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Krishnamurthy K, Urioste SN, Cusnir M, Schwartz M, Alghamdi S, Sriganeshan V, Poppiti R. The mutational landscape of upper gastrointestinal adenocarcinomas- A study of similarities and differences. Pathol Res Pract 2022; 232:153830. [DOI: 10.1016/j.prp.2022.153830] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 02/13/2022] [Accepted: 02/24/2022] [Indexed: 12/14/2022]
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2
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Davoodvandi A, Fallahi F, Tamtaji OR, Tajiknia V, Banikazemi Z, Fathizadeh H, Abbasi-Kolli M, Aschner M, Ghandali M, Sahebkar A, Taghizadeh M, Mirzaei H. An Update on the Effects of Probiotics on Gastrointestinal Cancers. Front Pharmacol 2021; 12:680400. [PMID: 34992527 PMCID: PMC8724544 DOI: 10.3389/fphar.2021.680400] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 11/26/2021] [Indexed: 12/28/2022] Open
Abstract
Because of their increasing prevalence, gastrointestinal (GI) cancers are regarded as an important global health challenge. Microorganisms residing in the human GI tract, termed gut microbiota, encompass a large number of living organisms. The role of the gut in the regulation of the gut-mediated immune responses, metabolism, absorption of micro- and macro-nutrients and essential vitamins, and short-chain fatty acid production, and resistance to pathogens has been extensively investigated. In the past few decades, it has been shown that microbiota imbalance is associated with the susceptibility to various chronic disorders, such as obesity, irritable bowel syndrome, inflammatory bowel disease, asthma, rheumatoid arthritis, psychiatric disorders, and various types of cancer. Emerging evidence has shown that oral administration of various strains of probiotics can protect against cancer development. Furthermore, clinical investigations suggest that probiotic administration in cancer patients decreases the incidence of postoperative inflammation. The present review addresses the efficacy and underlying mechanisms of action of probiotics against GI cancers. The safety of the most commercial probiotic strains has been confirmed, and therefore these strains can be used as adjuvant or neo-adjuvant treatments for cancer prevention and improving the efficacy of therapeutic strategies. Nevertheless, well-designed clinical studies are still needed for a better understanding of the properties and mechanisms of action of probiotic strains in mitigating GI cancer development.
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Affiliation(s)
- Amirhossein Davoodvandi
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Farzaneh Fallahi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Omid Reza Tamtaji
- Students’ Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Vida Tajiknia
- Department of Surgery, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zarrin Banikazemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Hadis Fathizadeh
- Department of Laboratory Sciences, Sirjan Faculty of Medicine Sciences, Sirjan, Iran
| | - Mohammad Abbasi-Kolli
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Michael Aschner
- Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States
| | - Maryam Ghandali
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Amirhossein Sahebkar
- Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohsen Taghizadeh
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran
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Chellappan DK, Leng KH, Jia LJ, Aziz NABA, Hoong WC, Qian YC, Ling FY, Wei GS, Ying T, Chellian J, Gupta G, Dua K. The role of bevacizumab on tumour angiogenesis and in the management of gynaecological cancers: A review. Biomed Pharmacother 2018; 102:1127-1144. [DOI: 10.1016/j.biopha.2018.03.061] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2018] [Revised: 03/09/2018] [Accepted: 03/11/2018] [Indexed: 02/06/2023] Open
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Chen JY, Xu L, Fang WM, Han JY, Wang K, Zhu KS. Identification of PA28β as a potential novel biomarker in human esophageal squamous cell carcinoma. Tumour Biol 2017; 39:1010428317719780. [PMID: 29020885 DOI: 10.1177/1010428317719780] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common and serious malignancies in China. However, the exact mechanisms of tumor formation and progression are unclear. As late diagnosis and poor therapeutic efficacy result in lower survival rates, identifying biomarkers for early detection, prognostic evaluation, and recurrence monitoring of ESCC is necessary. Here we analyzed 10 protein expression profiles of ESCC core tissues and paired normal esophageal epithelial tissues using two-dimensional gel electrophoresis. We excised 29 protein spots with two-fold or greater differential expression between cancer and normal tissues and identified them using matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight mass spectrometry. The role of PA28β in ESCC cell was confirmed using cell growth, colony formation and soft agar in TE-1 cells pre- and post- PA28β transfection. Compared to their expression in the adjacent normal epithelia, 12 proteins, including transgelin (TAGLN), were upregulated in ESCC tissues; 17 proteins, including proteasome activator 28-beta subunit (PA28β), were downregulated (p < 0.05). Western blotting and immunohistochemistry confirmed that PA28β was significantly underexpressed in ESCC tissues. The functional assays demonstrate that PA28β inhibited cell growth, proliferation and malignancy of TE-1 cells. Among the differentially expressed proteins, PA28β is a potential tumor inhibitor.
