910540307] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
We have developed a sensitive ELISA using MAb 4D3 for the detection of a novel epitope on Small Intestinal Mucin Antigen (SIMA) and report here that SIMA is present in the serum of patients with colorectal cancer. SIMA has been shown to occur in tissue from a high proportion of patients with colorectal cancer. SIMA derived from serum was similar to tissue-derived SIMA: both eluted in the void volume of a Superose 6 column indicating a molecular weight above 5,000 kDa and they exhibited similar buoyant densities on CsCl gradients. The ELISA was most reliable after pre-treatment of serum with 0.4 M perchloric acid to remove interfering substances. The upper limit for SIMA in normal serum was set as the mean plus 2 standard deviations determined from a group of 97 healthy control subjects. In a sample of 113 patients with colorectal cancer, SIMA serum levels were elevated in 15% of patients with Dukes' Stage A, 38% with Stage B, 32% with Stage C and 75% with Stage D colorectal cancer. SIMA serum levels were compared with those of the widely used tumor marker, carcinoembryonic antigen (CEA). The SIMA assay detected a significant number of sera that were not detected by the test for CEA. We propose that SIMA will prove to be a valuable serological tumor marker, in combination with CEA and other tumor markers, for the detection of colorectal cancer.
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Affiliation(s)
- G D Pinczower
- Biochemistry Department, Monash University, Clayton, Victoria, Australia
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Pilbrow SJ, Hertzog PJ, Pinczower GD, Linnane AW. Expression of large intestinal mucin antigen (LIMA) epitopes in the normal and neoplastic gastrointestinal tract. J Pathol 1993; 169:361-73. [PMID: 7684076 DOI: 10.1002/path.1711690314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
This study has identified the expression in normal and neoplastic gastrointestinal (GI) tract of epitopes on the colonic mucin LIMA (large intestinal mucin antigen), which are unique markers of normal colonic differentiation. Six anti-LIMA monoclonal antibodies (MAbs) (22D4, 9B5, 2C3, 23B2, 46A2, and 10B3) were studied immunohistochemically in normal GI tract, colorectal adenomas, and colorectal and gastric cancers. All MAbs showed specificities consistent with distinct epitopes, five of which were neuraminidase-resistant and four periodate-sensitive. Each reacted with mucin in 60-100 per cent normal colons--MAbs 10B3 and 23B2 also with small intestinal mucin--but none with gastric mucin. Five MAbs showed crypt and regional gradients in normal colon, MAbs, 22D4, 9B5, and 2C3 showing a hierarchy of reactivities in the crypt. Individual adenomas showed decreasing goblet cell (GC) LIMA expression with increasing size. However, 30 per cent of familial adenomatous polyposis (FAP) patients had generalized background losses of 9B5 and 2C3 GC reactivity, retaining 22D4, whilst 44 per cent of non-FAP patients lost 22D4 GC reactivity, regaining 9B5 and 2C3--evidence for polymorphism of mucin expression. All colorectal cancers expressed LIMA epitopes (frequently weaker than normal), and three MAbs (22D4, 9B5, and 2C3) showed deeper than normal staining in adjacent crypts. Eighty-five per cent of gastric cancers also expressed LIMA epitopes.
