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Ben Rejeb S, Aloui D, Ayari A, Chouchen A. Prognostic Significance of C-MYC and EGFR Overexpression in Gastrointestinal Stromal Tumors: An Immunohistochemical Study. Appl Immunohistochem Mol Morphol 2025; 33:43-48. [PMID: 39636317 DOI: 10.1097/pai.0000000000001235] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/30/2023] [Accepted: 10/14/2024] [Indexed: 12/07/2024]
Abstract
INTRODUCTION In addition to mutations in KIT and PDGFRA, many other genetic alterations have been described in gastrointestinal stromal tumors (GISTs), including amplifications of C-MYC and EGFR, which are often associated with increased protein expression. The main of this study was to investigate the prognostic significance of C-MYC and EGFR expression in GISTs using immunohistochemistry (IHC). METHODS We collected all GIST cases over a 16-year period. These cases were tested using antibodies against C-MYC (Leica, clone EP121) and EGFR (Leica, clone 113). C-MYC staining was assessed using the H-score method for nuclear, cytoplasmic, and combined staining. For EGFR staining (either cytoplasmic or nuclear), the intensity was graded as follows: 0 (no staining), 1 (weak staining), 2 (moderate staining), and 3 (strong staining). The percentage of positive cells was evaluated using a semiquantitative approach. Statistical analysis was performed using SPSS24. RESULTS A total of 37 cases were included in our study. Nuclear expression of C-MYC was observed in 43% of the cases, with a high H-score in 43%. A statistically significant association was found between a high nuclear H-score for C-MYC and mitotic rate (P=0.046), as well as a high Ki-67 proliferation rate (P=0.046). However, no statistically significant associations were identified between the nuclear H-score of C-MYC and other clinical, pathologic, or survival data. Cytoplasmic expression of C-MYC was noted in 22% of cases, but no significant correlations were found with the clinicopathological data. EGFR staining was observed in 86% of cases, with a high score of 51%. EGFR expression was significantly associated with the mitotic index (P=0.012) and Ki-67 proliferation rate (P=0.046). CONCLUSIONS Our findings suggest that both C-MYC and EGFR may be overexpressed and/or amplified in GISTs, indicating their potential prognostic role. This could also pave the way for therapeutic strategies targeting these proteins.
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Affiliation(s)
| | | | - Asma Ayari
- Department of Pathology, Rabta's Hospital, Marsa, Tunisia
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Vallilas C, Sarantis P, Kyriazoglou A, Koustas E, Theocharis S, Papavassiliou AG, Karamouzis MV. Gastrointestinal Stromal Tumors (GISTs): Novel Therapeutic Strategies with Immunotherapy and Small Molecules. Int J Mol Sci 2021; 22:493. [PMID: 33419029 PMCID: PMC7825300 DOI: 10.3390/ijms22020493] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/17/2020] [Revised: 01/03/2021] [Accepted: 01/04/2021] [Indexed: 02/08/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common types of malignant mesenchymal tumors in the gastrointestinal tract, with an estimated incidence of 1.5/100.000 per year and 1-2% of gastrointestinal neoplasms. About 75-80% of patients have mutations in the KIT gene in exons 9, 11, 13, 14, 17, and 5-10% of patients have mutations in the platelet-derived growth factor receptor a (PDGFRA) gene in exons 12, 14, 18. Moreover, 10-15% of patients have no mutations and are classified as wild type GIST. The treatment for metastatic or unresectable GISTs includes imatinib, sunitinib, and regorafenib. So far, GIST therapies have raised great expectations and offered patients a better quality of life, but increased pharmacological resistance to tyrosine kinase inhibitors is often observed. New treatment options have emerged, with ripretinib, avapritinib, and cabozantinib getting approvals for these tumors. Nowadays, immune checkpoint inhibitors form a new landscape in cancer therapeutics and have already shown remarkable responses in various tumors. Studies in melanoma, non-small-cell lung cancer, and renal cell carcinoma are very encouraging as these inhibitors have increased survival rates. The purpose of this review is to present alternative approaches for the treatment of the GIST patients, such as combinations of immunotherapy and novel inhibitors with traditional therapies (tyrosine kinase inhibitors).
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Affiliation(s)
- Christos Vallilas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.V.); (P.S.); (E.K.); (A.G.P.)
| | - Panagiotis Sarantis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.V.); (P.S.); (E.K.); (A.G.P.)
| | - Anastasios Kyriazoglou
- 2nd Propaedeutic Department of Medicine, ATTIKON University Hospital, 12462 Athens, Greece;
| | - Evangelos Koustas
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.V.); (P.S.); (E.K.); (A.G.P.)
| | - Stamatios Theocharis
- First Department of Pathology, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Athanasios G. Papavassiliou
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.V.); (P.S.); (E.K.); (A.G.P.)
| | - Michalis V. Karamouzis
- Molecular Oncology Unit, Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, 11527 Athens, Greece; (C.V.); (P.S.); (E.K.); (A.G.P.)
