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Flídrová M, Hájková N, Hojný J, Dvořák J, Michálková R, Krkavcová E, Laco J, McCluggage WG, Giordano G, Silini EM, Michalová K, Bizoń M, Němejcová K, Dundr P, Kendall Bártů M. Unraveling the Molecular Landscape of Uterine Tumor Resembling Ovarian Sex Cord Tumor: Insights From A Clinicopathological, Morphologic, Immunohistochemical, and Molecular Analysis of 35 Cases. Mod Pathol 2024; 37:100611. [PMID: 39265954 DOI: 10.1016/j.modpat.2024.100611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Revised: 08/09/2024] [Accepted: 09/01/2024] [Indexed: 09/14/2024]
Abstract
Uterine tumor resembling ovarian sex cord tumor (UTROSCT) is a rare tumor of uncertain lineage and low malignant potential. Most tumors behave in a benign manner, but a subset of UTROSCT exhibit an aggressive clinical course with recurrences and metastases. The recurrent molecular alterations in UTROSCT mostly represent gene fusions involving NCOA1-3. We performed a comprehensive clinicopathological, morphologic, immunohistochemical, and molecular analysis on a cohort of 35 UTROSCT. The tumors exhibited various architectural patterns (diffuse, corded/trabecular, tubular, sertoliform, fascicular, whorled, nested, microfollicular, and pseudoglandular), often in combination. The immunohistochemical analysis confirmed the polyphenotypic immunoprofile, often with coexpression of sex cord-stromal, smooth muscle, and epithelial markers, as well as hormone receptors. Next-generation sequencing RNA analysis revealed recurrent NCOA1-3 gene fusions in 22/32 analyzed cases (69%), including ESR1::NCOA3 (11/22), GREB1::NCOA2 (7/22), ESR1::NCOA2 (3/22), and GREB1::NCOA1 (1/22). Tumor mutation burden was low in all cases. The fusion-positive cases exhibited statistically significant association with whorled architecture, conversely necrosis was associated with fusion-negative status. We did not find a significant relationship between any architectural pattern and GREB1 alterations, but the NCOA2-altered tumors were associated with pseudoglandular architecture. The GREB1-altered cases occurred in older patients and tended to be more often intramural masses compared with ESR1-altered cases. On the contrary, the ESR1-altered cases presented more often like submucosal or polypoid tumors. Two tumors exhibited aggressive behavior with recurrent disease. Both of these cases harbored a GREB1::NCOA2 fusion. Unsupervised hierarchical cluster analysis of our cohort revealed 2 main clusters. The tumors with GREB1 or NCOA2 fusion cluster together, suggesting that there are underlying molecular differences between these cases and cases with ESR1::NCOA3 fusion or without fusion. Our findings contribute to the growing knowledge about a rare neoplasm with currently uncertain biological behavior.
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Affiliation(s)
- Miroslava Flídrová
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.
