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Gan S, Li C, Hou R, Tian G, Zhao Y, Ren D, Zhou W, Zhao F, Lv K, Yang J. Dynamic changes of the immune microenvironment in the development of gastric cancer caused by inflammation. MOLECULAR THERAPY. ONCOLOGY 2024; 32:200849. [PMID: 39228396 PMCID: PMC11369508 DOI: 10.1016/j.omton.2024.200849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Revised: 06/21/2024] [Accepted: 07/16/2024] [Indexed: 09/05/2024]
Abstract
Precancerous lesions typically precede gastric cancer (GC), but the molecular mechanisms underlying the transition from these lesions to GC remain unclear. Therefore, it is urgent to understand this transition from precancerous lesions to GC, which is crucial for the early diagnosis and treatment of GC. In this study, we merged multiple single-cell RNA sequencing datasets to investigate the molecular changes in distinct cell types associated with the progression of GC. First, we observed an increasing abundance of immune cells and a decrease in non-immune cells from non-atrophic gastritis to GC. Five immune cell types were significantly enriched in GC compared to precancerous lesions. Moreover, we found that the interleukin (IL)-17 signaling pathway and Th17 cell differentiation were significantly up-regulated in immune cell subsets during GC progression. Some genes in these processes were predominantly expressed at the GC stage, highlighting their potential as diagnostic markers. Furthermore, we validated our findings using bulk RNA sequencing data from The Cancer Genome Atlas and confirmed consistent immune cell changes during GC progression. Our study provides insights into the immune infiltration and signaling pathways involved in the development of GC, contributing to the development of early diagnosis and targeted treatment strategies for this malignancy.
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Affiliation(s)
- Siyuan Gan
- School of Mathematical Sciences, Ocean University of China, Qingdao, China
| | - Changfu Li
- Department of Digestive Internal Medicine, Daqing Longnan Hospital, The Fifth Affiliated Hospital of Qiqihar Medical College, Daqing 163000, China
| | - Rui Hou
- Geneis Beijing Co., Ltd, Beijing 100102, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao 266000, China
| | - Geng Tian
- Geneis Beijing Co., Ltd, Beijing 100102, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao 266000, China
| | - Yuan Zhao
- School of Electrical and Information Engineering, Anhui University of Technology, Ma'anshan, China
| | - Dan Ren
- Department of Pathology, Daqing Longnan Hospital, The Fifth Affiliated Hospital of Qiqihar Medical College, Daqing 163000, China
| | - Wenjing Zhou
- Department of Oncology, Hiser Medical Center of Qingdao, No. 4, Renmin Road, Shibei District, Qingdao, China
| | - Fei Zhao
- School of Mathematical Sciences, Ocean University of China, Qingdao, China
| | - Kebo Lv
- School of Mathematical Sciences, Ocean University of China, Qingdao, China
| | - Jialiang Yang
- Geneis Beijing Co., Ltd, Beijing 100102, China
- Qingdao Geneis Institute of Big Data Mining and Precision Medicine, Qingdao 266000, China
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Ryabokon RV, Tsukanov VV, Khorzhevskii VA, Vasyutin AV, Tonkikh JL. Epithelial cell proliferation index in patients with atrophic gastritis depending on the presence of complete or incomplete intestinal metaplasia in the gastric antrum. MEDITSINSKIY SOVET = MEDICAL COUNCIL 2024:28-34. [DOI: 10.21518/ms2024-199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/12/2024]
Abstract
Introduction. There is a debate about the significance of intestinal metaplasia (IM) subtypes for the development of gastric cancer. Therefore, determining the indicators of cellular renewal in individuals with complete and incomplete IM is certainly a topical issue.Aim. To study the proliferative activity of epithelial cells of the gastric antrum in patients with Helicobacter pylori-positive antral atrophic gastritis depending on the subtype of IM.Materials and methods. The study included 20 people with chronic antral non-atrophic gastritis (CNG; group A), 20 patients with chronic antral atrophic gastritis (CAG) without IM (group B), 20 patients with CAG with complete IM (group C) and 20 people with CAG with incomplete IM (group D). The stage of chronic gastritis was assessed by the morphological method in accordance with the modified Sydney classification. Typing of IM foci in the gastric mucosa was performed using the PAS reaction. Proliferation activity was studied by the expression of nuclear protein Ki67 using immunohistochemistry.Results. The proliferation index in the foci of complete BM in group C was 5%, and in group D in the foci of incomplete BM the Ki67 expression index was significantly higher and was 39% (p < 0.001). Outside the foci of metaplasia, the proliferation index was 23.5% in group C and 19% in group D (p = 0.06).Conclusion. We have registered significantly higher proliferation indicators of gastric epithelial cells in foci with incomplete IM compared to foci with complete IM. Determination of proliferation indicators in foci of incomplete intestinal metaplasia may be a marker of an increased risk of developing gastric cancer.
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Affiliation(s)
- R. V. Ryabokon
- Federal Research Center “Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences”, Research Institute of Medical Problems of the North;
Krasnoyarsk Regional Pathology-Anatomic Bureau
| | - V. V. Tsukanov
- Federal Research Center “Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences”, Research Institute of Medical Problems of the North
| | | | - A. V. Vasyutin
- Federal Research Center “Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences”, Research Institute of Medical Problems of the North
| | - J. L. Tonkikh
- Federal Research Center “Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences”, Research Institute of Medical Problems of the North
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Kiliçarslan A, Varli G. Should Special Staining (AB/PAS) be Routinely Performed in Gastric Biopsies for the Detection of Intestinal Metaplasia? Int J Surg Pathol 2024; 32:217-222. [PMID: 37131333 DOI: 10.1177/10668969231169050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Background. Gastric intestinal metaplasia increases the risk of gastric cancer by nine times. Although attempts are made to diagnose it using endoscopic methods, the final diagnosis is established by examining and reporting biopsy samples. Although there are studies in the literature that do not recommend routine special staining, many laboratories routinely perform alcian blue/periodic acid Schiffs (AB/PAS) staining, in addition to hematoxylin and eosin (H&E) staining. In this study, we examined the need for performing routine special staining. Methods. Seven hundred forty-one consecutive gastric biopsies obtained from the archive of our laboratory in 2019 were included in the study. One day after evaluating the cases using H&E, they were evaluated with AB/PAS without examining the H&E results. Result. All of the intestinal metaplasia lesions detected in H&E were observed with AB/PAS. However, we missed 14 (13.73%) of 102 intestinal metaplasia lesions with H&E that we detected using AB/PAS. We found the sensitivity and specificity of H&E in detecting intestinal metaplasia were 86.3% and 99.7%, respectively. When we retrospectively examined the 14 missed lesions in H&E staining, we could observe intestinal metaplasia in six biopsies, but it was not possible in eight (7.8%). Conclusion. Considering that gastric intestinal metaplasia is a precancerous lesion, we think that this ratio (13.73%) is high and that the number of malignancies can be reduced with a low-cost special stain. In this context, we advocate and recommend routinely performing inexpensive special staining such as AB/PAS to detect intestinal metaplasia in all gastric biopsies.
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Affiliation(s)
- Ahmet Kiliçarslan
- Department of Pathology, Elazığ Fethi Sekin City Hospital, Elazığ, Turkey
| | - Gökhan Varli
- Department of Pathology, Karaman Training and Research Hospital, University Mh, Karaman, Turkey
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Sugano K, Moss SF, Kuipers EJ. Gastric Intestinal Metaplasia: Real Culprit or Innocent Bystander as a Precancerous Condition for Gastric Cancer? Gastroenterology 2023; 165:1352-1366.e1. [PMID: 37652306 DOI: 10.1053/j.gastro.2023.08.028] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 08/16/2023] [Accepted: 08/22/2023] [Indexed: 09/02/2023]
Abstract
Gastric intestinal metaplasia (GIM), which denotes conversion of gastric mucosa into an intestinal phenotype, can occur in all regions of the stomach, including cardiac, fundic, and pyloric mucosa. Since the earliest description of GIM, its association with gastric cancer of the differentiated (intestinal) type has been a well-recognized concern. Many epidemiologic studies have confirmed GIM to be significantly associated with subsequent gastric cancer development. Helicobacter pylori, the principal etiologic factor for gastric cancer, plays the most important role in predisposing to GIM. Although the role of GIM in the stepwise progression model of gastric carcinogenesis (the so-called "Correa cascade") has come into question recently, we review the scientific evidence that strongly supports this long-standing model and propose a new progression model that builds on the Correa cascade. Eradication of H pylori is the most important method for preventing gastric cancer globally, but the effect of eradication on established GIM, is limited, if any. Endoscopic surveillance for GIM may, therefore, be necessary, especially when there is extensive corpus GIM. Recent advances in image-enhanced endoscopy with integrated artificial intelligence have facilitated the identification of GIM and neoplastic lesions, which will impact preventive strategies in the near future.
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Affiliation(s)
| | - Steven F Moss
- Alpert Medical School of Brown University, Providence, Rhode Island
| | - Ernst J Kuipers
- Erasmus Medical Center, Rotterdam and Minister, Ministry of Health, Welfare, and Sport, Hague, The Netherlands
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Hajdu SI. Pathfinders in oncology from the first clinical use of single-agent chemotherapy to the introduction of mammography. Cancer 2021; 127:12-26. [PMID: 33095913 DOI: 10.1002/cncr.33223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 09/01/2020] [Accepted: 09/03/2020] [Indexed: 01/18/2023]
Abstract
During the period from 1942 to 1962, treatment attempts with single-agent chemotherapy such as nitrogen mustard and urethan gained limited application. However, the groundbreaking success with aminopterin in the treatment of patients with pediatric acute leukemia and methotrexate in the treatment of gestational choriocarcinoma established single-agent chemotherapy as a pioneering contribution to oncology. The landmark discovery that early-stage Hodgkin disease is curable with radiation made radiotherapy into an essential specialty of oncology. Although radical surgical treatment dominated the field of surgery, the excision of localized cancers with or without adjuvant radiation emerged as new modality in therapy. Cytopathology and surgical pathology became new fields in medicine and pathologists became an integral part of the preoperative, intraoperative, and postoperative care of patients with cancer. The discovery of multiple new drugs demonstrated promising results and widened the field of oncology from the laboratory to the clinic. In the etiology of cancer, precancerous conditions were named and carcinoma of the lung was definitively linked to cigarette smoking. All things considered, the progress made between 1942 and 1962 came about through the dedicated work of many individuals. However, there were 7 distinguished pathfinders (2 pathologists, 1 pediatric pathologist-oncologist, 1 radiation therapist, 1 physician-actuary, 1 gynecologist-oncologist, and 1 chemist) who, despite their different backgrounds, interests, and sex, made groundbreaking contributions to oncology.