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Shi SS, Wang YF, Bao W, Ye SB, Wu N, Wang X, Xia QY, Li R, Shen Q, Zhou XJ. Genetic and epigenetic alterations of SDH genes in patients with sporadic succinate dehydrogenase-deficient gastrointestinal stromal tumors. Pathol Int 2019; 69:350-359. [PMID: 31273876 DOI: 10.1111/pin.12809] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/22/2018] [Accepted: 04/21/2019] [Indexed: 01/28/2023]
Abstract
This study aimed to investigate the association of SDH gene mutations and promoter methylation with succinate dehydrogenase-deficient gastrointestinal stromal tumors (SDH-deficient GISTs) and to further discuss the potential molecular mechanisms underlying SDHB expression loss in these tumors. First, a total of 26 patients with SDH-deficient GISTs were selected by identifying the loss of SDHB protein expression and wild-type for KIT and PDGFRa mutations. Then SDH gene mutations and promoter methylation were detected by DNA sequencing and methylation-specific polymerase chain reaction, respectively, and the clinical and pathological data of SDH-deficient GISTs patients were collected and analyzed accordingly. The results of genetic testing demonstrated that 38.46% (10/26) of these patients harbored mutations in SDHB, SDHC, and SDHD genes (3 cases with double mutations). Besides, aberrant promoter methylation of SDH genes was detected in 10 out of 26 cases (38.46%), including 8 cases in SDHA gene, 3 cases in SDHB gene, 1 case in both SDHA and SDHB genes. It is suggested that SDH gene mutations and promoter methylation may contribute to the loss of SDH protein expression in sporadic SDH-deficient GISTs. This study indicated that the genetic and epigenetic alterations of SDH genes may occur during tumor formation.
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Affiliation(s)
- Shan-Shan Shi
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Yan-Feng Wang
- Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, P. R. China
| | - Wei Bao
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Sheng-Bin Ye
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Nan Wu
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Xuan Wang
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Qiu-Yuan Xia
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Rui Li
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Qin Shen
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Xiao-Jun Zhou
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
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Shi SS, Wu N, He Y, Wei X, Xia QY, Wang X, Ye SB, Li R, Rao Q, Zhou XJ. EGFR
gene mutation in gastrointestinal stromal tumours. Histopathology 2017; 71:553-561. [PMID: 28485054 DOI: 10.1111/his.13251] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 02/01/2017] [Accepted: 05/04/2017] [Indexed: 12/22/2022]
Affiliation(s)
- Shan-Shan Shi
- Department of Pathology; Jinling Hospital; Clinical Medical School of Southern Medical University; Nanjing China
| | - Nan Wu
- Department of Pathology; Jinling Hospital; Clinical Medical School of Southern Medical University; Nanjing China
| | - Yan He
- Department of Pathology; Jinling Hospital; Clinical Medical School of Southern Medical University; Nanjing China
| | - Xue Wei
- Department of Pathology; Jinling Hospital; Clinical Medical School of Southern Medical University; Nanjing China
| | - Qiu-Yuan Xia
- Department of Pathology; Jinling Hospital; Clinical Medical School of Southern Medical University; Nanjing China
| | - Xuan Wang
- Department of Pathology; Jinling Hospital; Clinical Medical School of Southern Medical University; Nanjing China
| | - Sheng-Bin Ye
- Department of Pathology; Jinling Hospital; Clinical Medical School of Southern Medical University; Nanjing China
| | - Rui Li
- Department of Pathology; Jinling Hospital; Clinical Medical School of Southern Medical University; Nanjing China
| | - Qiu Rao
- Department of Pathology; Jinling Hospital; Clinical Medical School of Southern Medical University; Nanjing China
| | - Xiao-Jun Zhou
- Department of Pathology; Jinling Hospital; Clinical Medical School of Southern Medical University; Nanjing China
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Novel receptor tyrosine kinase targeted combination therapies for imatinib-resistant gastrointestinal stromal tumors (GIST). Oncotarget 2015; 6:1954-66. [PMID: 25557174 PMCID: PMC4385828 DOI: 10.18632/oncotarget.3021] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/23/2015] [Accepted: 12/09/2015] [Indexed: 12/31/2022] Open
Abstract
Background: c-Kit/α-PDGFR targeted therapies are effective for gastrointestinal stromal tumors (GIST), but, >50% develop drug resistance. Methods: RTK expression (c-Kit, c-Met, AXL, HER-1, HER-2, IGF-1R) in pre-/post-imatinib (IM) GIST patient samples (n=16) and 4 GIST cell lines were examined for RTK inhibitor activity. GIST-882 cells were cultured in IM every other day, cells collected (1 week to 6 months) and analyzed by qRT-PCR and Western blotting. Results: Immunohistochemistry pre-/post-IM demonstrated continued expression of c-Kit and HER1, while a subset expressed IGF-1R, c-Met and AXL. In GIST cells (GIST-882, GIST430/654, GIST48) c-Kit, HER1 and c-Met are co-expressed. Acute IM over-express c-Kit while chronic IM, lose c-Kit and HER-1 in GIST882 cells. GIST882 and GIST430/654 cells have an IC50 0.077 and 0.59 μM to IM respectively. GIST48 have an IC50 0.66 μM to IM, 0.91 μM to amuvatinib [AMU] and 0.67 μM to erlotinib (Erl). Synergistic combinations: GIST882, AMU + Erl (CI 0.20); IM + AMU (CI 0.50), GIST430/654, IM + afatinib (CI 0.39); IM + AMU (CI 0.42), GIST48, IM + afatinib (CI 0.03); IM + AMU (CI 0.04); AMU + afatinib (CI 0.36); IM + Erl (CI 0.63). Conclusion: Targeting c-Kit plus HER1 or AXL/c-Met abrogates IM resistance in GIST.