| | - Nikola Hájková
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Jan Hojný
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Jiří Dvořák
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Romana Michálková
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Eva Krkavcová
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Jan Laco
- The Fingerland Department of Pathology, Charles University, Faculty of Medicine Hradec Králové and University Hospital Hradec Králové, Hradec Králové, Czech Republic
| | - W Glenn McCluggage
- Department of Pathology, Belfast Health and Social Care Trust, Belfast, United Kingdom
| | - Giovanna Giordano
- Department of Medicine and Surgery, Pathology Unit, University of Parma, Parma, Italy
| | - Enrico Maria Silini
- Department of Medicine and Surgery, Pathology Unit, University of Parma, Parma, Italy
| | - Květoslava Michalová
- Department of Pathology, Charles University, Faculty of Medicine in Plzeň, Bioptical Laboratory, Ltd, Plzeň, Czech Republic
| | | | - Kristýna Němejcová
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Pavel Dundr
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
| | - Michaela Kendall Bártů
- Department of Pathology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic
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Kneissl J, Hartmann A, Pfarr N, Erlmeier F, Lorber T, Keller S, Zwingenberger G, Weichert W, Luber B. Influence of the HER receptor ligand system on sensitivity to cetuximab and trastuzumab in gastric cancer cell lines. J Cancer Res Clin Oncol 2016; 143:573-600. [PMID: 27933395 PMCID: PMC5352771 DOI: 10.1007/s00432-016-2308-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Accepted: 11/17/2016] [Indexed: 12/18/2022]
Abstract
Purpose Gastric cancer remains a major health concern, and improvement of the therapeutic options is crucial. Treatment with targeted therapeutics such as the EGFR-targeting antibody cetuximab or the HER2-targeting antibody trastuzumab is either ineffective or moderately effective in this disease, respectively. In this study, we analysed the involvement of the HER receptor ligands amphiregulin (AREG), epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF) and transforming growth factor alpha (TGFα) in the responsiveness of gastric cancer cell lines to cetuximab and trastuzumab. Methods A panel of 11 gastric cancer cell lines was characterized for cetuximab and trastuzumab sensitivity, ligand secretion and expression and activation of the HER receptors using WST-1 cell proliferation assays, ELISAs and Western blot analyses. We further investigated the effects of an exogenous ligand application on the cetuximab and trastuzumab sensitivity. Results We found no correlation between TGFα secretion and the sensitivity to cetuximab or trastuzumab. For AREG, we confirmed previous results indicating that this ligand is a positive predictor of cetuximab sensitivity. Exogenous HB-EGF was effective in rescuing sensitive cell lines from inhibition of cell proliferation by both, cetuximab and trastuzumab. Conclusions Our data indicate that HB-EGF may be a useful marker for the prediction of trastuzumab sensitivity in gastric cancer. Electronic supplementary material The online version of this article (doi:10.1007/s00432-016-2308-z) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Julia Kneissl
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Anja Hartmann
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Nicole Pfarr
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Franziska Erlmeier
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Thomas Lorber
- Institute for Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland
| | - Simone Keller
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Gwen Zwingenberger
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Wilko Weichert
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany
| | - Birgit Luber
- Institut für Allgemeine Pathologie und Pathologische Anatomie, Technische Universität München, Klinikum rechts der Isar, Trogerstr. 18, 81675, Munich, Germany.
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Wu J, Tong S, Zhan Z, Zhang J, Chen C, Hu S, Wang R. TGF-α gene variations and increased susceptibility of gastric cancer in an Eastern Chinese Han population. Biomarkers 2013; 19:9-15. [PMID: 24237184 DOI: 10.3109/1354750x.2013.859736] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Transforming growth factor-alpha (TGF-α) correlates with deep invasion, advanced stage and poor prognosis in gastric cancer. Genetic variants in the 3' untranslated region (UTR) of TGF-α gene may influence the stability and post-transcriptional regulation of mRNA and contribute to gastric cancer predisposition. To test this hypothesis, we genotyped five polymorphisms in 3'UTR (rs3771527, rs503314, rs473698, rs3732253 and rs538118) and one in 3' near region (rs11466306) of the TGF-α gene by polymerase chain reaction-ligation detection reaction methods (PCR-LDR). We found that GA/AA genotype of rs11466306 in the 3' near gene could increase the risk of overall gastric cancer (adjusted OR = 1.499, 95%CI: 1.101-2.041), compared to the wild homozygous GG genotype. Meanwhile, the risk effect was more obvious in the intestinal gastric cancer and gastric noncardia cancer (adjusted OR = 1.682, 95%CI: 1.188-2.380; adjusted OR = 1.495, 95%CI: 1.072-2.086, respectively), but not for the diffuse type and gastric cardia cancer (p > 0.05). CT/TT genotype for rs3732253 in the 3' UTR was associated with increased risk of intestinal gastric cancer (adjusted OR = 1.464, 95%CI: 1.036-2.069), compared to their wild homozygous genotypes. These findings indicate that potentially functional TGF-α gene variant may contribute to the risk of intestinal gastric cancer and/or gastric noncardia cancer and could be used as molecular markers for detecting intestinal gastric cancer and/or gastric noncardia cancer in Chinese Han population.