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Affiliation(s)
- S J Pilbrow
- Biochemistry Department, Monash University, Clayton, Victoria, Australia
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Micots I, Augeron C, Laboisse CL, Muzeau F, Mégraud F. Mucin exocytosis: a major target for Helicobacter pylori. J Clin Pathol 1993; 46:241-5. [PMID: 8463418 PMCID: PMC501178 DOI: 10.1136/jcp.46.3.241] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
AIMS To determine whether Helicobacter pylori impairs the secretory function of mucous cells. METHODS The mucus secreting human cell line CL. 16E, maintained as confluent monolayers on nitrocellulose filters, was infected with H pylori strain CIP 101260. After three hours of incubation with H pylori the monolayers were washed and reincubated with fresh culture medium for various time periods (24, 48, or 72 hours) before evaluating both the morphology and function of mucous cells. For morphological studies, epithelial monolayers were fixed in situ and processed for both standard histochemistry on paraffin wax sections, and electron microscopy. To measure mucins secreted from cultured cells, the cells were metabolically labelled with 3H-glucosamine. Undegraded mucins were quantitated as the radioactive glycoproteins blocked at the stacker gel interface after sodium dodecyl sulphate-polyacrylamide gel electrophoresis of the secretory glycoproteins. RESULTS Control cultures of CL. 16E cells grew on filters as homogeneous monolayers of polarised mucous cells secreting a visco-elastic gel of mucins at the apical surface. In infected monolayers H pylori was in close contact with the apical surface of mucous cells. Cell counts and histological evaluation of the monolayers did not reveal any significant deleterious effect of H pylori on the mucous cells. H pylori induced only a modest inhibition of baseline mucus secretion from CL. 16E cells, this inhibition being significant only at 24 hours. In contrast, the mucus secretory response to two agents that raise intracellular cAMP and calcium--forskolin and ionophore A23187--was strongly inhibited. The inhibitory effect of H pylori on the exocytotic response was not paralleled by an inhibition of glycoprotein synthesis. CONCLUSION Considering the fact that the exocytotic response to a variety of secretagogues constitutes the primary line of defence of the gastric mucosa in an emergency, it is suggested that H pylori exerts its deleterious effects by weakening this important physiological defence.
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Affiliation(s)
- I Micots
- Laboratoire de Bactériologie-Enfants, Hôpital Pellegrin, Bordeaux, France
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35
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Sakamoto J, Watanabe T, Teramukai S, Akiyama S, Morimoto T, Takagi H, Nakazato H, Ueda R, Takahashi T. Distribution of adenosine deaminase binding protein in normal and malignant tissues of the gastrointestinal tract studied by monoclonal antibodies. J Surg Oncol 1993; 52:124-34. [PMID: 8096885 DOI: 10.1002/jso.2930520214] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
A mouse monoclonal antibody V-715 was raised against fresh colon cancer tissues. Biochemical analysis elucidated that the antigen defined was adenosine deaminase binding protein (ADBP). In colon cancer cell lines, V-715 was positive in 8 out of 16 differentiated cancers and in 2 out of 8 poorly differentiated cancers. In frozen sections, ADBP was expressed in 17 out of 33 differentiated colon cancers, but none of 4 poorly differentiated colon cancers. In normal colon, the expression was observed in epithelium. In gastric cancers, ADBP was expressed in 10 out of 15 differentiated cancers, but weakly or only heterogenously expressed in 2 out of 8 poorly differentiated cancers. In normal gastric mucosa, ADBP was mainly detected in the foveolar epithelium, but was weakly or not expressed in the deep gastric glands. Carcinoid tumors and malignant lymphoma of the stomach did not express ADBP. These results suggest that ADBP may act as a marker of enterocytic differentiation in normal and neoplastic gastrointestinal cells, and might be exploitable in clinical and pathological diagnosis of gastrointestinal cancers.
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Affiliation(s)
- J Sakamoto
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan
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36
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Zweibaum A. [Differentiation of human colon cancer cells: a new approach to colon cancer]. BULLETIN DE L'ACADEMIE NATIONALE DE MEDECINE 1993; 177:63-71; discussion 71-3. [PMID: 8319114 DOI: 10.1007/978-1-4757-0286-6_3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Our purpose is to demonstrate that some human colon cancer cells are able to express the same differentiation features as normal intestinal epithelial cells and to report experimental data which suggest that these particular cells are spontaneously resistant and adaptable to anticancer drugs. The concept of normal differentiation of colon cancer cells is supported by observations made with two cultured cell lines, Caco-2 and HT-29. The cell line Caco-2 expresses spontaneously and homogeneously an enterocytic differentiation. The cell line HT-29 is heterogeneous as it contains a small proportion (< 5%) of differentiated cells of either enterocytic or mucus-secreting type. Homogeneous populations of differentiated HT-29 cells of either type have been isolated by pressure selection. In order to investigate whether the pressure associated with anti-cancer drugs would result in the selection of differentiated populations, HT-29 cells were cultured in the presence of increasing concentrations of methotrexate and 5-fluorouracil. The resulting resistant populations were found to be totally differentiated. This supports the view that the small proportion of parental cells which are able to differentiate are also able to spontaneously resist to drug pressure. These results imply that the concept of cellular differentiation should be considered by pathologists. They also imply that basic research should be developed in order to unravel which mechanisms of drug resistance are specifically associated with the ability of the cells to differentiate.