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Wong NACS, Wingate J, Gradhand E. Response to correspondence: An immunohistochemical study of potential diagnostic and therapeutic biomarkers of wild-type gastrointestinal stromal tumours. Histopathology 2015; 67:747-9. [DOI: 10.1111/his.12690] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/29/2022]
Affiliation(s)
| | - Jenny Wingate
- Department of Histopathology; Bristol Royal Infirmary; Bristol UK
| | - Elise Gradhand
- Department of Histopathology; Bristol Royal Infirmary; Bristol UK
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Wong NACS, Wingate J, Gradhand E. An immunohistochemical study of potential diagnostic and therapeutic biomarkers of wild-type gastrointestinal stromal tumours. Histopathology 2015; 67:378-85. [DOI: 10.1111/his.12667] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 12/15/2014] [Accepted: 02/02/2015] [Indexed: 12/26/2022]
Affiliation(s)
| | - Jenny Wingate
- Department of Histopathology; Bristol Royal Infirmary; Bristol UK
| | - Elise Gradhand
- Department of Histopathology; Bristol Royal Infirmary; Bristol UK
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Jiang J, Jin MS, Suo J, Wang YP, He L, Cao XY. Evaluation of malignancy using Ki-67, p53, EGFR and COX-2 expressions in gastrointestinal stromal tumors. World J Gastroenterol 2012; 18:2569-75. [PMID: 22654456 PMCID: PMC3360457 DOI: 10.3748/wjg.v18.i20.2569] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 07/08/2011] [Revised: 09/27/2011] [Accepted: 10/27/2011] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the role of expressions of Ki-67, p53, epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) in gastrointestinal stromal tumor (GIST) grading and prognosis. METHODS Tumor tissue was collected retrospectively from 96 patients with GIST. Antibodies against Ki-67, p53, EGFR and COX-2 were used for immunohistochemical staining. Tumor grading was designated according to a consensus system and the staining was quantified in 3 categories for each antibody in the statistical analysis. RESULTS The Ki-67 expression in GISTs was significantly associated with the size of the tumors, mitotic rate and the risk of malignancy (χ(2) = 15.51, P = 0.02; χ(2) = 22.27, P < 0.001; χ(2) = 20.05; P < 0.001). The p53 expression was also significantly correlated with mitotic rate and the risk of malignancy (χ(2) = 9.92, P = 0.04; χ(2) = 9.97; P = 0.04). Over-expression of Ki-67 was strongly correlated with poor survival (χ(2) = 10.44, P = 0.006), but no correlation was found between the expression of p53, EGFR or COX-2 and survival. Multivariate analysis further demonstrated that Ki-67 expression (relative risk = 15.78, 95% CI: 4.25-59.37) could be used as an independent prognostic value for GIST patients. Adjuvant imatinib therapy could improve clinical outcomes in the patients with high risk and intermediate risk of recurrence after complete tumor resections (median survival time: 52 mo vs 37 mo, χ(2) = 7.618, P = 0.006). CONCLUSION Our results indicated that the expression of Ki-67 could be used as an independent prognostic factor for GIST patients.
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Parampalli U, Crossland C, Longley J, Morrison I, Sayegh M. A Rare Case of Gastrointestinal Stromal Tumour in Pregnancy Presenting with Upper Gastrointestinal Bleeding. J Gastrointest Cancer 2012; 43 Suppl 1:S80-3. [PMID: 22252170 DOI: 10.1007/s12029-011-9360-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/13/2023]
Affiliation(s)
- U Parampalli
- Department of General Surgery, Worthing Hospital, Lyndhurst Road, Worthing, West Sussex, BN11 2DH, UK.
| | - C Crossland
- Department of General Surgery, Worthing Hospital, Lyndhurst Road, Worthing, West Sussex, BN11 2DH, UK
| | - J Longley
- Department of General Surgery, Worthing Hospital, Lyndhurst Road, Worthing, West Sussex, BN11 2DH, UK
| | - I Morrison
- Department of Histopathology, Worthing Hospital, Lyndhurst Road, Worthing, West Sussex, BN11 2DH, UK
| | - M Sayegh
- Department of General Surgery, Worthing Hospital, Lyndhurst Road, Worthing, West Sussex, BN11 2DH, UK
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Nakagawa M, Nabeshima K, Asano S, Hamasaki M, Uesugi N, Tani H, Yamashita Y, Iwasaki H. Up-regulated expression of ADAM17 in gastrointestinal stromal tumors: coexpression with EGFR and EGFR ligands. Cancer Sci 2009; 100:654-62. [PMID: 19298600 PMCID: PMC11158838 DOI: 10.1111/j.1349-7006.2009.01089.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 11/03/2008] [Revised: 12/16/2008] [Accepted: 12/17/2008] [Indexed: 12/17/2022] Open
Abstract
Metalloproteinase activities of a disintegrin and metalloproteinases (ADAMs), matrix metalloproteinases (MMPs), and membrane type (MT-)MMPs are involved in many aspects of tumor biology. ADAMs are transmembrane proteins that cleave membrane-anchored proteins to release soluble factors, and thereby mediate important biological phenomena in tumors. The aim of this study was to analyze histopathology, expression and roles of metalloproteinases, especially ADAMs, in gastric gastrointestinal stromal tumor (GIST). Histopathology and immunohistochemical expression of ADAMs were examined in 89 gastric GISTs. In 11 GISTs, ADAM expression was examined at mRNA and protein levels by reverse transcription-polymerase chain reaction (RT-PCR) and immunoblotting, respectively. RT-PCR analysis showed frequent expression of ADAM9 (91%), ADAM10 (64%), ADAM17 (82%), MMP-2 (82%), and MT1-MMP (73%). However, ADAM17 and MMP-2 were the only metalloproteinases that were up-regulated in GISTs at the protein level compared with non-neoplastic gastric tissues. ADAM17 was immunohistochemically expressed in 93% of GIST versus 16% of normal gastric tissues. Furthermore, CD117-positive interstitial cells of Cajal in normal gastric tissues were all negative for ADAM17 with double immunostaining. Expressions of epidermal growth factor receptor (EGFR) and several EGFR ligands such as amphiregulin, heparin-binding epidermal growth factor (HB-EGF), betacellulin, and epiregulin were also demonstrated in GIST by RT-PCR. Protein expression of EGFR, phosphorylated EGFR, amphiregulin, and HB-EGF, both of which can be shed by ADAM17, was confirmed in tumors coexpressing ADAM17 by immunoblotting. Moreover, proteolytically cleaved soluble forms of amphiregulin were identified in tumor extracts. Considered together, the results suggest that ADAM17 may contribute to the progression and growth of GIST through shedding of EGFR ligands and consequent EGFR stimulation. ADAM17, as a major sheddase in GIST, could be potentially a suitable target in anticancer treatment of imatinib-resistant GISTs.