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Singh R, Balasubramanian I, Zhang L, Gao N. Metaplastic Paneth Cells in Extra-Intestinal Mucosal Niche Indicate a Link to Microbiome and Inflammation. Front Physiol 2020; 11:280. [PMID: 32296343 PMCID: PMC7138011 DOI: 10.3389/fphys.2020.00280] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 03/12/2020] [Indexed: 12/12/2022] Open
Abstract
Paneth cells are residents of the intestinal epithelium. Abnormal appearance of Paneth cells has been widely documented in non-intestinal tissues within the digestive tract and even observed in non-gastrointestinal organs. Although metaplastic Paneth cells are part of the overarching pathology of intestinal metaplasia (IM), only a fraction of intestinal metaplastic lesions contain Paneth cells. We survey literature documenting metaplastic Paneth cells to gain insights into mechanism underlying their etiologic development as well as their potential relevance to human health. A synthesized view from this study suggests that the emergence of metaplastic Paneth cells at extra-intestinal mucosal sites likely represents a protective, anti-bacterial, and inflammatory response evoked by an altered microbial activity.
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Affiliation(s)
- Rajbir Singh
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States
| | | | - Lanjing Zhang
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States.,Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, Piscataway, NJ, United States.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States.,Department of Pathology, Princeton Medical Center, Plainsboro, NJ, United States
| | - Nan Gao
- Department of Biological Sciences, Rutgers University, Newark, NJ, United States.,Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, United States
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Pilotti S, Rilke F, Del Vecchio M. Correlation between Histopathology and Natural History of Intestinal-Type Adenocarcinoma and Diffuse Undifferentiated Carcinoma of the Stomach. TUMORI JOURNAL 2018; 59:193-217. [PMID: 4354102 DOI: 10.1177/030089167305900303] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
A total of 400 cases of surgically removed carcinoma of the stomach between 1955 and 1967 were reclassified histologically in two basic types: the adenocarcinoma of intestinal type and the diffuse undifferentiated carcinoma. The identification of both types was possible in all cases, which were then divided thus: 296 (74%) of the intestinal and 104 (26%) of the diffuse type with a ratio of 2.85:1. The papillary, medullary, scirrhous and colloid variants of the intestinal type represented together 31.4% of these cases; the micro-glandular and the colloid variants of the diffuse carcinoma represented 53.8%. In the 127 regional cases (42.9%) of the intestinal type all the lymph node metastases had the same histological structure as the primary whereas in the 43 regional cases (41.3%) of the diffuse type the structure was of the intestinal type in 4 cases (9.3%). Atrophic gastritis and intestinal metaplasia were found in the gastric mucosa adjacent to the tumor in 91.9% of the males and in 91.2% of the females with the intestinal type; corresponding figures for the diffuse carcinoma are 21.6% and 45.9% (p < 0.000000001). Of 296 cases of the intestinal type 194 were males and 102 females with a ratio M/F = 1.90; the ratio for 61 males and 43 females with diffuse carcinoma was 1.41. There was no evidence of a statistical relationship between sex and histological type of tumor. Mean age for males with the intestinal type was 59.0 yrs, with diffuse carcinoma 55.9 (p < 0.05); for females with the intestinal type was 60.6 yrs, and with diffuse carcinoma 55.3 (p < 0.001). The age-group with the highest predominance of diffuse carcinoma was below 55 years (54.8% of the cases). In females below 55 yrs of age the diffuse type was more frequent than the intestinal type. In the three age groups considered (≤ 55, 56–65, ≥ 65 years) the diffuse carcinoma showed the same distribution in both sexes, whereas the intestinal type revealed less uniformity. Survival rates after 5 years followup of 221 patients with localized disease calculated by means of the life table method were 50% for the intestinal type and 42% for the diffuse carcinoma. Median survival time was 4 years and 9 months for the former and 3 years and 6 months for the latter. Adequate information on 264 cases demonstrated that 70% lived in the Province of Milan; the ratio of intestinal type carcinomas to diffuse carcinomas was 3.33 in Brianza (provincial area north of Milan) and 2.05 in the city of Milan. No relevant association was found between blood group and histologic type of carcinoma. From 1955 to 1967 the ratio between the intestinal and the diffuse type in the patients operated in this Institute seemed to indicated a slightly increasing trend.
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8
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Abstract
Numerous epidemiologic, morphologic and experimental studies have demonstrated the precancerous significance of intestinal metaplasia. We report here the results of a histochemical study of intestinal metaplasia in which 2 types were observed: one with sialomucin-secreting cells typical of the small intestine, and the other with sulphomucin-secreting cells typical of colonic mucosa. The correlation between colonic type intestinal metaplasia and gastric cancer is explored, since a significant precancerous value for this type of intestinal metaplasia is suggested.
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9
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Parisi V, Picone A, Mastro AA, Cerra R. Clinical-statistical Correlation in 286 Cases of Diffuse and Intestinal Carcinoma of the Stomach. TUMORI JOURNAL 2018; 62:25-38. [PMID: 1014114 DOI: 10.1177/030089167606200104] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
286 gastric carcinoma cases have been classified according to Lauren's system. The intestinal and diffuse histotypes are compared, and correlated with the epidemiologic data, type of operation and follow-up. The results show that total gastrectomy is indicated in diffuse carcinoma.
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10
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JAERVI O, LAUREN P. GASTRIC GLANDULAR TUMOURS PROVIDED WITH EXCRETORY DUCTS, AND CRITICISM OF THE THEORY OF THE TUMOURS ARISING IN HETEROTOPIC PANCREAS. ACTA ACUST UNITED AC 2017; 62:1-23. [PMID: 14197674 DOI: 10.1111/apm.1964.62.1.1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
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Powell AGMT, Hughes DL, Wheat JR, Lewis WG. The 100 most influential manuscripts in gastric cancer: A bibliometric analysis. Int J Surg 2016; 28:83-90. [DOI: 10.1016/j.ijsu.2016.02.028] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Revised: 01/27/2016] [Accepted: 02/03/2016] [Indexed: 12/22/2022]
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12
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Meng W, Gu T, Gao LM, Zong ZG, Meng L, Fu ZZ, Guo L. Correlation of cadherin-17 protein expression with clinicopathological features and prognosis of patients with sporadic gastric cancer. ACTA ACUST UNITED AC 2015; 48:1077-86. [PMID: 26421870 PMCID: PMC4661023 DOI: 10.1590/1414-431x20154645] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2014] [Accepted: 04/28/2015] [Indexed: 12/15/2022]
Abstract
This study aimed to explore the correlations between cadherin-17 (CDH17) protein expression and the clinicopathological features and prognosis of patients with sporadic gastric cancer (GC). Nine relevant studies of 1,960 patients were identified using electronic database searches supplemented with a manual search in strict accordance with inclusion and exclusion criteria. Statistical analyses were conducted using STATA 12.0 statistical software. Relative risks and 95% confidence intervals were determined, and Z test was used to measure the significance of the overall effect size. A total of nine eligible cohort studies were included in this meta-analysis. The expression of CDH17 in patients with diffuse GC was significantly higher than in those with intestinal-type GC. Moreover, the tumor depth of invasion differed significantly between patients with positive CDH17 (CDH17+) and negative CDH17 (CDH17-) GC. However, there were no significant differences between CDH17+ and CDH17- GC patients with respect to tumor node metastasis clinical stages, histological grades, or lymph node metastasis. Despite the differences in invasive depth, there was no significant difference in 5-year survival rates between CDH17+ and CDH17- GC patients. Our meta-analysis provides evidence that CDH17 protein expression may be associated with the development of GC, suggesting that CDH17 is an important biomarker that could be useful for the early diagnosis of GC. However, CDH17 levels do not appear to impact overall survival.
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Affiliation(s)
- W Meng
- First Affiliated Hospital, Hebei North University, Zhangjiakou, Hebei Province, China
| | - T Gu
- Department of Medical Oncology, First Hospital of Qinhuangdao, Qinhuangdao, Hebei Province, China
| | - L M Gao
- Department of Medical Oncology, First Hospital of Qinhuangdao, Qinhuangdao, Hebei Province, China
| | - Z G Zong
- First Affiliated Hospital, Hebei North University, Zhangjiakou, Hebei Province, China
| | - L Meng
- Department of Anesthesiology, Guilin Medical University, Guilin, Guangxi Province, China
| | - Z Z Fu
- Department of Medical Oncology, First Hospital of Qinhuangdao, Qinhuangdao, Hebei Province, China
| | - L Guo
- School of Medicine, Nanjing University, Nanjing, Jiangsu Province, China
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Sørdal Ø, Waldum H, Nordrum IS, Boyce M, Bergh K, Munkvold B, Qvigstad G. The gastrin receptor antagonist netazepide (YF476) prevents oxyntic mucosal inflammation induced by Helicobacter pylori infection in Mongolian gerbils. Helicobacter 2013; 18:397-405. [PMID: 23865485 DOI: 10.1111/hel.12066] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
OBJECTIVE Long-term Helicobacter pylori infection causes gastritis leading to hypergastrinemia and predisposes to gastric cancer. Our aim was to assess the role of gastrin in oxyntic mucosal inflammation in H. pylori-infected Mongolian gerbils by means of the gastrin receptor antagonist netazepide (YF476). DESIGN We studied 60 gerbils for 18 months and left five animals uninfected (control group), inoculated 55 with H. pylori, and treated 28 of the infected animals with netazepide (Hp+YF476 group). Twenty-seven infected animals were given no treatment (Hp group). We measured plasma gastrin and intraluminal pH. H. pylori detection and histologic evaluations of the stomach were carried out. RESULTS All 55 inoculated animals were H. pylori positive at termination. Eighteen animals in the Hp group had gastritis. There was a threefold increase in mucosal thickness in the Hp group compared to the Hp+YF476 group, and a threefold increase in oxyntic neuroendocrine cells in the Hp group compared to the Hp+YF476 group (p < .05). All animals in the Hp+YF476 group had macro- and microscopically normal findings in the stomach. Plasma gastrin was higher in the Hp group than in the control group (172 ± 16 pmol/L vs 124 ± 5 pmol/L, p < .05) and highest in the Hp+YF476 group (530 ± 36 pmol/L). Intraluminal pH was higher in the Hp group than in the Hp+YF476 group (2.51 vs 2.30, p < .05). CONCLUSION The gastrin antagonist netazepide prevents H. pylori-induced gastritis in Mongolian gerbils. Thus, gastrin has a key role in the inflammatory reaction of the gastric mucosa to H. pylori infection in this species.