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Affiliation(s)
- A Zweibaum
- Unité de Recherches sur la différenciation cellulaire intestinale, INSERM U178, Villejuif
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37
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Pilbrow SJ, Hertzog PJ, Linnane AW. The adenoma-carcinoma sequence in the colorectum--early appearance of a hierarchy of small intestinal mucin antigen (SIMA) epitopes and correlation with malignant potential. Br J Cancer 1992; 66:748-57. [PMID: 1419617 PMCID: PMC1977410 DOI: 10.1038/bjc.1992.351] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The colorectal adenoma-carcinoma sequence was examined in relation to the ectopic expression of the oncofoetal Small Intestinal Mucin Antigen (SIMA), to the development of morphologic changes in the adenoma and perineoplastic mucosa and to indices of malignant potential. Four anti-SIMA MAbs, which define a novel hierarchy of SIMA epitopes in the normal small intestine and adjacent to colorectal cancers, were used in a retrospective immunohistochemical study of Familial Adenomatous Polyposis (FAP, n = 183) and non-familial (n = 44) adenomas. Inappropriate expression of SIMA epitopes was first detected in mucosa adjacent to minute microadenomas larger than three glands, and with increase in size, in increasing amounts within adenomas themselves, but not with microadenomas smaller than three glands or regions of flat mucosa free of adenomas. SIMA epitope expressed in mucosa adjacent to adenomas preceded changes in perineoplastic morphology, which progressed with adenoma growth to resemble transitional mucosa (TM) adjacent to cancers. Thus, the onset of both SIMA expression and morphological changes in TM were consistent with reactive rather than pre-existing field change phenomena. The previously reported hierarchy of four SIMA epitopes (5C5, 3D4, 4D3, 6C5) was also consistently observed in the adenoma-carcinoma sequence, and applied to (i) the order of epitope detection, (ii) the number of positive adenomas and (iii) extent of staining; (iv) the height in the crypt and (v) distance from the adenoma to which epitopes were expressed in perineoplastic mucosa. These observations are consistent with a progression of changes in mucin composition with adenoma development. The percentage of positive adenomas and reactivity scores for each anti-SIMA MAb correlated with increasing adenoma size, degree of dysplasia and growth pattern. SIMA expression appears to predate the earliest reported oncogene and tumour suppressor gene changes, was persistent and increased throughout adenoma development. SIMA epitopes are thus markers of very early neoplastic change, whose expression correlates with malignant potential and may contribute to the accumulation of changes necessary for tumourigenesis.