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Affiliation(s)
- Jin-Yan Chen
- 1 Institute for Immunology, Fujian Academy of Medical Sciences, Fuzhou, China.,2 Fujian Provincial Key Laboratory of Medical Analysis, Fuzhou, China
| | - Li Xu
- 3 Department of Physiology, Basic Medical College of Putian University, Putian, China
| | - Wei-Min Fang
- 4 Fujian Provincial Cancer Hospital, Fuzhou, China
| | - Jun-Yong Han
- 1 Institute for Immunology, Fujian Academy of Medical Sciences, Fuzhou, China.,2 Fujian Provincial Key Laboratory of Medical Analysis, Fuzhou, China
| | - Kun Wang
- 1 Institute for Immunology, Fujian Academy of Medical Sciences, Fuzhou, China.,2 Fujian Provincial Key Laboratory of Medical Analysis, Fuzhou, China
| | - Kun-Shou Zhu
- 4 Fujian Provincial Cancer Hospital, Fuzhou, China
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Kim SY, Kim MS, Lee MK, Kim JS, Yi HK, Nam SY, Lee DY, Hwang PH. PPARγ induces growth inhibition and apoptosis through upregulation of insulin-like growth factor-binding protein-3 in gastric cancer cells. ACTA ACUST UNITED AC 2015; 48:226-33. [PMID: 25590353 PMCID: PMC4381942 DOI: 10.1590/1414-431x20144212] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2014] [Accepted: 10/13/2014] [Indexed: 12/23/2022]
Abstract
Peroxisome proliferator activator receptor-gamma (PPARγ) is a ligand-activated
transcriptional factor involved in the carcinogenesis of various cancers.
Insulin-like growth factor-binding protein-3 (IGFBP-3) is a tumor
suppressor gene that has anti-apoptotic activity. The purpose of this study was to
investigate the anticancer mechanism of PPARγ with respect to
IGFBP-3. PPARγ was overexpressed in SNU-668 gastric cancer cells
using an adenovirus gene transfer system. The cells in which PPARγ was overexpressed
exhibited growth inhibition, induction of apoptosis, and a significant increase in
IGFBP-3 expression. We investigated the underlying molecular
mechanisms of PPARγ in SNU-668 cells using an IGFBP-3 promoter/luciferase reporter
system. Luciferase activity was increased up to 15-fold in PPARγ transfected cells,
suggesting that PPARγ may directly interact with IGFBP-3 promoter to induce its
expression. Deletion analysis of the IGFBP-3 promoter showed that luciferase activity
was markedly reduced in cells without putative p53-binding sites (-Δ1755, -Δ1795).
This suggests that the critical PPARγ-response region is located within the
p53-binding region of the IGFBP-3 promoter. We further demonstrated an increase in
PPARγ-induced luciferase activity even in cells treated with siRNA to silence p53
expression. Taken together, these data suggest that PPARγ exhibits its anticancer
effect by increasing IGFBP-3 expression, and that IGFBP-3 is a significant tumor
suppressor.