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Affiliation(s)
- Øystein Sørdal
- Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology (NTNU), Trondheim, Norway
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14
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Hajdu SI, Vadmal M. A note from history: Landmarks in history of cancer, Part 6. Cancer 2013; 119:4058-82. [PMID: 24105604 DOI: 10.1002/cncr.28319] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Accepted: 07/09/2013] [Indexed: 11/09/2022]
Abstract
In the 3 decades from 1940 to 1970, the United States became the nucleus for research, diagnosis, and treatment of cancer. The discovery of anticancer drugs, and the clinical demonstration that chemotherapy and radiation can cure cancer and have the ability to prevent recurrence of cancer, were incontrovertibly the most remarkable groundbreaking events. Consequently, the trend of less surgery and more multimodality therapy began. The introduction of radioautography, mammography, ultrasonography, computed tomography, Papanicolaou smear, and other novel laboratory tests furthered early detection of cancer and refined accurate diagnosis. The unequivocal linking of lung cancer to cigarette smoking made medical history. The delineation of the potential role of oncogenes adduced new thoughts about oncogenesis and cancer prevention, and pathologists finalized the classification and nosology of tumors. Finally, it is worth noting that although more advances were made in the detection, diagnosis, and treatment of cancers than any other period in history, the overall mortality rate of patients with cancer remained high and unchanged.
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15
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Helicobacter pylori infection and gastric carcinogenesis in rodent models. Semin Immunopathol 2012; 35:177-90. [PMID: 23111700 DOI: 10.1007/s00281-012-0357-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2012] [Accepted: 10/15/2012] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori infection is an important factor for gastric carcinogenesis in human. In carcinogen-treated Mongolian gerbils, H. pylori infection enhances stomach carcinogenesis, while infection alone induced severe hyperplasia called heterotopic proliferative glands. A high-salt diet or early acquisition of the bacteria exacerbates inflammation and carcinogenesis. Oxygen radical scavengers or anti-inflammatory chemicals as well as eradication of H. pylori are effective to prevent carcinogenesis. H. pylori-associated inflammation induces intestinal metaplasia and intestinalization of stomach cancers independently. It is necessary to control cancer development not only in H. pylori-positive cases but also in H. pylori-negative metaplastic gastritis.
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Marongiu F, Doratiotto S, Sini M, Serra MP, Laconi E. Cancer as a disease of tissue pattern formation. ACTA ACUST UNITED AC 2012; 47:175-207. [DOI: 10.1016/j.proghi.2012.08.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/27/2012] [Indexed: 12/21/2022]
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17
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Ji R, Zuo XL, Yu T, Gu XM, Li Z, Zhou CJ, Li YQ. Mucosal barrier defects in gastric intestinal metaplasia: in vivo evaluation by confocal endomicroscopy. Gastrointest Endosc 2012; 75:980-7. [PMID: 22325805 DOI: 10.1016/j.gie.2011.12.016] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2011] [Accepted: 12/14/2011] [Indexed: 12/23/2022]
Abstract
BACKGROUND Helicobacter pylori infection and intestinal metaplasia (IM) are associated with gastric cancer. An impaired gastric mucosal barrier could be involved in this carcinogenesis. OBJECTIVE To evaluate laser confocal laser endomicroscopy (CLE) for in vivo functional imaging of mucosal barrier defects in patients with IM. DESIGN Prospective, controlled study. SETTING A tertiary-care academic center. PATIENTS This study involved patients with IM of the gastric mucosa who underwent CLE for surveillance. INTERVENTIONS Specific IM mucosa and non-IM mucosa in patients were identified by CLE, and targeted biopsy samples were taken for histopathology and electron microscopy. MAIN OUTCOME MEASUREMENTS Post-CLE assessment of paracellular fluorescein leakage was devised and validated by electron microscopy. We also evaluated the effect of H pylori eradication on the mucosal barrier. RESULTS Forty-two patients were included. Of non-IM samples, the paracellular permeability was significantly increased in H pylori-positive samples compared with H pylori-negative controls (54 ± 31% vs 3 ± 6%, P < .05). Of IM samples, the permeability was significantly increased in both H pylori-negative and H pylori-positive samples (67 ± 34% and 72 ± 28% vs 3 ± 6%, both P < .05). The results of post-CLE assessment correlated well with the electron microscopy findings (R(2) 0.834, P < .0001). After the eradication of H pylori, the paracellular barrier dysfunction of non-IM mucosa was significantly improved as shown by electron microscopy and CLE (both P < .001). However, there was no significant change in IM mucosa. LIMITATIONS Single-center study. CONCLUSIONS CLE allows functional imaging of mucosal barrier defects. Gastric IM is associated with an impaired paracellular barrier irrespective of H pylori eradication.
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Affiliation(s)
- Rui Ji
- Department of Gastroenterology, Qilu Hospital, Shandong University, Jinan, China
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18
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Abstract
Invasive gastric carcinoma is preceded by a cascade of precancerous lesions. The first recognized histologic change is active chronic inflammation, which may persist as such: non-atrophic chronic gastritis (no gland loss), or advance to multifocal atrophic gastritis (MAG), the first real step in the precancerous cascade. The following steps are: intestinal metaplasia (first "complete" and then "incomplete"); dysplasia, first low grade and then high grade (equivalent to "carcinoma in situ"). The following step is invasive carcinoma, which is thought to be associated with degradation of the intercellular matrix.
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Affiliation(s)
- Pelayo Correa
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0252, USA.
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19
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Dinis-Ribeiro M, Areia M, de Vries AC, Marcos-Pinto R, Monteiro-Soares M, O'Connor A, Pereira C, Pimentel-Nunes P, Correia R, Ensari A, Dumonceau JM, Machado JC, Macedo G, Malfertheiner P, Matysiak-Budnik T, Megraud F, Miki K, O'Morain C, Peek RM, Ponchon T, Ristimaki A, Rembacken B, Carneiro F, Kuipers EJ. Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Endoscopy 2012; 44:74-94. [PMID: 22198778 PMCID: PMC3367502 DOI: 10.1055/s-0031-1291491] [Citation(s) in RCA: 475] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Atrophic gastritis, intestinal metaplasia, and epithelial dysplasia of the stomach are common and are associated with an increased risk for gastric cancer. In the absence of guidelines, there is wide disparity in the management of patients with these premalignant conditions. The European Society of Gastrointestinal Endoscopy (ESGE), the European Helicobacter Study Group (EHSG), the European Society of Pathology (ESP) and the Sociedade Portuguesa de Endoscopia Digestiva (SPED) have therefore combined efforts to develop evidence-based guidelines on the management of patients with precancerous conditions and lesions of the stomach (termed MAPS). A multidisciplinary group of 63 experts from 24 countries developed these recommendations by means of repeat online voting and a meeting in June 2011 in Porto, Portugal. The recommendations emphasize the increased cancer risk in patients with gastric atrophy and metaplasia, and the need for adequate staging in the case of high grade dysplasia, and they focus on treatment and surveillance indications and methods.
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Affiliation(s)
- M. Dinis-Ribeiro
- Department of Gastroenterology, Portuguese Oncology Institute of Porto, Portugal, Centre for Research in Health Technologies and Information Systems (CINTESIS), Medical Faculty, Porto, Portugal
| | - M. Areia
- Department of Gastroenterology, Portuguese Oncology Institute of Coimbra, Portugal, Centre for Research in Health Technologies and Information Systems (CINTESIS), Medical Faculty, Porto, Portugal
| | - A. C. de Vries
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
| | - R. Marcos-Pinto
- Department of Gastroenterology, Centro Hospitalar do Porto, Portugal, Institute of Biomedical Sciences, University of Porto (ICBAS/UP), Porto, Portugal
| | - M. Monteiro-Soares
- Centre for Research in Health Technologies and Information Systems (CINTESIS), Medical Faculty, Porto, Portugal
| | - A. O'Connor
- AMNCH/TCD, Adelaide and Meath Hospital/Trinity College, Gastroenterology Department, Dublin, Ireland
| | - C. Pereira
- Molecular Oncology Research Group, Portuguese Oncology Institute of Porto, Portugal
| | - P. Pimentel-Nunes
- Department of Gastroenterology, Portuguese Oncology Institute of Porto, Portugal
| | - R. Correia
- Centre for Research in Health Technologies and Information Systems (CINTESIS), Medical Faculty, Porto, Portugal
| | - A. Ensari
- Department of Pathology, Ankara University Medical School, Ankara, Turkey
| | - J. M. Dumonceau
- Département de Gastroénterologie et d'Hépatopancréatologie, H.U.G. Hôpital Cantonal, Geneve, Switzerland
| | - J. C. Machado
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal
| | - G. Macedo
- Department of Gastroenterology, Centro Hospitalar S. João/Medical Faculty, Porto, Portugal
| | - P. Malfertheiner
- Klinik der Gasroenterologie, Hepatologie und Infektologie, Otto von Guericke Universität Magdeburg, Magdeburg, Germany
| | - T. Matysiak-Budnik
- Service d'Hépato-Gastroentérologie, Hôtel Dieu, CHU de Nantes, Nantes, France
| | - F. Megraud
- Inserm U853 & Université Bordeaux, Laboratoire de Bacteriologie, Bordeaux, France
| | - K. Miki
- Japan Research Foundation of Prediction, Diagnosis and Therapy for Gastric Cancer (JRF PDT GC), Tokyo, Japan
| | - C. O'Morain
- AMNCH/TCD, Adelaide and Meath Hospital/Trinity College, Gastroenterology Department, Dublin, Ireland
| | - R. M. Peek
- Division of Gastroenterology, Vanderbilt University School of Medicine, Nashville, USA
| | - T. Ponchon
- Hôpital Edouard Herriot, Department of Digestive Diseases, Lyon, France
| | - A. Ristimaki
- Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland., Genome-Scale Biology, Research Program Unit, University of Helsinki, Helsinki, Finland
| | - B. Rembacken
- Centre for Digestive Diseases, The General Infirmary at Leeds, Leeds, United Kingdom
| | - F. Carneiro
- Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), Porto, Portugal, Department of Pathology, Medical Faculty/Centro Hospitalar S. João, Porto, Portugal
| | - E. J. Kuipers
- Department of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands
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Abstract
Invasive gastric carcinoma is preceded by a cascade of precancerous lesions. The first recognized histologic change is active chronic inflammation, which may persist as such: non-atrophic chronic gastritis (no gland loss), or advance to multifocal atrophic gastritis (MAG), the first real step in the precancerous cascade. The following steps are: intestinal metaplasia (first "complete" and then "incomplete"); dysplasia, first low grade and then high grade (equivalent to "carcinoma in situ"). The following step is invasive carcinoma, which is thought to be associated with degradation of the intercellular matrix.