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Affiliation(s)
- S J Pilbrow
- Biochemistry Department, Monash University, Clayton, Victoria, Australia
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38
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39
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Tenti P, Aguzzi A, Riva C, Usellini L, Zappatore R, Bara J, Samloff IM, Solcia E. Ovarian mucinous tumors frequently express markers of gastric, intestinal, and pancreatobiliary epithelial cells. Cancer 1992; 69:2131-42. [PMID: 1311984 DOI: 10.1002/1097-0142(19920415)69:8<2131::aid-cncr2820690820>3.0.co;2-a] [Citation(s) in RCA: 43] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
In 100 mucinous tumors of the ovary (37 benign, 24 borderline, and 39 malignant), the authors determined by histochemical and immunohistochemical techniques the frequencies and patterns of expression of a total of nine markers of gastric, intestinal, and pancreatobiliary duct epithelial cells. M1, a mucin antigen, and cathepsin E (CaE), an aspartic proteinase, two markers of normal gastric superficial/foveolar epithelial cells, were expressed in 95 and 92 tumors, respectively. Periodic acid-concanavalin A-reactive mucin or pepsinogen (PG) II, markers of gastric mucus neck and pyloric gland cells, were found in 79 tumors. All of these tumors also expressed M1 or CaE. DU-PAN-2 and the N-terminal epitope of gastrin-releasing peptide, markers of normal pancreatobiliary duct cells, were found in 70 and 49 tumors, respectively, and CAR-5 and M3SI, markers of intestinal mucin, were expressed in 51 and 30 tumors, respectively. All tumors expressed at least two of the nine markers studied; none expressed PG I, a marker of gastric chief cells. The mucopeptic cell marker, PG II, was significantly more common in benign and borderline than in malignant tumors (P less than 0.005), whereas CAR-5 and M3SI, markers of intestinal mucin, were expressed significantly more often in malignant than in benign and borderline tumors (P less than 0.001). By electron microscopic examination, many tumor cells had fine structural features characteristic of gastric superficial/foveolar and pyloric gland cells, intestinal columnar or goblet cells, and endocervical cells. The results indicate that gastroenteropancreatic cell differentiation--and, in particular, gastric type differentiation--is a prominent feature of ovarian mucinous tumors.
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Affiliation(s)
- P Tenti
- Instituto Ricovera e Cura a Carattere Scientifico Policlinico San Matteo, Policlinico S. Matteo, Pavia, Italy
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40
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Lipkin M. Gastrointestinal cancer: pathogenesis, risk factors and the development of intermediate biomarkers for chemoprevention studies. JOURNAL OF CELLULAR BIOCHEMISTRY. SUPPLEMENT 1992; 16G:1-13. [PMID: 1469890 DOI: 10.1002/jcb.240501102] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Dietary, environmental and genetic factors contribute to the etiology, pathogenesis and risk for gastrointestinal cancers. Measurements of cell proliferation and differentiation further identify abnormal cellular properties associated with increased susceptibility to gastrointestinal cancer. In precancerous esophagus, the proliferative compartment increases in size, increased ploidy and dysplasia develop, and epithelial cells express abnormal cytokeratins and ectopic tumor-associated antigens. In precancerous stomach, increased proliferative activity and metaplasia develop. Intestinal enzymes and mucins are expressed and normal gastric antigens are replaced by intestinal or embryonic antigens. In flat colonic mucosa and in colonic adenomas, expansions of the proliferative compartment occur. Gene expression is modified, gene deletions occur and blood group-related antigens are modified as the cells undergo abnormal differentiation and develop into adenomas and carcinomas. Chemopreventive regimens are now being tested to determine whether they modify such intermediate biomarkers toward normal levels characteristic of lower risk for neoplasia. It is anticipated that the utilization of intermediate biomarkers in chemoprevention studies may permit more novel chemopreventive regimens to be tested in human subjects than heretofore was possible.