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Affiliation(s)
- S Y Kim
- Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea
| | - M S Kim
- Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea
| | - M K Lee
- Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea
| | - J S Kim
- Department of Biochemistry, School of Dentistry, Chonbuk National University, Jeonju, Korea
| | - H K Yi
- Department of Biochemistry, School of Dentistry, Chonbuk National University, Jeonju, Korea
| | - S Y Nam
- Department of Alternative Therapy, Jeonju University, Jeonju, Korea
| | - D Y Lee
- Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea
| | - P H Hwang
- Department of Pediatrics, Chonbuk National University Hospital, Jeonju, Korea
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Abstract
Over the last several decades, the incidence of adenocarcinoma of the gastroesophageal junction (GEJ) has been increasing in developed countries. Although complete surgical resection remains the cornerstone of treatment for resectable disease, long-term outcomes are poor and recurrence rates are high with surgery alone in patients presenting with locally advanced disease. Multimodal therapy has been shown to improve survival; however, the optimal therapeutic approach remains controversial, and practices vary across the world. Preoperative chemoradiotherapy is generally used in the U.S., whereas perioperative chemotherapy without radiation is favored in most European countries. In this review, we discuss why the treatment of locally advanced GEJ tumors remains controversial, examine the evidence for various multimodal approaches, discuss their respective pros and cons, evaluate the role of radiation therapy, highlight some ongoing and planned clinical trials, and suggest areas that need further research.
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Affiliation(s)
- Noman Ashraf
- Department of Hematology/Oncology, University of South Florida/James A. Haley Veterans' Hospital, Tampa, Florida, USA; Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
| | - Sarah Hoffe
- Department of Hematology/Oncology, University of South Florida/James A. Haley Veterans' Hospital, Tampa, Florida, USA; Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
| | - Richard Kim
- Department of Hematology/Oncology, University of South Florida/James A. Haley Veterans' Hospital, Tampa, Florida, USA; Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa, Florida, USA
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Ku GY, Ilson DH. Emerging mAbs for the treatment of esophagogastric cancer. Expert Opin Emerg Drugs 2014; 20:63-74. [DOI: 10.1517/14728214.2015.983072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
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Yang X, Cheng L, Yao L, Ren H, Zhang S, Min X, Chen X, Zhang J, Li M. Involvement of chromosome region maintenance 1 (CRM1) in the formation and progression of esophageal squamous cell carcinoma. Med Oncol 2014; 31:155. [PMID: 25148895 DOI: 10.1007/s12032-014-0155-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 07/29/2014] [Indexed: 11/29/2022]
Abstract
Chromosome region maintenance 1 (CRM1) has been related to several malignancies. The predictive value of CRM1 in the malignance and prognosis of esophageal squamous cell carcinoma (ESCC), however, is not clear yet. In this study, we displayed that CRM1 expression was up-regulated in ESCC using immunohistochemistry and Western blot. Statistical analysis demonstrated that patients with high CRM1 levels indicated shorter survival period. We further found that silencing CRM1 caused apoptosis in ESCC cell lines. Moreover, knockdown of CRM1 disturbed the expression of tumor suppressor proteins and inhibited NF-κB activity in ESCC cell lines, especially if the cell line was treated with 5-fluorouracil. In consequence, our results for the first time indicated that CRM1 was dysregulated in ESCC, and suppression of CRM1 expression which resulted in inhibiting of NF-κB signaling might be developed into a new strategy in ESCC therapy.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Apoptosis/drug effects
- Biomarkers, Tumor/analysis
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Squamous Cell/chemistry
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/mortality
- Cell Line, Tumor
- Disease Progression
- Esophageal Neoplasms/chemistry
- Esophageal Neoplasms/metabolism
- Esophageal Neoplasms/mortality
- Esophageal Squamous Cell Carcinoma
- Esophagus/chemistry
- Esophagus/metabolism
- Female
- Humans
- Immunohistochemistry
- Karyopherins/analysis
- Karyopherins/genetics
- Karyopherins/metabolism
- Male
- Mice
- Mice, Nude
- Middle Aged
- NF-kappa B/metabolism
- Prognosis
- RNA, Small Interfering/genetics
- RNA, Small Interfering/metabolism
- Receptors, Cytoplasmic and Nuclear/analysis
- Receptors, Cytoplasmic and Nuclear/genetics
- Receptors, Cytoplasmic and Nuclear/metabolism
- Survival Analysis
- Exportin 1 Protein
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Affiliation(s)
- Xiaojing Yang
- Jiangsu Province Key Laboratory for Inflammation and Molecular Drug Target, Nantong University, Jiangsu, 226001, People's Republic of China
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Ku GY, Ilson DH. Emerging tyrosine kinase inhibitors for esophageal cancer. Expert Opin Emerg Drugs 2013; 18:219-30. [PMID: 23725567 DOI: 10.1517/14728214.2013.805203] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
INTRODUCTION Because of the poor prognosis for patients with esophagogastric cancers (EGCs), increasing attention has focused on targeted agents. AREAS COVERED Targets include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), Her2, mammalian target of rapamycin (mTOR), and MET. We briefly discuss preclinical data and the rationale for targeting these pathways and summarize the results of clinical trials of tyrosine kinase inhibitors (TKIs) against these targets. EXPERT OPINION While anti-EGFR therapy has been extensively investigated, completed Phase III trials suggest that this is not a promising target. A Phase III trial of an anti-VEGF antibody failed to show improvement in the primary endpoint of overall survival but response rates and progression-free survival were improved; a Phase III trial of an anti-VEGF receptor 2 antibody in second-line therapy did show improved survival. As such, Phase II and III evaluations of anti-VEGF TKIs are ongoing. The only Food and Drug Administration-approved targeted therapy in EGC is trastuzumab, an anti-Her2 antibody, and the results of a Phase III evaluation of lapatinib, an anti-Her2 TKI, are awaited. Phase III evaluation of an mTOR inhibitor has been negative. Finally, MET inhibition appears to have significant clinical potential and early testing of MET TKIs is underway.