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Affiliation(s)
- Motomichi Nakagawa
- Department of Pathology, Fukuoka University Hospital and School of Medicine, Fukuoka 814-0180, Japan
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Targeting apoptosis as an approach for gastrointestinal cancer therapy. Drug Resist Updat 2009; 12:55-64. [PMID: 19278896 DOI: 10.1016/j.drup.2009.02.002] [Citation(s) in RCA: 106] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 01/05/2009] [Revised: 02/09/2009] [Accepted: 02/10/2009] [Indexed: 12/27/2022]
Abstract
Cancers in the gastrointestinal system account for a large proportion of malignancies and cancer-related deaths with gastric cancer and colorectal cancer being the most common ones. For those patients in whom surgical resection is not possible, other therapeutic approaches are necessary. Disordered apoptosis has been linked to cancer development and treatment resistance. Apoptosis occurs via extrinsic or intrinsic signaling each triggered and regulated by many different molecular pathways. In recent years, the selective induction of apoptosis in tumor cells has been increasingly recognized as a promising approach for cancer therapy. A detailed understanding of the molecular pathways involved in the regulation of apoptosis is essential for developing novel effective therapeutic approaches. Apoptosis can be induced by many different approaches including activating cell surface death receptors (for example, Fas, TRAIL and TNF receptors), inhibiting cell survival signaling (such as EGFR, MAPK and PI3K), altering apoptosis threshold by modulating pro-apoptotic and anti-apoptotic members of the Bcl-2 family, down-regulating anti-apoptosis proteins (such as XIAP, survivin and c-IAP2), and using other pro-apoptotic agents. In this review, the authors reviewed the currently reported apoptosis-targeting approaches in gastrointestinal cancers.
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Feigin ME, Muthuswamy SK. ErbB receptors and cell polarity: new pathways and paradigms for understanding cell migration and invasion. Exp Cell Res 2008; 315:707-16. [PMID: 19022245 DOI: 10.1016/j.yexcr.2008.10.034] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 10/02/2008] [Revised: 10/19/2008] [Accepted: 10/20/2008] [Indexed: 12/25/2022]
Abstract
The ErbB family of receptor tyrosine kinases is involved in initiation and progression of a number of human cancers, and receptor activation or overexpression correlates with poor patient survival. Research over the past two decades has elucidated the molecular mechanisms underlying ErbB-induced tumorigenesis, which has resulted in the development of effective targeted therapies. ErbB-induced signal transduction cascades regulate a wide variety of cell processes, including cell proliferation, apoptosis, cell polarity, migration and invasion. Within tumors, disruption of these core processes, through cooperative oncogenic lesions, results in aggressive, metastatic disease. This review will focus on the ErbB signaling networks that regulate migration and invasion and identify a potential role for cell polarity pathways during cancer progression.
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Affiliation(s)
- Michael E Feigin
- Cold Spring Harbor Laboratory, One Bungtown Road, Cold Spring Harbor, NY 11724, USA
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Gao LB, Wei YS, Zhou B, Wang YY, Liang WB, Li C, Li Y, Bai P, Fang WL, Xue H, Zhang L. No association between epidermal growth factor and epidermal growth factor receptor polymorphisms and nasopharyngeal carcinoma. ACTA ACUST UNITED AC 2008; 185:69-73. [PMID: 18722874 DOI: 10.1016/j.cancergencyto.2008.04.019] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 03/31/2008] [Revised: 04/24/2008] [Accepted: 04/25/2008] [Indexed: 12/22/2022]
Abstract
Numerous candidate genes have been proposed as susceptibility factors for the development of nasopharyngeal carcinoma (NPC). Epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) interaction plays a pivotal role in cell proliferation, differentiation, and tumourigenesis of epithelial tissues. To our knowledge, however, no study has examined the relationship between the EGF/EGFR and NPC. The aim of this study is to investigate the potential association between single-nucleotide polymorphisms of EGF +61 G/A and EGFR +2073 A/T and NPC. A total of 173 patients with NPC and 206 age- and sex-matched controls were the participants. Genotypes were determined using a polymerase chain reaction-restriction fragment length polymorphism strategy and DNA sequencing. There were no significant differences in the genotype and allele frequencies of EGF +61 G/A and EGFR +2073 A/T polymorphisms between the group of patients with NPC and the control group in a Chinese population (for EGF +61 G/A: OR=1.29, 95% CI: 0.95-1.74; for EGFR +2073 A/T: OR=0.91, 95% CI: 0.67-1.23). Further studies are still needed to explore the complicated interaction between environmental factors and EGF +61 G/A and EGFR +2073 A/T polymorphisms in the risk of NPC, particularly in ethnically different populations.
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Affiliation(s)
- Lin-Bo Gao
- Department of Forensic Biology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China
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Abstract
Epidermal growth factor receptor (EGFR) plays an important role in cancer biology and offers a promising molecular therapeutic target. The expression profile of EGFR in gastrointestinal stromal tumors (GISTs) is derived from a limited number of small series samples and case reports. We evaluated the involvement of EGFR in human gastric GISTs. Tissue microarray sections representing 33 gastric GISTs with known follow-up were surveyed by immunohistochemistry, using antibodies specific for EGFR. Expression of EGFR was identified in 8/33 (24.2%) cases, and tended to be present in tumors of smaller size (3.69+/-0.66 cm vs. 10.69+/-1.52 cm, P=0.0001), fewer mitoses (3.5+/-1.0/50 high power field vs. 23.44+/-7.61, P=0.0073), and lower necrosis percentages (0% vs. 5.37+/-1.37%, P=0.0003); the expression was more frequently seen in the benign/probably benign category (6/8, 75%, P=0.047), than in gastric GISTs that lacked EGFR expression. Expression showed a trend as a favorable prognostic indicator but did not reach statistical significance, although the number of cases was limited. This observation suggests that EGFR is present in some gastric GISTs, especially in small tumors, and might participate in the growth regulation of human gastric GISTs. Expression of EGFR in some gastric GISTs might be of clinical significance with the recent emergence of EGFR-targeted therapies.