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Affiliation(s)
- Juan Wu
- Discipline of Chinese and Western Integrative Medicine, Nanjing University of Chinese Medicine , Nanjing , China
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Lemos-González Y, Rodríguez-Berrocal FJ, Cordero OJ, Gómez C, Páez de la Cadena M. Alteration of the serum levels of the epidermal growth factor receptor and its ligands in patients with non-small cell lung cancer and head and neck carcinoma. Br J Cancer 2007; 96:1569-78. [PMID: 17453000 PMCID: PMC2359945 DOI: 10.1038/sj.bjc.6603770] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Serum levels of the soluble epidermal growth factor receptor (sEGFR) and its ligands epidermal growth factor (EGF), transforming growth factor-α (TGF-α) and amphiregulin (AR) were measured in healthy donors and patients with non-small cell lung cancer (NSCLC) and head and neck carcinoma (HNC). In NSCLC, we found sEGFR and EGF levels significantly lowered in patients with respect to healthy donors. In HNC patients, significantly diminished levels were found in the case of sEGFR, EGF and also AR. In both malignancies, no significant association was found between the serum levels of the molecules and the patients' gender, age or smoking habit. Only a significant association was found between the decrease of sEGFR and the absence of distant metastasis in NSCLC and the tumour stage in HNC. The most interesting result was that combining sEGFR and EGF, sensitivities of 88% in NSCLC and 100% in HNC were reached without losing specificity (97.8% in both cases). The use of discriminant analysis and logistic regression improved the sensitivity for NSCLC and the specificity for HNC. These data demonstrate a potentially interesting value of the serum levels of sEGFR and EGF, especially when combined, as markers for NSCLC and HNC.
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Affiliation(s)
- Y Lemos-González
- Departamento de Bioquímica, Genética e Inmunología, Universidad de Vigo, As Lagoas-Marcosende s/n, 36310, Vigo, Spain
| | - F J Rodríguez-Berrocal
- Departamento de Bioquímica, Genética e Inmunología, Universidad de Vigo, As Lagoas-Marcosende s/n, 36310, Vigo, Spain
| | - O J Cordero
- Departamento de Bioquímica y Biología Molecular, Universidad de Santiago de Compostela, San Francisco s/n, 15782, Santiago de Compostela, Spain
| | - C Gómez
- Servicio de Oncología Médica, Complejo Hospitalario Universitario de Vigo, Pizarro 22, 36204, Vigo, Spain
| | - M Páez de la Cadena
- Departamento de Bioquímica, Genética e Inmunología, Universidad de Vigo, As Lagoas-Marcosende s/n, 36310, Vigo, Spain
- E-mail:
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Zheng L, Walters EH, Wang N, Whitford H, Orsida B, Levvey B, Bailey M, Williams TJ, Snell GI. Effect of inhaled fluticasone propionate on BAL TGF-β1 and bFGF concentrations in clinically stable lung transplant recipients. J Heart Lung Transplant 2004; 23:446-55. [PMID: 15063404 DOI: 10.1016/s1053-2498(03)00199-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2002] [Revised: 04/04/2003] [Accepted: 04/17/2003] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Inhaled fluticasone propionate (FP) therapy decreases inflammation and sub-basement membrane thickness in asthmatic airways. Bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTRs) involves progressive airway fibrosis and obliteration. Therefore, augmented immunosuppression may be of some benefit in treating BOS. In this study, we examined the effect of 3 months of treatment with high-dose inhaled FP on the concentrations of 2 fibrogenic factors, transforming growth factor (TGF)-beta(1) and beta fibrogenic growth factor (bFGF) in bronchoalveolar lavage (BAL) fluid from clinically stable LTRs. METHODS We conducted a randomized, double-blind, placebo-controlled, parallel group study with inhaled FP (750 microg, twice/day for 3 months) in 28 LTRs (15 