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Affiliation(s)
- Geoffrey Y Ku
- Memorial Sloan-Kettering Cancer Center, Department of Medicine, Gastrointestinal Oncology Service, 300 East 66th Street, New York, NY 10065, USA
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10
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Restoring KLF5 in esophageal squamous cell cancer cells activates the JNK pathway leading to apoptosis and reduced cell survival. Neoplasia 2013; 15:472-80. [PMID: 23633919 DOI: 10.1593/neo.122126] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2012] [Revised: 03/07/2013] [Accepted: 03/12/2013] [Indexed: 01/26/2023] Open
Abstract
Esophageal cancer is the eighth most common cancer in the world and has an extremely dismal prognosis, with a 5-year survival of less than 20%. Current treatment options are limited, and thus identifying new molecular targets and pathways is critical to derive novel therapies. Worldwide, more than 90% of esophageal cancers are esophageal squamous cell cancer (ESCC). Previously, we identified that Krüppel-like factor 5 (KLF5), a key transcriptional regulator normally expressed in esophageal squamous epithelial cells, is lost in human ESCC. To examine the effects of restoring KLF5 in ESCC, we transduced the human ESCC cell lines TE7 and TE15, both of which lack KLF5 expression, with retrovirus to express KLF5 upon doxycycline induction. When KLF5 was induced, ESCC cells demonstrated increased apoptosis and decreased viability, with up-regulation of the proapoptotic factor BAX. Interestingly, c-Jun N-terminal kinase (JNK) signaling, an important upstream mediator of proapoptotic pathways including BAX, was also activated following KLF5 induction. KLF5 activation of JNK signaling was mediated by KLF5 transactivation of two key upstream regulators of the JNK pathway, ASK1 and MKK4, and inhibition of JNK blocked apoptosis and normalized cell survival following KLF5 induction. Thus, restoring KLF5 in ESCC cells promotes apoptosis and decreases cell survival in a JNK-dependent manner, providing a potential therapeutic target for human ESCC.
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11
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Guggenheim DE, Shah MA. Gastric cancer epidemiology and risk factors. J Surg Oncol 2012; 107:230-6. [PMID: 23129495 DOI: 10.1002/jso.23262] [Citation(s) in RCA: 360] [Impact Index Per Article: 27.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2012] [Accepted: 08/20/2012] [Indexed: 12/11/2022]
Abstract
Gastric cancer is a prevalent yet heterogeneous disease. From diet and lifestyle to genetics and ethnicity, our appreciation of the complexity of gastric cancer has evolved. This review will discuss the epidemiology of gastric cancer focusing on trends across various risk categories. We realize that gastric cancer is not merely a single disease, but rather individual diseases within a single organ-a distinction that will aid our understanding of disease heterogeneity and its significance.