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Abstract
Human epidermal growth factor receptor-2 (HER-2) encodes for the transmembrane glycoprotein HER-2 that is involved in activation of intracellular signal transduction pathways that control cell growth and differentiation. HER-2 is overexpressed in approximately 20% of patients with breast cancer and has been associated with poorer prognosis. Since 1998, the anti-HER-2 antibody trastuzumab has been used for the treatment of patients with HER-2-positive breast cancers. However, little information is available about the relationship between HER-2 and gastrointestinal stromal tumors. This study's purpose was to determine the HER-2 status in gastrointestinal stromal tumors. We found that all 477 cases included in this study were negative (score 0) by immunohistochemistry using HercepTest, and no HER-2 gene amplification was detected in 71 cases submitted to fluorescence in situ hybridization. These results show that HER-2 may not have any role in gastrointestinal stromal tumor pathogenesis and that the neoplasm may not be suitable for treatment with trastuzumab.
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Affiliation(s)
- Lisandro Ferreira Lopes
- Consultoria em Patologia, Botucatu, Sao Paulo, Brazil Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil
| | - Carlos E Bacchi
- Consultoria em Patologia, Botucatu, Sao Paulo, Brazil Department of Pathology, University of Sao Paulo Medical School, Sao Paulo, SP, Brazil.
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Lopes LF, Ojopi EB, Bacchi CE. Gastrointestinal stromal tumor in Brazil: clinicopathology, immunohistochemistry, and molecular genetics of 513 cases. Pathol Int 2008; 58:344-52. [PMID: 18477213 DOI: 10.1111/j.1440-1827.2008.02235.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/27/2023]
Abstract
The aim of the present study was to evaluate the clinicopathological, immunohistochemical, and molecular genetic features of gastrointestinal stromal tumors in Brazil and compare them with cases from other countries. Five hundred and thirteen cases were retrospectively analyzed. HE-stained sections and clinical information were reviewed and the immunohistochemical expression of CD117, CD34, smooth-muscle actin, S-100 protein, desmin, CD44v3 adhesion molecule, p53 protein, epidermal growth factor receptor, and Ki-67 antigen was studied using tissue microarrays. Mutation analysis of KIT and platelet-derived growth factor receptor-alpha genes was also performed. There was a slight female predominance (50.3%) and the median age at diagnosis was 59 years. The tumors were mainly located in the stomach (38.4%). Immunohistochemistry showed that CD117 was expressed in 95.7% of cases. Epidermal growth factor receptor expression was observed in 84.4% of tumors. p53 protein expression was found only in 2.6% of cases but all belonged to the high-risk group for aggressive behavior according to the National Institutes of Health consensus approach. No CD44v3 adhesion molecule expression was detected. KIT exon 11 mutations were the most frequent (62.2%). The present data confirm that gastrointestinal stromal tumors in Brazilian patients do not differ from tumors occurring in other countries.
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Affiliation(s)
- Lisandro Ferreira Lopes
- Department of Pathology, University of Sao Paulo Medical School and Pathology Reference Lab, Botucatu, Sao Paulo, Sau Paulo State, Brazil
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17
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Abstract
Gastrointestinal stromal tumor is the most common mesenchymal neoplasm of the gastrointestinal tract. Mutually exclusive KIT or platelet-derived growth factor receptor-alpha mutations are key events in gastrointestinal stromal tumor pathogenesis, and specific treatment targeting KIT/platelet-derived growth factor receptor-alpha activation is available. Epidermal growth factor receptor plays an important role in cancer biology and also constitutes a promising molecular target of therapy. Very few reports have been published in the literature about the relationship between gastrointestinal stromal tumor and epidermal growth factor receptor. The aim of this study was to investigate epidermal growth factor receptor immunohistochemical expression and epidermal growth factor receptor gene amplification in 82 consecutive gastrointestinal stromal tumor cases using tissue microarray technique. Hematoxylin- and eosin-stained sections and clinical information were reviewed, and expression of CD117 (KIT), CD34 and epidermal growth factor receptor was investigated by immunohistochemistry. Epidermal growth factor receptor gene copy number was determined using fluorescence in situ hybridization. Immunohistochemistry revealed that CD117 and CD34 were expressed in 96 and 57% of tumors, respectively. Variable epidermal growth factor receptor protein immunohistochemical overexpression was detected in 96% of gastrointestinal stromal tumor cases, but none of the 75 cases with represented tumor tissue cores and countable fluorescence signals exhibited epidermal growth factor receptor gene amplification by fluorescence in situ hybridization. These results show that there is no correlation between epidermal growth factor receptor protein overexpression by immunohistochemistry and epidermal growth factor receptor gene amplification by fluorescence in situ hybridization. Considering that the mechanisms of epidermal growth factor receptor protein overexpression are not well understood and the possibility that anti-epidermal growth factor receptor therapy may be beneficial for patients with gastrointestinal stromal tumor that overexpresses epidermal growth factor receptor, additional studies are encouraged.