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Affiliation(s)
- M Lipkin
- Irving Weinstein Laboratory for Gastrointestinal Cancer Prevention, Memorial Sloan-Kettering Cancer Center, New York, NY 10021
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41
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Hertzog PJ, Pilbrow SJ, Pedersen J, Polglase AL, Lawson M, Linnane AW. Aberrant expression of intestinal mucin antigens associated with colorectal carcinoma defined by a panel of monoclonal antibodies. Br J Cancer 1991; 64:799-808. [PMID: 1931599 PMCID: PMC1977491 DOI: 10.1038/bjc.1991.404] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Small intestine mucin antigen (SIMA) is an oncofoetal antigen for the colon and is distinct from the normal large intestinal mucin antigen (LIMA). In the present study, a panel of anti-SIMA and anti-LIMA monoclonal antibodies (MAb) was used to charaterise altered mucin expression in colorectal adenocarcinomas, by immunohistochemistry and quantitative immunoassays of tissue extracts. These results are compared with CEA expression and correlated with various clinicopathological indices. All mucin MAb reacted with a high proportion of the 100 colon cancers of every stage, histological type (including non-mucinous cancers), differentiation, site, or size. Inappropriate SIMA production was detected by either anti-SIMA MAb 4D3 or 4A1, even in 85% of early stage cancers. MAb 4D3 reacted with a higher proportion of cancers of smaller size and better differentiation. At the subcellular level, both anti-SIMA MAb showed reactivity typical of normal mucin, i.e., goblet cell and extracellular mucin. The normal colonic antigen, LIMA, was also detectable in the majority of cases, but quantitatively overproduced in some cases and reduced in others. However, in contrast to SIMA, LIMA was detected in predominantly undifferentiated cancer cells but not in goblet cells. Heterogeneity of MAb reactivity between cases and complementarity within each cancer was frequently observed. Mucin reactive with at least one of the MAb was detected in all of the CEA-negative cancers. A high rate of inappropriate SIMA expression was also detected in the perineoplastic transitional mucosa (88%, c.f. CEA, 35%) and adjacent, morphologically normal mucosa (80% c.f. CEA, 24%), indicating biochemical changes similar to the cancer. This panel of anti-mucin MAb demonstrated altered mucin glycoprotein metabolism associated with the development and progression of most colorectal cancers, which emphasises their utility as indicators of neoplastic change in the colon, and their superiority to CEA.
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Affiliation(s)
- P J Hertzog
- Centre for Molecular Biology and Medicine, Monash University, Clayton, Victoria, Australia
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42
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Hertzog PJ, Robinson HC, Ma J, Mackay IR, Linnane AW. Oncofetal expression of the human intestinal mucin glycoprotein antigens in gastrointestinal epithelium defined by monoclonal antibodies. Int J Cancer 1991; 48:355-63. [PMID: 1710206 DOI: 10.1002/ijc.2910480308] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
A mucin preparation from a colonic adenocarcinoma was used to prepare monoclonal antibodies (MAbs) that reacted specifically either with normal adult small-intestine mucin antigen(s) (SIMA), or normal adult large-intestine mucin antigen(s) (LIMA). Both SIMA and LIMA show a unique oncofetal pattern of expression. Thus SIMA was expressed in early fetal stomach, large and small intestines but thereafter only in the normal small intestine. SIMA expression was detected immunohistochemically in cancers of the colorectum (82/112) and stomach (48/86). LIMA was detected in the stomach of the early fetus but thereafter only in the normal large intestine. LIMA expression was detected in 61/86 cancers of the stomach. Moreover, both SIMA and LIMA were expressed inappropriately in mucosa adjacent to tumors, indicative of the detection of possible pre-malignant epithelium. We used a sandwich ELISA and biochemical procedures to show that the SIMA and LIMA molecules were large extensively glycosylated multi-unit mucin glycoproteins that differed markedly from each other. SIMA, whether extracted from normal small-intestine or colonic cancers, had a molecular weight above 1.000 kDa, a mean buoyant density 1.33 g/ml and s value of 4.8. LIMA had a molecular weight above 10.000 kDa, a mean buoyant density 1.45 g/ml and an s value 9.5. The SIMA and LIMA epitopes were judged to be carbohydrate in nature by reason of their resistance to harsh physical chemical treatments or protease digestion, and sensitivity to periodate oxidation, neuraminidase or beta elimination. Only the SIMA epitope was sensitive to neuraminidase. In conclusion, MAbs to carbohydrate-dependent epitopes on SIMA and LIMA identify the oncofetal pattern of expression of these distinct intestinal mucin glycoproteins in colonic and gastric carcinoma. These MAbs will be useful in further studies of the significance of oncofetal mucin expression during carcinogenesis.