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Affiliation(s)
- Douglas E Guggenheim
- Center for Advanced Digestive Care, New York-Presbyterian Hospital, Weill Cornell Medical College of Cornell University, New York, New York 10021, USA
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12
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Abstract
INTRODUCTION Esophageal cancer is an aggressive disease with poor prognosis. The majority of the patients are diagnosed at an advanced stage and many with early stage disease will develop recurrent disease. AREAS COVERED Angiogenesis is essential to the progress and aggressiveness of solid malignancies. Success of anti-angiogenic therapy in colorectal, lung and breast cancers is a proof of principle. Thus far, evidence for benefit from anti-angiogenic therapy in esophageal cancer is lacking. Several Phase II trials with different agents have provided mixed results and the only Phase III trial in the esophageal and gastric cancer failed to show that these agents improve overall survival (OS). However, lack of observed benefit could be due to the challenges specific to the management of esophageal cancers as well as issues with the design of clinical trials for anti-angiogenic therapy. EXPERT OPINION An understanding of the biology of the esophageal cancer and its management is essential to the development of anti-angiogenic therapy in this disease. This article reviews the management of esophageal cancer and elaborates on the challenges in the development of anti-angiogenic therapy in esophageal cancer. At the end, strategies are proposed for successful development of anti-angiogenic therapy in esophageal cancer.
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Affiliation(s)
- Afsaneh Barzi
- Keck School of Medicine, Medical Oncology, Norris Comprehensive Cancer Center, 1414 Eastlake Ave. Suite 3440, Los Angeles, CA 90033, USA.
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Yang J, Zhang G, Chen J. CCND1 G870A polymorphism is associated with increased risk of colorectal cancer, especially for sporadic colorectal cancer and in Caucasians: a meta-analysis. Clin Res Hepatol Gastroenterol 2012; 36:169-77. [PMID: 22322158 DOI: 10.1016/j.clinre.2011.11.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Revised: 11/10/2011] [Accepted: 11/25/2011] [Indexed: 02/04/2023]
Abstract
AIMS To detect the association between G870A polymorphism of cyclin D1 (CCND1) gene and colorectal cancer. METHODS We performed a systematic literature and abstract search using PubMed, EMBase digital database. Keywords included CCND1, cyclin D1, polymorphism, SNP, colon cancer, rectal cancer and colorectal cancer. "And", "OR" and "NOT" were used as conjunction to narrow and widen the search. Data were extracted by two investigators independently, and meta-analysis was carried out by using Review Manager 4.2.8. The following pairwised combinations of genotypes for the CCND1 G870A polymorphism were evaluated: AA vs. GG, AG vs. GG, AA+AG vs. GG. Subsequently, sub-group analyses for cancer type, ethnicity, and the family history were performed. Sensitivity analysis was conducted by excluding the articles deviated from Hardy-Weinberg equilibrium. RESULTS Using GG genotype as a reference, A carriers were associated with a significantly increased cancer risk (OR=1.15, 95%CI=1.06-1.25, P=0.001, P(heterogeneity)=0.130), especially with rectal cancer (OR=1.24, 95%CI=1.02-1.51, P=0.030, P(heterogeneity)=0.570) and sporadic colorectal cancer (OR=1.26, 95%CI=1.08-1.46, P=0.003, P(heterogeneity)=0.730). The effect of A carriers on cancer also existed in Caucasians (OR=1.19, 95%CI=1.06-1.32, P=0.002, P(heterogeneity)=0.100). CONCLUSIONS CCND1 G870A polymorphism is associated with the increased risk of colorectal cancer, especially for sporadic colorectal cancer and in Caucasians.
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Affiliation(s)
- Jing Yang
- Department of gastroenterology, the Third Affiliated Hospital of Suzhou University, Changzhou, China.