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18
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Zandi R, Larsen AB, Andersen P, Stockhausen MT, Poulsen HS. Mechanisms for oncogenic activation of the epidermal growth factor receptor. Cell Signal 2007; 19:2013-23. [PMID: 17681753 DOI: 10.1016/j.cellsig.2007.06.023] [Citation(s) in RCA: 200] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Received: 05/16/2007] [Accepted: 06/14/2007] [Indexed: 10/23/2022]
Abstract
The Epidermal growth factor receptor (EGFR) is a membrane spanning glycoprotein, which frequently has been implicated in various cancer types. The mechanisms by which EGFR becomes oncogenic are numerous and are often specific for each cancer type. In some tumors, EGFR is activated by autocrine/paracrine growth factor loops, whereas in others activating mutations promote EGFR signaling. Overexpression and/or amplification of the EGFR gene are prevalent in many cancer types leading to aberrant EGFR signaling. In addition, failure to attenuate receptor signaling by receptor downregulation can also lead to cellular transformation. Heterodimerization of EGFR with ErbB2 inhibits downregulation of EGFR and thereby prolongs growth factor signaling. This also indicates that cross-talk between EGFR and heterologous receptor systems serves as another mechanism for oncogenic activation of EGFR. Because of its role in tumor promotion, the EGFR has been intensely studied as a therapeutic target. There are currently two major mechanisms by which the EGFR is targeted: antibodies binding to the extracellular domain of EGFR and small-molecule tyrosine-kinase inhibitors. However, tumorigenesis is a multi-step process involving several mutations, which might explain why EGFR therapeutics has only been partially successful. This highlights the importance of pinpointing the mechanisms by which EGFR becomes oncogenic in a particular cancer. In this review, each of the above mentioned mechanisms will be discussed, as a detailed molecular and genetic understanding of how EGFR contributes to the malignant phenotype might offer new promise for the design, development and clinical evaluation of future tumor-specific anticancer approaches.
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Affiliation(s)
- Roza Zandi
- Department of Radiation Biology, The Finnsen Centre, Copenhagen University Hospital, 9 Blegdamsvej, DK-2100 Copenhagen, Denmark
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19
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Maas CPHJ, ter Haar G, van der Gaag I, Kirpensteijn J. Reclassification of Small Intestinal and Cecal Smooth Muscle Tumors in 72 Dogs: Clinical, Histologic, and Immunohistochemical Evaluation. Vet Surg 2007; 36:302-13. [PMID: 17547593 DOI: 10.1111/j.1532-950x.2007.00271.x] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 02/04/2023]
Abstract
OBJECTIVES To reclassify canine small intestinal and cecal leiomyoma (LM) and leiomyosarcoma (LMS) into smooth muscle and gastrointestinal stromal tumors (GIST) using histologic and immunohistochemical (IH) analysis and to report clinical findings and survival data. STUDY DESIGN Retrospective review of cases. ANIMALS Dogs (n=47) with small intestinal (40 LMS; 7 LM) and 25 dogs with cecal tumors (23 LMS; 2 LM). METHODS Clinical and survival data were reviewed. Tissue sections were reevaluated for light-microscopic malignancy criteria and examined for expression of SMA, desmin, vimentin, S-100, and CD117 (KIT) by immunohistochemistry. RESULTS Reclassification resulted in 2 LM, 9 LMS, 19 GIST, and 17 GIST-like tumors in the small intestine and 23 GIST and 2 GIST-like tumors in the cecum. GIST-like tumors were morphologic and IH identical to GIST but lacked KIT expression. No significant difference in survival was observed for tumor type, location, histologic, or IH characteristics; however, dogs with cecal tumors were significantly older in age, presented more commonly with intestinal perforation and peritonitis, and less commonly with weight loss. Cecal tumors had more histologic malignancy criteria than small intestinal tumors. After excision, 1 and 2 year recurrence-free periods were 80.1% and 67.2% for small intestinal and 83.3% and 61.9% for cecal tumors. CONCLUSION Prognosis for intestinal tumors with histologic smooth muscle appearance is good after excision and not related to tumor type, location, histologic, or IH characteristics. CLINICAL RELEVANCE Clinical importance could not be demonstrated for reclassification, but may be for future treatment, of intestinal smooth muscle or stromal tumors.
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Affiliation(s)
- Ceriel P H J Maas
- Department of Clinical Sciences of Companion Animals, University of Utrecht, Utrecht, The Netherlands
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20
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Lanzafame S, Minutolo V, Caltabiano R, Minutolo O, Marino B, Gagliano G, D'Asta S. About a case of GIST occurring during pregnancy with immunohistochemical expression of epidermal growth factor receptor and progesterone receptor. Pathol Res Pract 2006; 202:119-23. [PMID: 16413690 DOI: 10.1016/j.prp.2005.08.013] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Received: 04/14/2005] [Accepted: 08/29/2005] [Indexed: 12/17/2022]
Abstract
The coexistence of gastrointestinal stromal tumors (GISTs) and pregnancy is very rare. We are the first to add to the literature a case report of GIST occurring during pregnancy with immunohistochemical staining for epidermal growth factor receptor (EGFR) and progesterone receptor (PgR). A role of PgR and EGFR in tumor growth should not be excluded, and these findings indicate that the expression of these receptors could provide pertinent biological information required to determine adequate therapeutic regimens. In conclusion, considering that GIST occurring during pregnancy is a rare event, with frequent delay in diagnosis, it is important to consider this diagnosis for early recognition, correct diagnosis, and a better outcome.
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Affiliation(s)
- S Lanzafame
- Department G.F. Ingrassia, Section of Anatomic Pathology, University of Catania, Santa Sofia 87 Street, 95123 Catania, Italy.