FP and 13 placebo). We recruited 23 healthy controls. We performed spirometry, bronchoscopy, and bronchoalveolar lavage procedures before treatment and after 3 months of treatment. We used commercially available enzyme-linked immunosorbent assay kits to measure BAL fluid TGF-beta(1) and bFGF concentrations. RESULTS In LTRs before treatment, BAL TGF-beta(1) concentrations (but not bFGF concentrations), total cell counts, and neutrophil percentage increased compared with controls (p < 0.05). We found no significant differences between FP and placebo groups at baseline measurements. After treatment, BAL TGF-beta(1) concentrations significantly increased in the FP group (p = 0.03), but we found no difference between FP and placebo groups; BAL bFGF concentrations increased during treatment in both groups compared with controls (p < 0.05), but not significantly within either patient group (p > 0.05). We found a reverse correlation between forced expiratory volume in 1 second (FEV(1)) and BAL TGF-beta(1) concentration in the FP group (r = -0.53, p = 0.04), and between FEV(1) and BAL TGF-beta(1) concentration in the placebo group (r = -0.74, p = 0.004). Multivariable analysis indicated no significant independent effects of inhaled FP in either BAL TGF-beta(1) or bFGF concentrations. CONCLUSIONS Bronchoalveolar fluid TGF-beta(1) concentrations increased in LTRs after transplantation and may correlate with the decrease in lung function. Inhaled FP added to conventional immunosuppression had no effect on TGF-beta(1) or bFGF production in BAL fluid.
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Affiliation(s)
- L Zheng
- Department of Respiratory Medicine, Alfred Hospital and Monash University Medical School, Melbourne, Australia
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Zhang XM, Wang XY, Sheng SR, Wang JR, Li J. Expression of tumor related genes NGX6, NAG-7, BRD7 in gastric and colorectal cancer. World J Gastroenterol 2003; 9:1729-33. [PMID: 12918109 PMCID: PMC4611532 DOI: 10.3748/wjg.v9.i8.1729] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
AIM: NGX6, NAG-7 and BRD7 genes are tumor related genes, which have been newly cloned by positional candidate cloning strategy. This study was designed to investigate the expression levels of NGX6, NAG-7 and BRD7 genes in human gastric and colorectal cancer tissues, and their corresponding normal tissues, and to investigate whether these genes play a role in the pathogenesis of gastric and colorectal cancers.
METHODS: Reverse transcription-polymerase chain reaction (RT-PCR), dot hybridization and Northern blot analysis were used to compare the expression levels of NGX6, NAG-7 and BRD7 genes in 34 gastric cancer tissues and 34 colorectal cancer tissues with their corresponding normal tissues of the same patients, respectively.
RESULTS: Among the 34 colorectal cancer specimens and the 34 gastric cancer specimens, the expression of NGX6 in 25 colorectal cancer tissues was absent or very weak (73.5%) by RT-PCR analysis. The down-regulation rate of NGX6 in colorectal cancer tissues was significantly higher than that in corresponding normal tissues (26.5%,9/34) (P < 0.005). Moreover, the down-regulation of NGX6 was significantly correlated with lymph node and/or distance metastases. Patients with lymph node and/or distance metastasis had much higher down-regulation rate of NGX6 than patients without metastases (93.8% vs 55.6%, P < 0.05). However no correlation was found between the expression of NGX6 and pathologic type of colorectal cancer in this study, and also the expression of NGX6 did not display any difference between gastric cancer and corresponding normal tissues (58.8% vs 70.6%, P > 0.25). Dot hybridization and Northern blot analysis confirmed the results of RT-PCR. Furthermore, NAG-7 and BRD7 mRNA was not up- or down-regulated in gastric and colorectal cancers compared with their corresponding normal tissues in our study.