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Abstract
Recent epidemiological studies in Serbia revealed that gastric carcinoma is the third and the fifth main cause of cancer morbidity in men and women, respectively. Despite the declining incidence of gastric cancer, it remains the second most common cause of cancer-related deaths as it is worldwide. A well-defined carcinogenic inflammation-metaplasia-dysplasia-cancer sequence typically precedes the development of most gastric adenocarcinomas. Alterations such as gastric mucosal atrophy and intestinal metaplasia are merely markers of increased risk, while gastric epithelial dysplasia (GED) represent a direct precursor of cancer. DNA damage and increased mucosal proliferation secondary to H pylori infection, combined with a suitable host susceptibility phenotype (eg, genetic polymorphisms in interleukin IL-1B, IL-1RN, and tumor necrosis factor a TNF-alpha genes), are important factors in this progression pathway. However, only a small minority of patients infected with H. pylori eventually develops gastric cancer, and eradication of H pylori in these patients does not seem to eliminate the risk of cancer completely. It has been shown that atrophy may be a better indicator of risk of cancer than intestinal metaplasia, and remains to be validated in routine clinical practice according to recent proposal for new quantitative methods. It is often associated with pseudopyloric gland metaplasia in the gastric corpus mucosa, which expresses a type of trefoil peptide, the spasmolytic polypeptide (termed spasmolytic polypeptide-expressing metaplasia or SPEM) and has been shown to be linked more closely to gastric cancer than intestinal metaplasia. Better histological characterization of adenomatous (or type I), hyperplastic (foveolar or type II) and tubule-neck (mucocellular or type III) GED, two-tiered grading system (low and high grade dysplasia) as well as the introduction of Padova and Vienna international classifications of dysplasia seem to be more helpful in GED surveillance and comparative studies. A combination of histopathological features, serum markers such as pepsinogen I, and molecular tests that analyze host susceptibility polymorphisms and bacterial virulence factors, may allow development of strategies for early detection of cancer in the future. At present, pathobiology of gastric cancerogenesis is far from known, despite the progressive knowledge on predisposing environmental conditions and genetic and epigenetic abnormalities, including tumour suppressor genes, oncogenes, microsatellite instability and hypermethylation or the significance of E-cadherin mutational status association with hereditary diffuse gastric cancer syndrome. Recent evidence regarding the importance of several histopathologically derived prognostic factors, such as resection margin status and lymph node metastases and their implications have also been discussed. We aim to review these aspects, with special relevance to gastric cancer specimen reporting.
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Bashash M, Hislop TG, Shah AM, Le N, Brooks-Wilson A, Bajdik CD. The prognostic effect of ethnicity for gastric and esophageal cancer: the population-based experience in British Columbia, Canada. BMC Cancer 2011; 11:164. [PMID: 21554722 PMCID: PMC3112158 DOI: 10.1186/1471-2407-11-164] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2010] [Accepted: 05/09/2011] [Indexed: 11/17/2022] Open
Abstract
Background Gastric and esophageal cancers are among the most lethal human malignancies. Their epidemiology is geographically diverse. This study compares the survival of gastric and esophageal cancer patients among several ethnic groups including Chinese, South Asians, Iranians and Others in British Columbia (BC), Canada. Methods Data were obtained from the population-based BC Cancer Registry for patients diagnosed with invasive esophageal and gastric cancer between 1984 and 2006. The ethnicity of patients was estimated according to their names and categorized as Chinese, South Asian, Iranian or Other. Cox proportional hazards regression analysis was used to estimate the effect of ethnicity adjusted for patient sex and age, disease histology, tumor location, disease stage and treatment. Results The survival of gastric cancer patients was significantly different among ethnic groups. Chinese patients showed better survival compared to others in univariate and multivariate analysis. The survival of esophageal cancer patients was significantly different among ethnic groups when the data was analyzed by a univariate test (p = 0.029), but not in the Cox multivariate model adjusted for other patient and prognostic factors. Conclusions Ethnicity may represent underlying genetic factors. Such factors could influence host-tumor interactions by altering the tumor's etiology and therefore its chance of spreading. Alternatively, genetic factors may determine response to treatments. Finally, ethnicity may represent non-genetic factors that affect survival. Differences in survival by ethnicity support the importance of ethnicity as a prognostic factor, and may provide clues for the future identification of genetic or lifestyle factors that underlie these observations.