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Affiliation(s)
- Pelayo Correa
- Division of Gastroenterology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-0252, USA.
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21
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Dinis-Ribeiro M, Areia M, de Vries AC, Marcos-Pinto R, Monteiro-Soares M, O’Connor A, Pereira C, Pimentel-Nunes P, Correia R, Ensari A, Dumonceau JM, Machado JC, Macedo G, Malfertheiner P, Matysiak-Budnik T, Megraud F, Miki K, O’Morain C, Peek RM, Ponchon T, Ristimaki A, Rembacken B, Carneiro F, Kuipers EJ. Management of precancerous conditions and lesions in the stomach (MAPS): guideline from the European Society of Gastrointestinal Endoscopy (ESGE), European Helicobacter Study Group (EHSG), European Society of Pathology (ESP), and the Sociedade Portuguesa de Endoscopia Digestiva (SPED). Virchows Arch 2011; 460:19-46. [PMID: 22190006 DOI: 10.1007/s00428-011-1177-8] [Citation(s) in RCA: 91] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2011] [Revised: 10/13/2011] [Accepted: 10/19/2011] [Indexed: 12/16/2022]
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22
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Cell lineage dynamics in the process leading to intestinal metaplasia. J Gastroenterol 2011; 46:620-8. [PMID: 21384254 DOI: 10.1007/s00535-011-0391-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Accepted: 01/30/2011] [Indexed: 02/04/2023]
Abstract
BACKGROUND Gene expression in the early stage of the transition to intestinal metaplasia in human gastric mucosa has not been determined. In this study, we investigated the temporal relationship between cell lineage changes and intestine-specific gene expression in the process leading to intestinal metaplasia, using Cdx2-transgenic mice. METHODS Cellular phenotypes were analyzed by immunohistochemistry and were compared with the gene expression profiles of cell lineage markers by real-time polymerase chain reaction. RESULTS Up to postnatal day (PD) 20, the gastric mucosae of Cdx2-transgenic mice were histologically similar to those of their normal littermates. However, at approximately PD 20, we observed the sporadic appearance of glands in which all the epithelial cells expressed Cdx2 (Cdx2-diffuse positive glands). In the Cdx2-diffuse positive glands, parietal cells had disappeared, the proliferating zone had moved from the isthmus to the base, and absorptive cells and goblet cells were recognized. In contrast, the surrounding mucosa retained the phenotype of the gastric gland in which only some of the epithelial cells expressed Cdx2. During PDs 30 and 40, the entire fundic mucosa changed to transdifferentiated mucosa that was a composite of intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia. An increase in the expression of intestine-specific genes, with a reciprocal decrease in gastric-specific gene expression, began much earlier than the emergence of Cdx2-diffuse positive glands. CONCLUSIONS A dramatic increase in intestine-specific gene expression precedes the morphological appearance of intestinal metaplasia and spasmolytic polypeptide-expressing metaplasia.
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23
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Lennerz JKM, Kim SH, Oates EL, Huh WJ, Doherty JM, Tian X, Bredemeyer AJ, Goldenring JR, Lauwers GY, Shin YK, Mills JC. The transcription factor MIST1 is a novel human gastric chief cell marker whose expression is lost in metaplasia, dysplasia, and carcinoma. THE AMERICAN JOURNAL OF PATHOLOGY 2010; 177:1514-33. [PMID: 20709804 PMCID: PMC2928982 DOI: 10.2353/ajpath.2010.100328] [Citation(s) in RCA: 99] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 05/25/2010] [Indexed: 01/10/2023]
Abstract
The lack of reliable molecular markers for normal differentiated epithelial cells limits understanding of human gastric carcinogenesis. Recognized precursor lesions for gastric adenocarcinoma are intestinal metaplasia and spasmolytic polypeptide expressing metaplasia (SPEM), defined here by ectopic CDX2 and TFF2 expression, respectively. In mice, expression of the bHLH transcription factor MIST1, normally restricted to mature chief cells, is down-regulated as chief cells undergo experimentally induced metaplasia. Here, we show MIST1 expression is also a specific marker of human chief cells. SPEM, with and without MIST1, is present in human lesions and, akin to murine data, likely represents transitional (TFF2(+)/MIST1(+) = "hybrid"-SPEM) and established (TFF2(+)/MIST1(-) = SPEM) stages. Co-visualization of MIST1 and CDX2 shows similar progressive loss of MIST1 with a transitional, CDX2(+)/MIST1(-) hybrid-intestinal metaplasia stage. Interinstitutional analysis and comparison of findings in tissue microarrays, resection specimens, and biopsies (n > 400 samples), comprising the entire spectrum of recognized stages of gastric carcinogenesis, confirm MIST1 expression is restricted to the chief cell compartment in normal oxyntic mucosa, rare in established metaplastic lesions, and lost in intraepithelial neoplasia/dysplasia and carcinoma of various types with the exception of rare chief cell carcinoma ( approximately 1%). Our findings implicate MIST1 as a reliable marker of mature, healthy chief cells, and we provide the first evidence that metaplasia in humans arises at least in part from the chief cell lineage.
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Affiliation(s)
- Jochen K M Lennerz
- Department of Pathology and Immunology, Washington University School of Medicine, Louis, MO 63110, USA
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24
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Jung SH, Chung WC, Lee KM, Paik CN, Jung JH, Lee MK, Lee YK, Chung IS. Risk factors in malignant transformation of gastric epithelial neoplasia categorized by the revised Vienna classification: endoscopic, pathological, and immunophenotypic features. Gastric Cancer 2010; 13:123-30. [PMID: 20602200 DOI: 10.1007/s10120-010-0550-7] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2009] [Accepted: 03/10/2010] [Indexed: 02/07/2023]
Abstract
BACKGROUND According to the revised Vienna classification, the surgical removal of gastric epithelial neoplasia category 3 (low-grade dysplasia) lesions is not necessary, whereas the removal of category 4 lesions (high-grade dysplasia and intramucosal cancer) is obligatory. However, approximately 15%-30% of low-grade adenomas/dysplasia progress to high-grade lesions or adenocarcinoma, and it is difficult to determine which lesions will advance to true malignancy. The aim of this study was to evaluate the endoscopic, pathological, and immunophenotypic differences between category 3 and 4 lesions according to the revised Vienna classification. METHODS All tissue samples were excised by endoscopic mucosal resection. Fifty-two category 3 tissue samples and 54 category 4 samples were evaluated by endoscopic findings; by pathology examination of the surrounding mucosa; and by CD10, MUC2, MUC5AC, MUC6, and RUNX3 immunohistochemical staining. RESULTS Univariate analysis showed that the size of the lesion, color change, ulceration, gastritis score of the surrounding mucosa, and positive expression of MUC6 were associated with category 4 lesions. Multivariate analysis showed that the size of the lesion, ulceration, and positive expression of MUC6 were strongly associated with category 4 lesions. CONCLUSION Lesions more than 17 mm in diameter or lesions that are associated with ulceration have the potential for malignant transformation. Positive immunoreactivity for MUC6 appears to be a complementary marker for malignant transformation of gastric epithelial neoplasia.
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Affiliation(s)
- Sung Hoon Jung
- Department of Internal Medicine and Pathology, College of Medicine, the Catholic University of Korea, Seoul, Korea
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25
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Direct repression of Sonic Hedgehog expression in the stomach by Cdx2 leads to intestinal transformation. Biochem J 2010; 427:423-34. [PMID: 20199401 DOI: 10.1042/bj20091177] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Shh (Sonic Hedgehog) is a morphogen involved in gastric fundic gland differentiation in the adult. Shh expression is reduced in Helicobacter pylori-associated intestinal metaplastic change of the gastric epithelium and mice that lack Shh show intestinal transformation of the gastric mucosa. Similarly, in the stomach of Cdx2 (caudal-type homeobox 2)-transgenic mice, the gastric mucosa is replaced by intestinal metaplastic mucosa. The aim of the present study was to use Cdx2-transgenic mice to investigate: (i) Shh expression in the intestinal metaplastic mucosa of the Cdx2-transgenic mouse stomach; and (ii) the relationship between Shh and Cdx2. We determined that Shh mRNA levels were dramatically reduced in the intestinal metaplastic mucosa of the Cdx2-transgenic mouse stomach compared with the normal (wild-type) mouse stomach. This was not due to hypermethylation of the Shh promoter, but instead we showed that Cdx2 directly bound to the TATA box region of the Shh promoter. Cdx2 also down-regulated transcription of the Shh gene in the human gastric carcinoma cell lines AGS, MKN45 and MKN74. In conclusion, Cdx2 reduced Shh expression by binding to the unmethylated Shh promoter in the intestinal metaplastic mucosa of Cdx2-transgenic mouse stomach.