CONCLUSION: The down-regulation of NGX6 may be closely associated with tumorigenesis and metastasis of colorectal carcinoma. However, it may not contribute to the development and progression of gastric carcinoma. In addition, the expression levels of NAG-7, and BRD7 did not alter in gastric and colorectal cancers. This seems to suggest that NAG-7 and BRD7 genes may not play a role in gastric and colorectal carcinogenesis.
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Affiliation(s)
- Xiao-Mei Zhang
- Department of Digestion Medicine, The Third Xiangya Hospital, Central South University, Changsha 410013, Hunan Province, China
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Barbieri C, Fujisawa MM, Yasuda CL, Metze IL, Oliveira EC, Santos LMB, Lopes LR, Andreollo NA. Effect of surgical treatment on the cellular immune response of gastric cancer patients. Braz J Med Biol Res 2003; 36:339-45. [PMID: 12640498 DOI: 10.1590/s0100-879x2003000300008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
Patients with gastric cancer have a variety of immunological abnormalities. In the present study the lymphocytes and their subsets were determined in the peripheral blood of patients with gastric cancer (N = 41) both before and after surgical treatment. The percent of helper/inducer CD4 T cells (43.6 +/- 8.9) was not different after tumor resection (43.6 +/- 8.2). The percent of the cytotoxic CD8+ T cell population decreased significantly, whether patients were treated surgically (27.2 +/- 5.8%, N = 20) or not (27.3 +/- 7.3%, N = 20) compared to individuals with inflammatory disease (30.9 +/- 7.5%) or to healthy individuals (33.2 +/- 7.6%). The CD4/CD8 ratio consequently increased in the group of cancer patients. The peripheral blood lymphocytes of gastric cancer patients showed reduced responsiveness to mitogens. The defective blastogenic response of the lymphocytes was not associated with the production of transforming growth factor beta (TGF- ) since the patients with cancer had reduced production of TGF- Beta1 (269 +/- 239 pg/ml, N = 20) in comparison to the normal individuals (884 +/- 175 pg/ml, N = 20). These results indicate that the immune response of gastric cancer patients was not significantly modified by surgical treatment when evaluated four weeks after surgery and that the immunosuppression observed was not due to an increase in TGF- 1 production by peripheral leukocytes.
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Affiliation(s)
- C Barbieri
- Departamento de Cirurgia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Campinas, SP, Brasil
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Xia L, Yuan YZ, Xu CD, Zhang YP, Qiao MM, Xu JX. Effects of epidermal growth factor on the growth of human gastric cancer cell and the implanted tumor of nude mice. World J Gastroenterol 2002; 8:455-8. [PMID: 12046069 PMCID: PMC4656420 DOI: 10.3748/wjg.v8.i3.455] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: Epidermal growth factor (EGF) plays an important role in the regulation of gastrointestinal tissue growth and development, and it can stimulate epithelial proliferation, cell differentiation and growth. It has been established that the EGF can promote gastric cytoprotection and ulcer healing. But the potential ability of EGF to regulate the gastric cancer growth is unknown. This study is to investigate the influence of EGF on human gastric cancer cell and the implanted tumor growth of nude mice.
METHODS: The cell growth rates of human gastric adenocarinoma cell lines MKN-28, MKN-45, SGC-7901 and normal human gastric epithelial cells 3T3 were assessed when incubated with recombinant human EGF (rhEGF, 0.05, 0.1, 0.5, 1.0, 10, 50, 100 mg·L-1) using MTT method. The cells of MKN-28, MKN-45, SGC-7901 (gastric cancer tissue 1.5 mm3) were implanted in the BALB/cA nude mice for 10 days. The EGF was given intraperitoneally (15, 30, 60 μg·kg-1) for 3 weeks. The body weights of the tumor-bearing animals and their tumor mass were measured afterwards to assess the mitogenic effect of rhEGF in the nude mice.