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Affiliation(s)
- P J Hertzog
- Centre for Molecular Biology and Medicine, Monash University, Clayton, Victoria, Australia
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43
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Sessa F, Bonato M, Frigerio B, Capella C, Solcia E, Prat M, Bara J, Samloff IM. Ductal cancers of the pancreas frequently express markers of gastrointestinal epithelial cells. Gastroenterology 1990; 98:1655-65. [PMID: 1692551 DOI: 10.1016/0016-5085(90)91104-e] [Citation(s) in RCA: 84] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
It has been found by immunohistochemical staining that antigens normally found in gastric and/or intestinal epithelial cells are expressed in most differentiated duct cell carcinomas of the pancreas. Among 88 such tumors, 93% and 92%, respectively, expressed M1 and cathepsin E, markers of gastric surface-foveolar epithelial cells, 51% expressed pepsinogen II, a marker of gastroduodenal mucopeptic cells, 48% expressed CAR-5, a marker of colorectal epithelial cells, and 35% expressed M3SI, a marker of small intestinal goblet cells. Most of the tumors also expressed normal pancreatic duct antigens; 97% expressed DU-PAN-2, and 59% expressed N-terminus gastrin-releasing peptide. In agreement with these findings, electron microscopy revealed malignant cells with fine structural features of gastric foveolar cells, gastric mucopeptic cells, intestinal goblet cells, intestinal columnar cells, pancreatic duct epithelial cells, and cells with features of more than one cell type. Normal pancreatic duct epithelium did not express any marker of gastrointestinal epithelial cells, whereas such benign lesions as mucinous cell hypertrophy and papillary hyperplasia commonly expressed gut-type antigens but rarely expressed pancreatic duct cell markers. By contrast, lesions characterized by atypical papillary hyperplasia commonly expressed both gastric and pancreatic duct cell markers. Metaplastic pyloric-type glands expressed pepsinogen II and, except for their expression of cathepsin E, were indistinguishable from normal pyloric glands. In marked contrast, the immunohistochemical and ultrastructural features of 14 ductuloacinar cell tumors were those of cells lining terminal ductules, centroacinar cells, and/or acinar cells; none expressed any gut-type antigen. The results indicate that gastrointestinal differentiation is common in both benign and malignant lesions of pancreatic duct epithelium and suggest that duct cell carcinomas are histogenetically related to gastric- and intestinal-type metaplastic changes of epithelial cells lining the main and interlobular ducts of the pancreas.
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Affiliation(s)
- F Sessa
- Instituto Ricovero e Cura a Carattere Scientifico Policlinico San Matteo, Pavia, Italy
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44
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Reid PE, Park CM. Carbohydrate histochemistry of epithelial glycoproteins. PROGRESS IN HISTOCHEMISTRY AND CYTOCHEMISTRY 1990; 21:1-170. [PMID: 2267321 DOI: 10.1016/s0079-6336(11)80069-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
- P E Reid
- Department of Pathology, Faculty of Medicine, University of British Columbia, Vancouver, Canada
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45
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Muraro R, Nuti M, Natali PG, Bigotti A, Simpson JF, Primus FJ, Colcher D, Greiner JW, Schlom J. A monoclonal antibody (D612) with selective reactivity for malignant and normal gastro-intestinal epithelium. Int J Cancer 1989; 43:598-607. [PMID: 2649441 DOI: 10.1002/ijc.2910430411] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
We describe the generation and characterization of a monoclonal antibody (MAb), designated D612, with selective reactivity for malignant and normal gastro-intestinal epithelium. MAb D612, a murine IgG2a, was generated using a membrane-enriched fraction of a human colon carcinoma biopsy as immunogen. Employing radioimmunoassays (RIAs) of biopsy extracts to a range of normal and neoplastic tissues, and both immunofluorescence and immunoperoxidase assays on frozen sections of a range of normal and neoplastic tissues, we have shown that MAb D612 binds to 82% of colorectal carcinomas tested (n = 67) and to normal gastro-intestinal epithelium, but does not bind similarly to either neoplastic or normal tissues from a wide range of other sites. Western blotting has shown MAb D612 to react with a high-molecular-weight antigen. Live cell RIAs and FACS analyses demonstrate the reactive epitope to be present on the surface of colon carcinoma cells. Immunohistochemical studies have shown intense membrane staining of colon adenocarcinomas with MAb D612; the vast majority of both primary and metastatic colon adenocarcinomas from a variety of sites were positive with many lesions showing homogeneous staining of virtually all cells present. Using human effector cells, we also showed that MAb D612 mediates antibody-dependent cell-mediated cytotoxicity (ADCC) of human colon carcinoma cells; this activity was enhanced in the presence of interleukin (IL-2). Radiolabelled D612-purified IgG selectively binds a human colon carcinoma xenograft in situ. The pattern of membrane-associated staining, the molecular weight of the reactive antigen, the IgG2a isotype, the ability to mediate ADCC in the presence of IL-2, and the immunohistochemical and RIA studies demonstrating highly restricted reactivity to malignant and normal gastro-intestinal tissue, all distinguish MAb D612 from other MAbs thus far described.