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26
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Zheng Y, Wang L, Zhang JP, Yang JY, Zhao ZM, Zhang XY. Expression of p53, c-erbB-2 and Ki67 in intestinal metaplasia and gastric carcinoma. World J Gastroenterol 2010; 16:339-44. [PMID: 20082479 PMCID: PMC2807954 DOI: 10.3748/wjg.v16.i3.339] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To compare two types of classification of intestinal metaplasia (IM) of the stomach and to explore their relationship to gastric carcinoma.
METHODS: Forty-seven cases of gastric IM were classified into type I, type II or type III according to mucin histochemical staining and compared with a novel classification in which the specimens were classified into simple IM (SIM) or atypical IM according to polymorphism in terms of atypical changes of the metaplastic epithelium. Forty-seven IM and thirty-seven gastric carcinoma samples were stained for p53, c-erbB-2 and Ki67 proteins by Envision immunohistochemical technique.
RESULTS: There were no significant differences in the expression of p53 and c-erbB-2 among type I, type II, type III IM and gastric carcinomas. The positive expression rate of Ki67 was significantly higher in gastric carcinomas than in type I IM while no significant Ki67 expression differences were observed among type II, type III IM and gastric carcinomas. The expression of p53, c-erbB-2 and Ki67 proteins in 20 SIM, 27 Atypical IM and 37 gastric carcinomas showed significant differences between SIM and gastric carcinomas while no significant differences were observed between Atypical IM and gastric carcinomas.
CONCLUSION: Atypical IM may better reveal the precancerous nature of IM and could be a helpful indicator in the clinical follow up of patients.
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27
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Sakamoto H, Mutoh H, Ido K, Satoh S, Kumagai M, Hayakawa H, Tamada K, Sugano K. Intestinal metaplasia in gallbladder correlates with high amylase levels in bile in patients with a morphologically normal pancreaticobiliary duct. Hum Pathol 2009; 40:1762-7. [PMID: 19716161 DOI: 10.1016/j.humpath.2009.06.008] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2009] [Revised: 06/04/2009] [Accepted: 06/11/2009] [Indexed: 12/31/2022]
Abstract
We reported previously that intestinal metaplasia in the gallbladder is strongly associated with expression of caudal-related homeobox transcription factor Cdx2. It has been documented that occult pancreatobiliary reflux, even in the absence of pancreaticobiliary maljunction, is associated with elevated risk of biliary malignancy. We ascertained the correlation between intestinal metaplasia in the gallbladder and occult pancreatobiliary reflux. In 196 patients with a normal pancreaticobiliary ductal arrangement who had undergone laparoscopic cholecystectomy, we performed intraoperative cholangiography and measured amylase levels in bile sampled from the gallbladder. The cutoff value for high cystic amylase was defined as a biliary amylase level higher than the normal upper limit of serum amylase (215 IU/L). We also retrospectively reviewed the cholecystectomized tissue specimens to investigate the presence of intestinal metaplasia and expression of Cdx2. Then, we explored the relationship between intestinal metaplasia in the gallbladder and occult choledocho-pancreatic reflux. Intestinal metaplasia was found in 16.8% (33/196) of the gallbladders. The prevalence of choledocho-pancreatic reflux revealed by intraoperative cholangiography was not significantly different between cases with intestinal metaplasia (5/33, 15.2%) and those without (25/163, 15.3%; P = .81). However, in cases with intestinal metaplasia, the rate of high cystic amylase (13/33, 39.4%) was significantly higher compared with cases without intestinal metaplasia (26/163, 16.0%, P = .005). In conclusion, intestinal metaplasia in the gallbladder is significantly correlated with high amylase levels in bile in patients with a morphologically normal pancreaticobiliary ductal arrangement.
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Affiliation(s)
- Hirotsugu Sakamoto
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Tochigi, Japan
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28
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29
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Larsen E, Johansen A. Primary superficial carcinomas of the duodenum. ACTA PATHOLOGICA ET MICROBIOLOGICA SCANDINAVICA 2009; 74:487-94. [PMID: 4313505 DOI: 10.1111/j.1699-0463.1968.tb03503.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Watanabe H, Fujii I, Terada Y. Induction of intestinal metaplasia in the rat gastric mucosa by local X-irradiation. Pathol Res Pract 2008; 170:104-14. [PMID: 18788156 DOI: 10.1016/s0344-0338(80)80159-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
Abstract
Attempts were made to learn about an optimal condition for the induction of intestinal metaplasia in the gastric mucosa. The gastric region of 5-week-old female Wistar rats was irradiated with 500 rad of X-ray daily for 6 times (Group I) or with 1,000 rad of X-ray every two days for 3 times (Group III). In addition, the effect of immunization by allogeneic stomach antigen on the intestinalization was studied in rats irradiated with 500 rad of X-ray daily for 6 times (Group II). In a group of rats (Group II) injected with allogeneic stomach antigen and X-irradiated the process of intestinalization was more accelerated as compared to that in rats treated with X-ray (Group I). The similar results were obtained in rats irradiated with 1,000 rad of X-ray 3 times (Group II). Intestinal metaplasia developed more later in the fundic gland mucosa which became usually atrophic due to the loss of parietal cell mass. There was an intimate association among the parietal cell loss in the fundic gland, a rise in pH value and the development of intestinal metaplasia. In all groups, no case of gastric adenocarcinoma was detected during observation period up to 52nd week.
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Affiliation(s)
- H Watanabe
- Department of Cancer Research, Research Institute for Nuclear Medicine and Biology, Hiroshima University, Hiroshima, 734 Japan
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31
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Abstract
Although incidences of stomach cancer have decreased over the past several decades, the disease remains an important public health problem. To identify pathological and molecular biochemical mechanisms, various experimental animal models have been established in rats and mice with chemical carcinogens including N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) and N-methyl-N-nitrosourea (MNU). Helicobacter pylori(H. pylori) is one of the most important factors for human stomach disorders, including neoplasia, and the H. pylori-infected and carcinogen-treated Mongolian gerbil (MG) has proven very useful for analyses of underlying processes. The findings with this model support the hypothesis that intestinal metaplasia is important not as a precancerous lesion but rather as a paracancerous condition and that intestinalization of stomach cancer progresses with chronic inflammation. Furthermore, dose-dependent enhancing effects of salt on stomach carcinogenesis could be demonstrated in MGs treated with MNU and H. pylori modifying surface mucous gel layer. H. pylori itself only causes chronic inflammation and acts as a promoter of stomach carcinogenesis in experimental models. Based on the precise pathological diagnosis of stomach lesions such as noncancerous heterotopic proliferative glands (HPG) and adenocarcinomas, a basis for understanding mechanisms of carcinogenesis has been established on which chemoprevention can be modeled.
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Affiliation(s)
- Tetsuya Tsukamoto
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, Nagoya, Japan.
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Holmes K, Egan B, Swan N, O’Morain C. Genetic Mechanisms and Aberrant Gene Expression during the Development of Gastric Intestinal Metaplasia and Adenocarcinoma. Curr Genomics 2007; 8:379-397. [PMID: 19412438 PMCID: PMC2671722 DOI: 10.2174/138920207783406460] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2007] [Revised: 09/21/2007] [Accepted: 09/28/2007] [Indexed: 02/07/2023] Open
Abstract
Gastric adenocarcinoma occurs via a sequence of molecular events known as the Correa's Cascade which often progresses over many years. Gastritis, typically caused by infection with the bacterium H. pylori, is the first step of the cascade that results in gastric cancer; however, not all cases of gastritis progress along this carcinogenic route. Despite recent antibiotic intervention of H. pylori infections, gastric adenocarcinoma remains the second most common cause of cancer deaths worldwide. Intestinal metaplasia is the next step along the carcinogenic sequence after gastritis and is considered to be a precursor lesion for gastric cancer; however, not all patients with intestinal metaplasia develop adenocarcinoma and little is known about the molecular and genetic events that trigger the progression of intestinal metaplasia into adenocarcinoma. This review aims to highlight the progress to date in the genetic events involved in intestinal-type gastric adenocarcinoma and its precursor lesion, intestinal metaplasia. The use of technologies such as whole genome microarray analysis, immunohistochemical analysis and DNA methylation analysis has allowed an insight into some of the events which occur in intestinal metaplasia and may be involved in carcinogenesis. There is still much that is yet to be discovered surrounding the development of this lesion and how, in many cases, it develops into a state of malignancy.
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Affiliation(s)
- K Holmes
- Department of Clinical Medicine, Trinity College Dublin, The Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland
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33
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FUJIMURA Y, MIZUNO M, TAKEDA M, SATO I, YAMAUCHI M, HOSOBE M, OHTANI K, KAMOI R, HONDA K, KOZUKA K, HOSHIKA K, UCHIDA J, KIHARA T, KIMOTO M, SANO K. A Nodule‐aggregating Lesion of the Rectum Associated with Gastric Adenoma —A Case Report—. Dig Endosc 2007. [DOI: 10.1111/j.1443-1661.1993.tb00625.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Affiliation(s)
- Yoshinori FUJIMURA
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Mitsuru MIZUNO
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Masaharu TAKEDA
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Ichiki SATO
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Mie YAMAUCHI
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Masayo HOSOBE
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Kimihiko OHTANI
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Ryuichi KAMOI
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Keisuke HONDA
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Kazushi KOZUKA
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Kazunori HOSHIKA
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Junichi UCHIDA
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | - Tsuyoshi KIHARA
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
| | | | - Kaiso SANO
- Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, Kurashiki, Japan
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34
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Abstract
Helicobacter infection is the leading cause of gastric cancer worldwide. Infection with this ubiquitous bacterium incites a chronic active immune response that persists for the life of the host, in the absence of antibiotic-induced eradication. It is the combination of bacterial factors, environmental insults, and the host immune response that drives the initiation and progression of mucosal atrophy, metaplasia, and dysplasia toward gastric cancer. Although it may seem intuitively obvious that removing the offending organism would negate the cancer risk, this approach is neither feasible (half of the world harbors this infection) nor is it straightforward. Most patients are infected in childhood, and present with various degrees of mucosal damage before any therapy. This review outlines the histologic progression of human Helicobacter infection from the early stages of inflammation through the development of metaplasia, dysplasia, and, finally, cancer. The effects of dietary and bacterial eradication therapy on disease progression and lesion reversibility are reviewed within the context of population studies and compared between study designs and populations tested. Eradication studies in the mouse model of infection prevents the formation of gastric cancer, and allows regression of established lesions, providing a useful model to study interaction between bacterium, environment, and host, without the difficulties inherent in human population studies. Recent advances in identifying the bone marrow-derived stem cell as the cell of origin of Helicobacter-induced gastric cancer in the murine model are discussed and interpreted in the context of human disease, and implications for future treatment are discussed.