RESULTS: Within the concentration range of 0.05-100 mg·L-1, rhEGF could increase the cell growth of normal 3T3 cells (cell growth rate 100% vs 102.8%, P < 0.05), but partially restrain the gastric cancer cell growth. The latter effect was related to cell differentiation. In 15-60 μg/kg rhEGF groups, the mean implanted tumor mass of MKN-28 cell were 1.75 g, 1.91 g, 2.08 g/NS group 1.97 g (P > 0.05), the mean tumor mass of SGC-7901 cell were 1.53 g, 1.07 g, 1.20 g/NS group 1.07 g (P > 0.05), and for MKN-45 cell, the tumor mass were respectively 1.92 g, 1.29 g, 1.77 g/NS group 1.82 g (P > 0.05). So rhEGF had no obvious effect on implanted MKN-28, SGC-7901 and MKN-45 tumor growth.
CONCLUSION: EGF has no stimulating effect on the human gastric cancer cell growth neither in vitro nor in vivo.
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Affiliation(s)
- Lu Xia
- Department of Gastroenterology, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, China.
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Konturek PC, Konturek SJ, Sulekova Z, Meixner H, Bielanski W, Starzynska T, Karczewska E, Marlicz K, Stachura J, Hahn EG. Expression of hepatocyte growth factor, transforming growth factor alpha, apoptosis related proteins Bax and Bcl-2, and gastrin in human gastric cancer. Aliment Pharmacol Ther 2001; 15:989-99. [PMID: 11421874 DOI: 10.1046/j.1365-2036.2001.01003.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND Gastric cancer is one of the most frequent neoplasms and a leading cause of the death world-wide. In recent years, epidemiological and animal studies demonstrated a link between gastric cancer and chronic infection with H. pylori. The exact mechanism responsible for the development of gastric cancer in H. pylori-infected patients still remains unclear. There is evidence that the up-regulation of certain growth factors could play an important role in the promotion of the gastric carcinogenesis. AIMS The present study was designed to determine the gene expression of major known growth factors such as transforming growth factor alpha (TGFalpha), hepatocyte growth factor (HGF) and gastrin in the gastric cancer tissue, the surrounding mucosa and, for comparison, in the normal gastric mucosa. Furthermore, the luminal and plasma levels of gastrin in patients with gastric cancer were determined. In addition, the gene and protein expressions of apoptosis-related proteins such as Bax and Bcl-2 were investigated by reverse transcription-polymerase chain reaction and Western blot. Twenty-five gastric cancer patients and 40 age- and gender-matched control subjects hospitalized with non-ulcer dyspepsia were included into this study. RESULTS An overall H. pylori-seropositivity among gastric cancer patients was about 72% and was significantly higher than in the controls (56%). The prevalence of CagA-positive strains was also significantly higher among gastric cancer patients than in controls (56% vs. 32%). The gene expression of HGF and TGFalpha was detected more frequently in gastric cancer tissue samples than in normal gastric mucosa (52% vs. 12% for HGF and 48% vs. 24% for TGFalpha). The extent of protein expression in Western blotting analysis for HGF and TGFalpha correlated with the mRNA expression of these factors. Gene expression of gastrin was detected in the antrum of all tested patients and in the majority (84%) of gastric cancer patients. The median plasma and luminal concentrations of gastrin in gastric cancer patients were significantly higher than in controls. The gene expression of bcl-2 was detected in all (100%) and that of proapoptotic bax only in 56% of gastric cancer samples. In comparison to the surrounding non-tumorous tisssue, the gene expression of bax was significantly down-regulated and the gene expression of bcl-2 was up-regulated in gastric cancer tissue. At the protein level, Bax was not detectable and Bcl-2 was seen in 80% of gastric cancer samples. CONCLUSIONS It is concluded that the patients infected with H. pylori, especially with CagA-positive strains, are at a higher risk of developing a gastric cancer. An increased production and release of gastrin, as well as an over-expression of growth factors such as HGF and TGFalpha, might contribute to the gastric carcinogenesis. In addition, a dysregulation of the Bax/Bcl-2 system with significant up-regulation of Bcl-2 is observed in gastric cancer.
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Affiliation(s)
- P C Konturek
- First Department of Medicine, University Erlangen-Nuremberg, Germany.
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