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Affiliation(s)
- R Muraro
- Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD 20892
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46
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Lipkin M. Biomarkers in the Identification of High-Risk Groups. COLORECTAL CANCER 1989. [DOI: 10.1007/978-3-642-85930-4_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Verstijnen CP, Arends JW, Moerkerk PT, Pijls M, Kuypers-Engelen B, Bosman FT. Colonic epithelium reactive monoclonal antibodies. Identification and immunohistochemical localization of the target epitopes. HISTOCHEMISTRY 1989; 92:397. [PMID: 2479618 DOI: 10.1007/bf00492497] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
We have produced a small library of colonic mucosa and colorectal carcinoma reactive monoclonal antibodies (MoAbs) by immunizations with extracts of human colon cancer tissue and a human colon cancer cell line. Hybridoma supernatants were tested on (normal and neoplastic) human tissues by immunoperoxidase methods to evaluate organ or tissue specificity. Initial biochemical characterization of the target antigens was performed by gelpermeation chromatography, Western blotting and competition assays. Based upon the immunoreactivity patterns and the characteristics of the antigen four groups of MoAbs could be distinguished. The first group concerns the antibodies PARLAM 3, 9 and 10. These antibodies react with an 87 kDa protein moiety in high molecular weight (2-5 x 10(6) Da) glycoproteins. In intestinal and colon mucosa these antibodies showed diffuse binding with goblet cells. In colon carcinoma decreased reactivity with these MoAbs was found. The second group consists of antibodies PARLAM 8, 12 and 13. These antibodies react with large (greater than 5 x 10(6) Da) glycoproteins, most likely with carbohydrate epitopes. By immunohistochemistry in normal colon mucosa the antibodies all show granular supranuclear reactivity with goblet cells. These antibodies show increased reactivity with colon adenomas and adenocarcinomas. A third group is formed by PARLAM 2, which also reacts with a large (greater than 5 x 10(6) Da) glycoprotein, showing a granular distribution in goblet cells. In colon carcinomas more extensive expression is found than in normal colonic mucosa. Finally, the fourth group consists of PARLAM 11, which also reacts with a large (greater than 5 x 10(6) Da) glycoprotein, located in the brush border of colonic columnar cells. These antibodies might be useful tools for the analysis of the expression of mucin related glycoproteins in normal, preneoplastic and neoplastic colon mucosa.
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Affiliation(s)
- C P Verstijnen
- Department of Pathology, State University of Limburg, Maastricht, The Netherlands
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Bara J, Gautier R, Le Pendu J, Oriol R. Immunochemical characterization of mucins. Polypeptide (M1) and polysaccharide (A and Leb) antigens. Biochem J 1988; 254:185-93. [PMID: 2460087 PMCID: PMC1135055 DOI: 10.1042/bj2540185] [Citation(s) in RCA: 47] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Seven monoclonal antibodies (MAbs) reacting with high-molecular-mass components (greater than 20,000 kDa) isolated from an ovarian mucinous cyst of an A Le(a-b+) patient are described. By the use of immunoradiometric methods, these MAbs characterized seven different epitopes associated with components having a density of 1.45 g/ml by CsCl-density-gradient ultracentrifugation, like mucins. Two MAbs reacted with A and Lewis blood-group antigens respectively (polysaccharide epitopes). The five other MAbs characterized five M1 epitopes (called a, b, c, d and e), mainly associated with components of more than 20,000 kDa and 2000 kDa. They were completely destroyed by papain and 2-mercaptoethanol treatment (polypeptide epitopes). Moreover, timed trypsin digestion of native mucin resulted in a progressive loss of M1 activity and degraded these mucins into smaller M1-positive fragments. The a and c epitopes were partially degraded from relatively high-molecular-mass fragments (2000 kDa to 500 kDa) into a 100 kDa fragment. The b and d epitopes were completely degraded into smaller fragments ranging from 100 kDa to 40 kDa. The e epitope was completely destroyed by trypsin. These different pathways of M1 antigen degradation suggest the occurrence of different epitopes located in separate regions of the mucin molecules.