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Affiliation(s)
- Pelayo Correa
- Division of Gastroenterology, Hepatology and Nutrition, Vanderbilt University Medical Center, Nashville, Tennessee, USA
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35
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Bir F, Calli-Demirkan N, Tufan AC, Akbulut M, Satiroglu-Tufan NL. Apoptotic cell death and its relationship to gastric carcinogenesis. World J Gastroenterol 2007; 13:3183-8. [PMID: 17589896 PMCID: PMC4436603 DOI: 10.3748/wjg.v13.i23.3183] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: To investigate the apoptotic process of cells within the intestinal metaplasia areas co-localizing with chronic gastritis and gastric carcinomas and to analyze the involvement of proteins regulating apoptosis in the process of intestinal metaplasia related gastric carcinogenesis.
METHODS: Forty-two gastric carcinoma and seventeen chronic gastritis cases were included in this study. All cases were examined for the existence of intestinal metaplasia. Ten cases randomly selected from each group were processed for TUNEL assay. TUNEL positive cells within the intestinal metaplasia areas, co-localizing either to gastric carcinoma or chronic gastritis, were counted and converted to apoptotic indices. In addition, p53, bcl-2 and bax expression patterns within these tissues were analyzed on the basis of immunohistochemistry.
RESULTS: Twenty-eight of the cases were intestinal and 14 of the cases were diffuse type adenocarcinomas. 64% (27/42) of the gastric carcinoma cases had intestinal metaplasia. Intestinal metaplasia co-localized more with intestinal type carcinomas compared with diffuse type carcinomas [75% (21/28) vs 42% (6/14), respectively; P≤ 0.05]. The mean apoptotic index in tumor cells was 0.70 ± 0.08. The mean apoptotic index in intestinal metaplasias co-localizing to tumors was significantly higher than that of intestinal metaplasias co-localizing to chronic gastritis (0.70 ± 0.03 vs 0.09 ± 0.01, respectively; P≤ 0.05). p53 positivity was not observed in areas of intestinal metaplasia adjacent to tumors or chronic gastritis. Intestinal metaplasia areas adjacent to tumors showed lower cytoplasmic bcl-2 positivity compared to intestinal metaplasia areas adjacent to chronic gastritis [55.5% (15/27) vs 70.5% (12/17), respectively]. On the other hand, intestinal metaplasia areas adjacent to tumors showed significantly higher cytoplasmic bax positivity compared to intestinal metaplasia areas adjacent to chronic gastritis [44.4% (12/27) vs 11.7% (2/17), respectively; P≤ 0.05].
CONCLUSION: Existence of apoptotic cells on the basis of TUNEL positivity is shown in intestinal metaplasias co-localizing to both diffuse and intestinal type gastric cancers in this study. Our results also suggested bax expression dependent induction of apoptosis especially in intestinal metaplasia areas adjacent to tumors. These findings strongly support the involvement of apoptotic mechanisms in the process of gastric carcinogenesis especially in the transition from intestinal metaplasia to gastric cancer. It may be suggested that induction of apoptosis in intestinal metaplasia areas adjacent to tumors may involve different mechanisms than induction by chronic inflammation.
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Affiliation(s)
- Ferda Bir
- Pamukkale Universitesi Tip Fakultesi, Patoloji ABD, Morfoloji, Kinikli 20070, Denizli, Turkey.
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Tsukamoto T, Mizoshita T, Tatematsu M. Gastric-and-intestinal mixed-type intestinal metaplasia: aberrant expression of transcription factors and stem cell intestinalization. Gastric Cancer 2007; 9:156-66. [PMID: 16952033 DOI: 10.1007/s10120-006-0375-6] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2006] [Accepted: 03/20/2006] [Indexed: 02/07/2023]
Abstract
Helicobacter pylori plays a causative role in the development of chronic atrophic gastritis, intestinal metaplasia (IM), and stomach cancer. Although IM has long attracted attention as a putative preneoplastic lesion for stomach cancers, its clinicopathologic significance has yet to be clarified in detail. Using gastric and intestinal epithelial cell markers, IM was here divided into two major types: a gastric-and-intestinal (GI) mixed type and a solely intestinal (I) type. In the former, gastric and intestinal phenotypic markers appeared not only at the glandular but also at the cellular level. Furthermore, neuroendocrine cells also showed intestinalization along with their exocrine counterparts. In animal models, GI-type IM was found to appear first, followed by the solely I type. Summarizing these data, it was suggested that IM might be caused by the gradual intestinalization of stem cells from the GI to the I type. The molecular mechanisms of IM include the ectopic expression of CDX1, CDX2, OCT-1, and members of the Erk pathway. Suppression of the expression of gastric transcription factors such as SOX2, genes that are involved in the Sonic hedgehog pathway, and RUNX3, a tumor suppressor gene, could be additional relevant alterations. The expression of PDX1 may also be associated with pseudopyloric gland metaplasia and IM. Detailed analysis of gene regulation may shed light on the molecular bases of gastric lesions, leading to strategies for chemoprevention.
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Affiliation(s)
- Tetsuya Tsukamoto
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, 464-8681, Japan
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Sakamoto H, Mutoh H, Ido K, Satoh K, Hayakawa H, Sugano K. A close relationship between intestinal metaplasia and Cdx2 expression in human gallbladders with cholelithiasis. Hum Pathol 2007; 38:66-71. [PMID: 16996572 DOI: 10.1016/j.humpath.2006.06.010] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2006] [Revised: 06/04/2006] [Accepted: 06/08/2006] [Indexed: 12/14/2022]
Abstract
We previously reported a case of a human gallbladder with cholelithiasis consisting of intestinal metaplasia with the expression of caudal-related homeobox transcription factor (Cdx2). However, it is unclear how often intestinal metaplasia and Cdx2 expression occur in human, nontumorous gallbladders with cholelithiasis. We studied the incidence of intestinal metaplasia and Cdx2 expression in human gallbladders with cholelithiasis. Gallbladders were resected under laparoscopy from 103 patients with cholelithiasis between September 2003 and March 2005. The mean age of the patients was 59.6 +/- 15.0 years (range, 22-92 years). We retrospectively reviewed these cases to look for the presence of intestinal metaplasia and the expression of Cdx2. In addition, the characteristics of intestinal metaplasia were examined by immunostaining for Muc2, chromogranin A, and serotonin. Intestinal metaplasia was found in 11.7% (12/103) of the gallbladders with cholelithiasis. The mean ages of patients with and without intestinal metaplasia were 60.8 +/- 15.4 and 59.4 +/- 14.9 years, respectively. Cdx2, Muc2, chromogranin A, and serotonin were expressed in 91.7% (11/12), 91.7% (11/12), 83.3% (10/12), and 50.0% (6/12) in intestinal metaplastic mucosa, respectively. Only one case (1.1%) that expressed Cdx2 without intestinal metaplasia did not express Muc2, chromogranin A, and serotonin. We found that 10.7% (11/103) of nontumorous gallbladders resected because of cholelithiasis under laparoscopy revealed intestinal metaplasia with Cdx2 expression.
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Affiliation(s)
- Hirotsugu Sakamoto
- Department of Medicine, Division of Gastroenterology, Jichi Medical University, Shimotsuke, Tochigi 329-0 431, Japan
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38
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Cunningham SC, Kamangar F, Kim MP, Hammoud S, Haque R, Iacobuzio-Donahue CA, Maitra A, Ashfaq R, Hustinx S, Heitmiller RE, Choti MA, Lillemoe KD, Cameron JL, Yeo CJ, Schulick RD, Montgomery E. Claudin-4, Mitogen-Activated Protein Kinase Kinase 4, and Stratifin Are Markers of Gastric Adenocarcinoma Precursor Lesions. Cancer Epidemiol Biomarkers Prev 2006; 15:281-7. [PMID: 16492916 DOI: 10.1158/1055-9965.epi-05-0539] [Citation(s) in RCA: 57] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Approximately 23,000 new gastric cancer cases and 12,000 associated deaths occur annually in the United States. Intestinal metaplasia and gastric epithelial dysplasia are precursor lesions to gastric adenocarcinoma, but are not readily detectable clinically, radiographically, or endoscopically. A noninvasive method of precursor detection would require the ability to distinguish precursor lesions from adjacent normal mucosa. In search of such markers, tissue microarrays were prepared for 133 patients of resected gastric adenocarcinoma. Tissue microarrays contained primary cancer, normal stomach, intestinal metaplasia, and gastric epithelial dysplasia and were probed with antibodies against nine potential markers that were either identified in a database of genes overexpressed in gastric adenocarcinoma or were already of interest to our laboratory: claudin-4, mitogen-activated protein kinase kinase 4 (MKK4), 14-3-3sigma (stratifin), S100A4, mesothelin, fascin, topoisomerase IIalpha, HER-2/neu, and epithelial growth factor receptor. Three markers discriminated gastric adenocarcinoma precursor lesions from normal gastric mucosa. Claudin-4 expression was present in 36 intestinal metaplasia lesions (100%) and 14 gastric epithelial dysplasia lesions (100%), but in only 16 normal stomach samples (15%). MKK4 expression was present in 24 intestinal metaplasia lesions (89%) and 12 gastric epithelial dysplasia lesions (100%), but in only 6 normal stomach samples (8%). Stratifin expression was present in 29 intestinal metaplasia lesions (97%) and 8 gastric epithelial dysplasia lesions (100%), but in only 2 normal stomach samples (3%). Sensitivity and specificity for detection of the precursor lesion intestinal metaplasia were 100% and 85%, respectively, for claudin-4; 89% and 92%, respectively, for MKK4; and 97% and 97%, respectively, for stratifin. In primary cancers, 123 of 125 (98.4%) were positive for claudin-4, 116 of 126 (94%) for MKK4, and 111 of 120 (92%) for stratifin. In conclusion, claudin-4, MKK4, and stratifin immunolabeling detects precursor lesions of gastric adenocarcinoma that are otherwise clinically, radiographically, and endoscopically inapparent. These findings may prove useful in the diagnosis and therapeutic targeting of gastric adenocarcinoma precursor lesions.