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21
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Yoshino N, Ishihara S, Rumi MAK, Ortega-Cava CF, Yuki T, Kazumori H, Takazawa S, Okamoto H, Kadowaki Y, Kinoshita Y. Interleukin-8 regulates expression of Reg protein in Helicobacter pylori-infected gastric mucosa. Am J Gastroenterol 2005; 100:2157-66. [PMID: 16181363 DOI: 10.1111/j.1572-0241.2005.41915.x] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Academic Contribution Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIM Chronic inflammation induced by Helicobacter pylori infection is closely associated with epithelial cell proliferation and apoptosis, which are related to cellular turnover in gastric mucosa. Reg protein is a regenerating gene product and a potent growth factor for gastric mucosal cells, however, little is known regarding its association with the pathogenesis of H. pylori infection. The aim of this study was to investigate Reg protein production and its regulation in H. pylori-associated gastritis. METHODS Gastric fundic biopsy samples were taken from patients with and without H. pylori infection. In vivo expression of Reg protein was examined by Western blotting and immunohistochemistry methods. The effects of interleukin (IL)-8 on Reg protein expression and transcriptional activation of the Reg gene in ECC10 cells were investigated by Western blotting and luciferase assays, respectively. RESULTS Reg expression was found localized in the deeper part of gastric fundic glands and clearly shown in chromogranin A-positive cells in the gastric corpus. Semiquantitative immunohistochemistry and Western blotting results for Reg expression were significantly associated with polymorphonuclear neutrophil activity and chronic inflammation of gastric mucosa. IL-8 production in the gastric mucosa was significantly augmented by H. pylori infection, while IL-8 dose-dependently stimulated Reg protein production and Reg promoter activity in vitro in cultured ECC10 cells. CONCLUSION The present study showed for the first time that Reg protein may be a potent stimulator of gastric epithelial cells in H. pylori-infected human gastric mucosa stimulated by IL-8. Further, our findings provide evidence of a novel link between Reg protein and H. pylori infection, which may help explain the molecular mechanisms underlying H. pylori-associated diseases, including gastric cancer.
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Affiliation(s)
- Nagisa Yoshino
- Department of Gastroenterology and Hepatology, Shimane University, School of Medicine, Izumo, Japan
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22
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Tornillo L, Duchini G, Carafa V, Lugli A, Dirnhofer S, Di Vizio D, Boscaino A, Russo R, Tapia C, Schneider-Stock R, Sauter G, Insabato L, Terracciano LM. Patterns of gene amplification in gastrointestinal stromal tumors (GIST). J Transl Med 2005; 85:921-31. [PMID: 15864317 DOI: 10.1038/labinvest.3700284] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/08/2022] Open
Abstract
Gastrointestinal stromal tumors (GIST) are the most common primary mesenchymal tumors of the gastrointestinal tract (GIT). They represent a wide clinico-pathological spectrum of tumors. No single histological or clinical parameter can predict the prognosis while the response to therapy is related to the type of KIT or PDGFRA mutation. Cytogenetic and CGH studies have identified frequent gross chromosomal aberrations but the target genes of these changes are unknown. To determine whether known oncogenes take part in genomic rearrangements and to investigate the potential clinical significance of their amplifications, nine known oncogenes (CMYC, MDM2, GLI1, CDK4, HER2, EGFR1, CCND1, FGF3, EMS) were analyzed by fluorescent in situ hybridization (FISH) on a tissue microarray (TMA) containing 94 primary GIST. Clinical follow-up information was available for 57 of these patients. Amplification was found for CMYC in three of 90 (3.3%), for MDM2 in five of 94 (5.3%), for EGFR1 in five of 94 (5.3%), and for CCND1 in seven of 79 (8.9%) evaluable cases. No amplifications were seen for HER2, GLI1, CDK4, FGF3, and EMS. Amplifications of MDM2 and CCND1 were associated with clinical and histological malignancy. In conclusion, our data show that gene amplification does occur in a subset of GIST. Identification of MDM2/CCND1 amplification may represent another molecular feature that could help in the evaluation of the behavior of GISTs.
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Affiliation(s)
- Luigi Tornillo
- Institute of Pathology, University of Basel, CH-4003 Basel, Switzerland.
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23
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Hiscox S, Morgan L, Barrow D, Dutkowskil C, Wakeling A, Nicholson RI. Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile and invasive phenotype: inhibition by gefitinib ('Iressa', ZD1839). Clin Exp Metastasis 2004; 21:201-12. [PMID: 15387370 DOI: 10.1023/b:clin.0000037697.76011.1d] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 01/09/2023]
Abstract
Despite an initial response to antihormonal therapies, the development of resistance will occur in a significant number of breast cancer patients. The mechanisms that underlie acquired resistance are not yet clear. Using a previously established in vitro cell model of tamoxifen resistance in MCF7 cells, shown to display autocrine epidermal growth factor receptor (EGFR) signalling, we assessed how resistance might modulate their metastatic phenotype in vitro, as metastatic disease is the single most important factor affecting the mortality of cancer patients. Furthermore, we investigated the effect of the EGFR tyrosine kinase inhibitor (EGFR-TKI), gefitinib ('Iressa', ZD1839; AstraZeneca), on this behaviour. The acquisition of tamoxifen resistance in MCF7 cells was accompanied by a dramatic and significant increase in their invasive and motile nature. The affinity of these cells for matrix components was also enhanced. Inhibition of EGFR signalling with gefitinib reduced both basal and TGF-alpha-stimulated invasion and motility and reduced cell-matrix adhesion. In conclusion, we demonstrate here that resistance to tamoxifen in breast cancer cells is accompanied by a significant increase in their basal motile and invasive activity, properties associated with increased metastatic potential. Inhibition of EGFR signalling by gefitinib significantly inhibited cell motility and invasion thus suggesting a role for the EGF receptor in the aggressive phenotype of tamoxifen-resistant breast cancer cells.
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Affiliation(s)
- Stephen Hiscox
- Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Redwood Building, King Edward VII Avenue, Cardiff, UK.