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Affiliation(s)
- J Bara
- Institut de Recherches sur le Cancer, C.N.R.S., Villejuif, France
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Daher N, Gautier R, Abourachid H, Decaens C, Bara J. Rat colonic carcinogenesis after ureterosigmoidostomy: pathogenesis and immunohistological study. J Urol 1988; 139:1331-6. [PMID: 3286898 DOI: 10.1016/s0022-5347(17)42913-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
A group of 44 rats underwent the equivalent of a ureterosigmoidostomy (US), while a second group of 18 rats underwent a pediculated graft (PG) of urothelial tissue in the sigmoid wall. Histological lesions were observed in the colon near the bladder colon junction in US rats exclusively. These lesions included dysplasias (5/23), cystic glands (4/23) and 10 neoplasms (9/23), three of which were adenomas, showing elements of juvenile polyp and tubular adenoma in one case. The seven other tumors showed typical histological features of colonic adenocarcinomas, but no frank evidence of parietal tumoral invasion was observed and their cancerous nature was questionable. It is probably a true carcinogenesis since we induced the same histological changes as those in the mucosae adjacent to colonic adenocarcinomas after human US surgery. Moreover, by immunoperoxidase using antibodies against mucus associated antigens (M1 and M3C antigens) we demonstrated that US rat carcinogenesis differs from dimethylhydrazine (DMH) rat carcinogenesis. Furthermore, our results suggest that urine may be an important factor in inducing this type of US carcinogenesis.
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Affiliation(s)
- N Daher
- Department of Urology, Amiens, France
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Fiocca R, Villani L, Tenti P, Cornaggia M, Finzi G, Capella C, Prat M, Bussolati G, Solcia E. Widespread expression of intestinal markers in gastric carcinoma: a light and electron microscopic study using BD-5 monoclonal antibody. J Clin Pathol 1988; 41:178-87. [PMID: 3350978 PMCID: PMC1141375 DOI: 10.1136/jcp.41.2.178] [Citation(s) in RCA: 32] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
BD-5 monoclonal antibody reacted with tumour cells in 262 of 316 cases of gastric cancers, including 121 of 134 early, 141 of 182 advanced tumours (p less than 0.01), and 113 of 146 glandular, 72 of 83 diffuse, 22 of 25 mucoid, and 55 of 59 mixed tumours. No difference in reactivity was observed between metastatic and non-metastatic advanced tumours. Immunocytochemical techniques applied to light and electron microscopical specimens of colorectal mucosa and gastric cancer showed that BD-5 immunoreactive material occurred in the Golgi complex, in small clear, to dense cored, cytoplasmic vesicles, and in the glycocalix of the luminal and lateral membranes of normal and neoplastic cells in the glands, as well as in the peripheral membrane of dispersed neoplastic cells. Mucin granules stored in the cytoplasm of goblet cells were unreactive or poorly reactive. Ultrastructural features consistent with colorectal type differentiation were observed in many reactive tumours. Unreactive tumours showing ultrastructural patterns consistent with intestinal differentiation, especially of small bowel type, were also observed. Signs of intestinal differentiation, including BD-5 immunoreactivity, often occur in gastric cancer, irrespective of histological type and stage of disease.
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Affiliation(s)
- R Fiocca
- IRCCS Policlinico San Matteo, Pavia, Italy
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