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Affiliation(s)
- Steven C Cunningham
- Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore Maryland 21231, USA
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Tatematsu M, Tsukamoto T, Mizoshita T. Significant Factors on Gastric Carcinogenesis Revealed by Experimental Animal Models. J Toxicol Pathol 2006. [DOI: 10.1293/tox.19.75] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Affiliation(s)
- Masae Tatematsu
- Division of Oncological Pathology, Aichi Cancer Center Research Institute
| | - Tetsuya Tsukamoto
- Division of Oncological Pathology, Aichi Cancer Center Research Institute
| | - Tsutomu Mizoshita
- Division of Oncological Pathology, Aichi Cancer Center Research Institute
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40
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41
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Wada R, Yamaguchi T, Tanizaki T. Mucin phenotypic expression and p53 gene abnormality of gastric super-minute well-differentiated adenocarcinoma: re-evaluation with relationship between histogenesis of well-differentiated adenocarcinoma and intestinal metaplasia in distal stomach. J Carcinog 2005; 4:14. [PMID: 16135257 PMCID: PMC1232858 DOI: 10.1186/1477-3163-4-14] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2005] [Accepted: 09/01/2005] [Indexed: 01/31/2023] Open
Abstract
Background Although the gastric well-differentiated adenocarcinoma in the distal stomach has been thought to develop via a intestinal metaplasia-carcinoma sequence, there are some disproofs from new mucin examinations for minute-size lesions in same type carcinoma. The current study was performed and pointed out the new findings for the solution to the problem according to the point described above. Methods 12 super-minute lesions (less than 1 mm in maximum diameter) of well-differentiated adenocarcinoma in distal stomach (SMCa), which were detected from the pathological examinations of 210 surgically resected stomach specimens, and the mucosa adjacent to these carcinoma lesions, were examined by immunohistochemical mucin stainings (MUC2 and CD-10: intestinal phenotype, 45M1 and MUC6: gastric phenotype) and p53-overexpression. And the analyses of the replication error of the microsatellites in chromosome 17 related p53 gene (TP53 and D17S786) (RER-p53MS) were performed in SMCa lesions, adjacent mucosa to each lesion and other gastric mucosa with intestinal metaplasia, because all SMCa lesions showed p53-overexpression immunohistochemically, decribed below. Results 1. The carcinoma cells in all SMCa lesions were positive for 45M1 and p53. On the other hand, no positive carcinoma cells for MUC6 were seen although the pyloric glands and the remnant pyloric gland in the SMCa lesions in the same slides were positive for MUC6. Ten lesions (83%) had intestinal phenotypic mucin (10 lesions: MUC2 (+), 4 lesions: CD10 (+)). Two lesions (17%) were positive for only 45M1 (gastric phenotypic mucin). 2. All of the mucosa adjacent to SMCa showed intestinal metaplasia (complete type: 7 regions, incomplete type: 5 regions). 3. RER-p53MS was confirmed in 42% (5/12 regions) of SMCa, in 42% (5/12 regions) of the mucosa adjacent to SMCa and 14% (6/42 regions) of the other intestinal metaplasia mucosa. Conclusion Most of the super-minute well-differentiated adenocarcinoma lesions in the distal stomach, which had both gastric and intestinal phenotypic mucin, are considered to develop from the tubular proliferative zone with the incomplete type of the intestinal metaplasia and p53 gene abnormality, while a part of them, which had only gastric phenotypic mucin, may derive from the gastric native tubules (non-metaplastic epithelium) with p53 gene abnormality.
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Affiliation(s)
- Ryo Wada
- The Department of Pathology, Juntendo Shizuoka Hospital of Juntendo University School of Medicine, Shizuoka, Japan
- The Department of Pathology(I), Juntendo University School of Medicine, Tokyo, Japan
| | | | - Takayuki Tanizaki
- The Department of Pathology, Juntendo Shizuoka Hospital of Juntendo University School of Medicine, Shizuoka, Japan
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Tanaka H, Tsukamoto T, Mizoshita T, Inada KI, Ogasawara N, Cao X, Kato S, Joh T, Tatematsu M. Expression of small intestinal and colonic phenotypes in complete intestinal metaplasia of the human stomach. Virchows Arch 2005; 447:806-15. [PMID: 16088401 DOI: 10.1007/s00428-005-0040-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2005] [Accepted: 06/26/2005] [Indexed: 12/15/2022]
Abstract
The incomplete intestinal metaplasia (IM) that is reported to be a risk factor for gastric carcinogenesis in man usually features sulfomucin production and thus is considered of colonic type. To cast light on the underlying mechanisms, we here examined the proportions of colonic and small intestinal phenotypes in IM by immunohistochemistry and real-time reverse transcription-polymerase chain reaction at the single isolated gland level. Carbonic anhydrase 1 (CA1) is a specific marker of colonic epithelial cells, whereas sucrase is specific to absorptive cells of the small intestine. Totals of 139 (23.5%) and 452 (76.5%) IM glands were judged to be CA1 positive and CA1 negative, respectively, in resected pyloric mucosa from cancer patients. The average score for MUC5AC in CA1-positive IMs was significantly lower than in CA1-negative counterpart tissue (P<0.0001), whereas the opposite was the case for sucrase (P<0.0001). High iron diamine-Alcian blue staining revealed CA1 expression to coincide with type I complete IM. The expression of CA1 mRNA strongly correlated with that of sucrase-isomaltase, and inversely with that of MUC5AC in isolated IM glands. In conclusion, CA1 could be colocalized with small intestinal proteins such as sucrase, but only rarely with the gastric mucin, MUC5AC. Its expression warrants further study, with the focus on stimulation and/or suppression mechanisms by gastric and intestinal transcription factors.
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Affiliation(s)
- Harunari Tanaka
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Nagoya, 464-8681, Japan
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Tsukamoto T, Mizoshita T, Mihara M, Tanaka H, Takenaka Y, Yamamura Y, Nakamura S, Ushijima T, Tatematsu M. Sox2 expression in human stomach adenocarcinomas with gastric and gastric-and-intestinal-mixed phenotypes. Histopathology 2005; 46:649-58. [PMID: 15910596 DOI: 10.1111/j.1365-2559.2005.02170.x] [Citation(s) in RCA: 82] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
AIMS Other than ectopic expression of intestinal transcription factors, Cdx1 and Cdx2, the molecular mechanisms underlying gastric and intestinal phenotypes of human stomach adenocarcinomas have yet to be clarified in detail. We have reported that Sox2, an HMG-box gastric transcription factor, is expressed in normal gastric mucosa and down-regulated in intestinal metaplasia. METHODS AND RESULTS We analysed mRNA levels of Sox2 and other differentiation markers in 50 surgically resected stomach adenocarcinomas, immunohistochemically classified into gastric (G), gastric-and-intestinal (GI)-mixed, solely intestinal (I), and null (N) types. Sox2 was found to be transcribed in G and GI-mixed type adenocarcinomas in accordance with MUC5AC and MUC6 expression, while Cdx1 and Cdx2 were up-regulated in GI-mixed and I types along with the expression of MUC2 and villin. In the N type, both gastric and intestinal transcription factors were suppressed. Immunohistochemistry confirmed expression of Sox2 in MUC5AC+ lesions and Cdx2 localization together with MUC2. A stomach adenocarcinoma cell line, KATOIII, demonstrated both MUC5AC and Sox2, although MUC5AC mRNA was not detected in the Sox2+ AGS cell line. CONCLUSIONS Sox2 may play an important role in maintaining a gastric phenotype in stomach cancers as well as in normal tissue, in cooperation with other cofactor(s).
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Affiliation(s)
- T Tsukamoto
- Division of Oncological Pathology, Aichi Cancer Centre Research Institute, Nagoya, Japan.
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Yao JC, Tseng JF, Worah S, Hess KR, Mansfield PF, Crane CH, Schnirer II, Reddy S, Chiang SS, Najam A, Yu C, Giacco GG, Xie K, Wu TT, Feig BW, Pisters PWT, Ajani JA. Clinicopathologic Behavior of Gastric Adenocarcinoma in Hispanic Patients: Analysis of a Single Institution's Experience Over 15 Years. J Clin Oncol 2005; 23:3094-103. [PMID: 15860869 DOI: 10.1200/jco.2005.08.987] [Citation(s) in RCA: 56] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Purpose To determine the clinicopathologic behavior of gastric adenocarcinoma in Hispanics by comparing Hispanic and non-Hispanic patients treated at a single cancer center. Patients and Methods Medical records of patients with invasive gastric cancer treated from 1985 to 1999 were reviewed. Diagnoses were pathologically confirmed. Differences in categorical variables were assessed using the χ2 test. Logistic regression was used for multivariate analyses. Median survival was estimated using the Kaplan-Meier method. Cox proportional hazards modeling was used to assess the impact of covariates. Results Of 1,897 patients, 301 (15.9%) were Hispanic. Hispanics were significantly younger at diagnosis than non-Hispanic whites (53.1 ± 14.4 years v 59.4 ± 12.7 years, respectively; P < .005) or African Americans (57.6 ± 15.3 years, P < .005). Hispanics were less likely to have proximal gastric cancers compared with whites (38.9% v 59.5%, respectively; P < .005). Hispanics were more likely to have mucinous/signet-ring type histology (42.5%) than whites (27.4%) and African Americans (32.5%; P < .005). Hispanics were more likely to require total gastrectomy (51%) compared with whites (38%), African Americans (38%), and Asians (36%; P = .039). Among patients with metastases at diagnosis, Hispanics were less likely to have liver metastasis than whites (30% v 44%, respectively; P = .009) but more likely to have peritoneal metastasis than whites and African Americans (54% v 41% and 47%, respectively; P = .002). In Cox analyses, Asian race, earlier stage, papillary/tubular histology, distal location, and younger age were favorable predictors of survival. Conclusion Hispanic ethnicity does not impact survival in gastric adenocarcinoma. However, histology, metastasis pattern, tumor localization, and other clinical parameters differ sufficiently to warrant further investigation into the epidemiology, pathogenesis, and molecular biology of gastric cancer in this population.