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24
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Sandberg AA, Bridge JA. Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors. gastrointestinal stromal tumors. CANCER GENETICS AND CYTOGENETICS 2002; 135:1-22. [PMID: 12072198 DOI: 10.1016/s0165-4608(02)00546-0] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Academic Contribution Register] [Indexed: 01/24/2023]
Affiliation(s)
- Avery A Sandberg
- Department of DNA Diagnostics, St. Joseph's Hospital and Medical Center, 350 West Thomas Road, Phoenix, AZ 85013, USA.
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25
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El-Obeid A, Hesselager G, Westermark B, Nistér M. TGF-alpha-driven tumor growth is inhibited by an EGF receptor tyrosine kinase inhibitor. Biochem Biophys Res Commun 2002; 290:349-58. [PMID: 11779176 DOI: 10.1006/bbrc.2001.6210] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/22/2022]
Abstract
The simultaneous presence of the EGFR and its ligand TGF-alpha in human tumor tissues suggests that autocrine TGF-alpha stimulation drives tumor growth. Here we show that autocrine TGF-alpha stimulation does cause increased tumor growth in vivo, an effect that was proven to be mediated via EGFR activation, and that this TGF-alpha/EGFR autocrine loop was accessible to an EGFR specific tyrosine kinase inhibitor. Clones of the EGFR expressing glioma cell line U-1242 MG were transfected with TGF-alpha cDNA using a tetracycline-inhibitory system for gene expression. TGF-alpha expression was inhibited by the presence of tetracycline, and subcutaneous tumors forming from cell lines injected into nude mice could be inhibited by feeding mice tetracycline. We confirmed that TGF-alpha mRNA and protein were present in these tumors and that, subsequently, the endogenous EGFR was activated. Tumor growth could be inhibited by an EGFR specific tyrosine kinase inhibitor of the type 4-(3-chloroanilino)-6,7-dimethoxy-quinazoline, administered daily by intraperitoneal injection, thereby interrupting the autocrine loop.
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Affiliation(s)
- A El-Obeid
- Department of Genetics and Pathology, Rudbeck Laboratory, University Hospital, Uppsala University, SE-751 85 Uppsala, Sweden
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26
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Abstract
A continuously increasing number of regulatory peptides has been demonstrated to be expressed in the intestine and to modulate several functional properties of various intestinal cell populations, including the intestinal epithelium and lamina propria cell populations. These regulatory peptides include members of the epidermal growth factor (EGF) family, the transforming growth factor beta (TGF-beta) family, the insulin-like growth factor (IGF) family, the fibroblast growth factor (FGF) family, the trefoil factor (TFF) family, the colony-stimulating factor (CSF) family, and a few other seemingly unrelated regulatory peptides, such as hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF), and various interleukins, interferons and tumour necrosis factor-related proteins. In addition to the well-known effects on cell proliferation, these regulatory peptide factors regulate several other functional properties of epithelial and other cell populations, such as differentiation, migration, and extracellular matrix deposition and degradation. This review is designed not to discuss all the identified factors in detail but to highlight some of the basic principles of growth factor action in the intestine. It focuses mainly on classical growth factors rather than interleukins and interferons.
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Affiliation(s)
- A U Dignass
- Department of Medicine, Division of Hepatology and Gastroenterology, Charité-Campus Virchow Clinic, Berlin, Germany.
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27
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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] [Academic Contribution 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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28
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Apoptosis, bcl-2 Expression, and p53 Expression in Gastrointestinal Stromal/Smooth Muscle Tumors. Appl Immunohistochem Mol Morphol 2001. [DOI: 10.1097/00022744-200103000-00005] [Citation(s) in RCA: 22] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/26/2022]
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29
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Apoptosis, bcl-2 Expression, and p53 Expression in Gastrointestinal Stromal/Smooth Muscle Tumors. Appl Immunohistochem Mol Morphol 2001. [DOI: 10.1097/00129039-200103000-00005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Academic Contribution Register] [Indexed: 11/27/2022]
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30
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Abstract
The mucosal epithelium of the alimentary tract represents a crucial barrier to a broad spectrum of noxious and immunogenic substances within the intestinal lumen. An impairment of the integrity of the mucosal epithelial barrier is observed in the course of various intestinal disorders including inflammatory bowel diseases (IBD), celiac disease, intestinal infections, and various other diseases. Furthermore, even under physiologic conditions temporary damage of the epithelial surface mucosa may be caused by proteases, residential flora, dietary compounds, or other factors. Generally, the integrity of the intestinal mucosal surface barrier is rapidly reestablished even after extensive destruction because of an enormous regenerative capability of the mucosal surface epithelium. Rapid resealing of the surface epithelium is accomplished by epithelial cell migration, also termed epithelial restitution, epithelial cell proliferation, and differentiation. Healing of the intestinal surface epithelium is regulated by a complex network of highly divergent factors, among them a broad spectrum of structurally distinct regulatory peptides that have been identified within the mucosa of the intestinal tract. These regulatory peptides, conventionally designated as growth factors and cytokines, play an essential role in regulating differential epithelial cell functions to preserve normal homeostasis and integrity of the intestinal mucosa. In addition, a number of other peptide molecules such as extracellular matrix factors and blood clotting factors, and also nonpeptide molecules including phospholipids, shortchain fatty acids, adenine nucleotides, trace elements, and pharmacological agents, have been demonstrated to modulate intestinal epithelial repair mechanisms. Some of these molecules may be released by platelets, adjacent stromal cells, inflammatory cells, or injured epithelial and nonepithelial cells and may play an important role in the modulation of intestinal injury. Repeated damage and injury of the intestinal surface are key features of various intestinal disorders including IBD and require constant repair of the epithelium. Enhancement of intestinal repair mechanisms by regulatory peptides or other modulatory factors may provide future approaches for the treatment of diseases that are characterized by injuries of the epithelial surface.
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Affiliation(s)
- A U Dignass
- Department of Medicine, Charité-Campus Virchow Clinic, Berlin, Germany.
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