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Affiliation(s)
- James C Yao
- Department of Gastrointestinal Medical Oncology, Unit 426, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
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Tatematsu M, Tsukamoto T, Mizoshita T. Role of Helicobacter pylori in gastric carcinogenesis: the origin of gastric cancers and heterotopic proliferative glands in Mongolian gerbils. Helicobacter 2005; 10:97-106. [PMID: 15810939 DOI: 10.1111/j.1523-5378.2005.00305.x] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Helicobacter pylori infection is well accepted to be a very important factor for the development of gastric carcinogenesis in the human stomach. In Mongolian gerbils treated with chemical carcinogens, H. pylori infection enhances glandular stomach carcinogenesis, and eradication of infection and results in curtailment of enhancing effects, particularly at early stages of associated inflammation. A high-salt diet exacerbates the effects of H. pylori infection on gastric carcinogenesis, and these two factors act synergistically to promote the development of gastric cancers in this animal model. However, the bacterium exerts the greater effects. Early acquisition significantly increases gastric chemical carcinogenesis in Mongolian gerbils, as compared to later infection. While heterotopic proliferative glands, hyperplastic and dilated glands localized beneath the muscularis mucosae, frequently develop with H. pylori infection alone in this animal model, they obviously regress on eradication, suggesting a relation to severe gastritis, rather than a malignant character. Furthermore, endocrine cells, positive for chromogranin A, are observed in the heterotopic proliferative glands, in contrast to cancerous lesions which lack endocrine elements. In conclusion, H. pylori is not an initiator, but rather a strong promoter of gastric carcinogenesis, whose eradication, together with reduction in salt intake, might effectively prevent gastric cancer development.
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Affiliation(s)
- Masae Tatematsu
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan.
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Niwa T, Ikehara Y, Nakanishi H, Tanaka H, Inada KI, Tsukamoto T, Ichinose M, Tatematsu M. Mixed gastric- and intestinal-type metaplasia is formed by cells with dual intestinal and gastric differentiation. J Histochem Cytochem 2005; 53:75-85. [PMID: 15637340 DOI: 10.1177/002215540505300109] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
We have proposed to divide intestinal metaplasia (IM) into two categories, i.e., a mixed gastric and intestinal (GI) type, and a solely intestinal (I) type, based on the residual gastric phenotype cells. The GI-mixed-type IM can be identified by the presence of both cells with either gastric or intestinal phenotypes in a single gland. This study is conducted to elucidate whether cells in the GI-mixed-type IM glands can simultaneously present both gastric and intestinal phenotypes. MUC5AC, MUC2, CD10 and villin expressions were investigated in 20 samples from five gastric cancer cases, directly using either AlexaFluor 488- or 568-labeled specific monoclonal antibodies and observed by fluorescent microscopy and confocal laser-scanning microscopy. GI-mixed IM glands comprise a population expressing MUC5AC and MUC2, MUC5AC and villin, and MUC5AC and CD10. MUC2 and villin expressions were reciprocally increased with decreasing MUC5AC expression, while CD10 expression was limited to cells with only a residual MUC5AC expression or no expression. These results suggest that a heterogeneous cell population with both gastric and intestinal phenotypes would develop into a single intestinal phenotype, as reflected in the progression of intestinal metaplasia from GI-mixed-type- to I-type IM-type glands.
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Affiliation(s)
- Toru Niwa
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan
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Hirano A, Yanai H, Shimizu N, Okamoto T, Matsubara Y, Yamamoto K, Okita K. Evaluation of epstein-barr virus DNA load in gastric mucosa with chronic atrophic gastritis using a real-time quantitative PCR assay. ACTA ACUST UNITED AC 2005; 34:87-94. [PMID: 15361640 DOI: 10.1385/ijgc:34:2-3:087] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
PURPOSE It is hypothesized that Epstein-Barr virus (EBV) has already infected the noncarcinomatous gastric mucosa before carcinogenesis of EBV-associated gastric carcinoma. However, the frequency and distribution of EBV infection in the gastric mucosa of chronic atrophic gastritis (CAG) are still unclear. To clarify these points, we evaluated the EBV DNA load in gastric mucosa with CAG. METHODS We tested samples from 35 CAG cases. Paired biopsy specimens from five sites of the stomach were obtained according to the Updated Sydney System. One of each pair of specimens was subjected to areal-time quantitative polymerase chain reaction (Q-PCR) assay to detect EBV. Q-PCR was performed using the LightCycler System (Roche, Mannheim, Germany). The other was subjected to hematoxylin and eosin (H&E) and Giemsa staining. The histological degree of CAG was graded according to the Updated Sydney System. To evaluate the surface distribution of gastric mucosal atrophic changes of CAG, we modified the endoscopic classification of Kimura and Takemoto. RESULT EBV DNA was detected in 65.7% (23 of 35 cases) of the gastric biopsy specimens of the cases examined. EBV DNA was detected most frequently (92.3%; 12 of 13 cases) in the cases with endoscopically moderate CAG (p < 0.01). There was a significant association between EBV detection and the presence of inflammatory cell infiltration and atrophy in the stomach with endoscopically moderate CAG. CONCLUSION EBV mainly infects the gastric mucosa of patients with moderate CAG.
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Affiliation(s)
- Atsuyoshi Hirano
- Department of Gastroenterology and Hepatology, Yamaguchi University School of Medicine, Yamaguchi 755-8505, Japan
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Wada R, Yamaguchi T, Tanizaki T. PATHOLOGICAL AND MOLECULAR-BIOLOGICAL STUDIES ON SEQUENCE FROM REFLUX ESOPHAGITIS TO DEVELOPMENT OF BARRETT's ADENOCARCINOMA. Dig Endosc 2005. [DOI: 10.1111/j.1443-1661.2005.00461.x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
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Fukamachi H, Ito K, Ito Y. Runx3-/- gastric epithelial cells differentiate into intestinal type cells. Biochem Biophys Res Commun 2004; 321:58-64. [PMID: 15358215 DOI: 10.1016/j.bbrc.2004.06.099] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2004] [Indexed: 12/19/2022]
Abstract
We have previously reported that Runx3, a runt domain transcription factor, is a major growth regulator of gastric epithelial cells, that a lack of RUNX3 function is causally related to the genesis and progression of human gastric cancer, and that expression of RUNX3 is greatly reduced in intestinal metaplasias in human stomachs. Here we examined the differentiation of Runx3-/- mouse gastric epithelial cells and found that some cells differentiated into intestinal type cells, which expressed Cdx2, a transcription factor that has been shown to induce intestinal metaplasia in transgenic mice. Differentiation of intestinal type cells was not found in culture of Runx3+/+ gastric epithelial cells. These results suggest that gastric epithelial cells can differentiate into intestinal type cells, probably due to expression of Cdx2 in them when the function of Runx3 is impaired. The relationship between loss of function of Runx3, formation of intestinal metaplasia, and gastric cancer was discussed.
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Affiliation(s)
- Hiroshi Fukamachi
- Department of Biological Sciences, Graduate School of Science, University of Tokyo, Tokyo 113-0033, Japan.
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Tsukamoto T, Inada K, Tanaka H, Mizoshita T, Mihara M, Ushijima T, Yamamura Y, Nakamura S, Tatematsu M. Down-regulation of a gastric transcription factor, Sox2, and ectopic expression of intestinal homeobox genes, Cdx1 and Cdx2: inverse correlation during progression from gastric/intestinal-mixed to complete intestinal metaplasia. J Cancer Res Clin Oncol 2003; 130:135-45. [PMID: 14655050 DOI: 10.1007/s00432-003-0519-6] [Citation(s) in RCA: 104] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2003] [Accepted: 10/09/2003] [Indexed: 12/17/2022]
Abstract
PURPOSE The molecular mechanisms underlying the development of intestinal metaplasia (IM) of the human stomach have yet to be clarified in detail. Besides ectopic expression of intestinal transcription factors, Cdx1 and Cdx2, little information is available regarding other regulatory factors. Hence, we here analyzed Sox2, a human homolog of a chicken gastric transcription factor, with reference to our new classification for gastric/intestinal (GI)-mixed type IM. METHODS Twenty specimens of surgically resected antral mucosa were subjected to a gland isolation technique. Isolated glands were classified into gastric (G), GI-mixed, and solely intestinal (I) types according to Alcian blue and paradoxical concanavalin A staining and were quantified for mRNA levels of gastrointestinal markers. RESULTS MUC5AC and MUC6 transcripts decreased with the progression of IM, while MUC2 and villin-1 were inversely correlated. Sox2 showed a gradual decrease from G, through GI, to the I type (G vs GI and GI vs I, P<0.01 and P<0.005, respectively). On the other hand, Cdx1 (G vs GI and GI vs I, P<0.0001 and P=0.337, respectively) and Cdx2 (G vs GI and GI vs I, P<0.0001 and P<0.05, respectively) appeared in IM. Immunohistochemical study confirmed decreased expression of Sox2 and ectopic emergence of Cdx2 protein in IM glands. CONCLUSION Down-regulation of Sox2, besides ectopic expression of Cdx genes, may be important factors for the development of IM.
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Affiliation(s)
- Tetsuya Tsukamoto
- Division of Oncological Pathology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Nagoya, Chikusa-ku, Japan.
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