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Affiliation(s)
- Morteza Bashash
- Cancer Control Research Program, BC Cancer Agency, Vancouver, Canada
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16
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Zhang J, Wang K, Zhang J, Liu SS, Dai L, Zhang JY. Using proteomic approach to identify tumor-associated proteins as biomarkers in human esophageal squamous cell carcinoma. J Proteome Res 2011; 10:2863-72. [PMID: 21517111 DOI: 10.1021/pr200141c] [Citation(s) in RCA: 113] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Esophageal squamous cell carcinoma (ESCC) is one of the most common cancers in China. The lower survival rate of ESCC is attributed to late diagnosis and poor therapeutic efficacy; therefore, the identification of tumor-associated proteins as biomarkers for early diagnosis, and the discovery of novel targets for therapeutic intervention, seems very important for increasing the survival rate of ESCC. To identify tumor-associated proteins as biomarkers in ESCC, we have analyzed ESCC tissues and adjacent normal tissues by two-dimensional electrophoresis (2DE) and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) analysis. The results showed that a total of 104 protein spots with different expression levels were found on 2DE, and 47 proteins were eventually identified by MALDI-TOF MS. Among these identified proteins, 33 proteins including keratin 17 (KRT17), biliverdin reductase B (BLVRB), proteasome activator subunit 1 (PSME1), manganese superoxide dismutase (MnSOD), high-mobility group box-1(HMGB1), heat shock protein 70 (HSP70), peroxiredoxin (PRDX1), keratin 13 (KRT13), and so on were overexpressed, and 14 proteins including cystatin B (CSTB), tropomyosin 2 (TPM2), annexin 1 (ANX1), transgelin (TAGLN), keratin 19 (KRT19), stratifin (SFN), and so on were down-expressed in ESCC. Biological functions of these proteins are associated with cell proliferation, cell motility, protein folding, oxidative stress, and signal transduction. In the subsequent study using immunoassay on ESCC serum samples and tissue-array slides, two representative proteins, HSP70 and HMGB1, were selected as examples for the purpose of validation. The results showed that both HSP70 and HMGB1 can induce autoantibody response in ESCC sera and have higher expression in ESCC tissues. Especially, the frequency of antibodies to HSP70 in ESCC sera was significantly higher than that in normal human sera. The preliminary results suggest that some of these identified proteins might contribute to esophageal cell differentiation and carcinogenesis, certain proteins could be used as tumor-associated antigen (TAA) biomarkers in cancer diagnosis, and further studies on these identified proteins should provide more evidence of how these proteins are involved in carcinogenesis of ESCC.
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Affiliation(s)
- Jintao Zhang
- Henan key laboratory of Tumor Epidemiology & Proteomics Research Center, College of Public Health, Zhengzhou University, Zhengzhou, Henan, P.R. China
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Nautiyal J, Kanwar SS, Majumdar APN. EGFR(s) in aging and carcinogenesis of the gastrointestinal tract. Curr Protein Pept Sci 2011; 11:436-50. [PMID: 20491625 DOI: 10.2174/138920310791824110] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2010] [Accepted: 05/20/2010] [Indexed: 12/24/2022]
Abstract
Cells of the gastrointestinal (GI) mucosa are subject to a constant process of renewal which, in normal adults, reflects a balance between the rates of cell production and cell loss. Detailed knowledge of these events is, therefore, essential for a better understanding of the normal aging processes as well as many GI diseases, particularly malignancy, that represent disorders of tissue growth. In general, many GI dysfunctions, including malignancy, increase with advancing age, and aging itself is associated with alterations in structural and functional integrity of the GI tract. Although the regulatory mechanisms for age-related increase in the incidence of GI-cancers are yet to be fully delineated, recent evidence suggests a role for epidermal growth family receptors and its family members {referred to as EGFR(s)} in the development and progression of carcinogenesis during aging. The present communication discusses the involvement of EGFR(s) in regulating events of GI cancers during advancing age and summarizes the current available therapeutics targeting these receptors. The current review also describes the effectiveness of ErbB inhibitors as well as combination therapies. Additionally, the involvement of GI stem cells in the development of the age-related rise in GI cancers is emphasized.
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Affiliation(s)
- Jyoti Nautiyal
- Veterans Affairs Medical Center, Wayne State University, Detroit, MI 48201, USA
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18
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Odze RD, Maley CC. Neoplasia without dysplasia: lessons from Barrett esophagus and other tubal gut neoplasms. Arch Pathol Lab Med 2010; 134:896-906. [PMID: 20524867 DOI: 10.5858/134.6.896] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT Classic pathology teaching emphasizes that neoplastic lesions of the gastrointestinal tract are characterized by architectural and cytologic abnormalities that distinguish it from normal tissue. Recent studies suggest that many important-and in some cases clonal-molecular abnormalities that lead to dysregulation of cell proliferation and differentiation (neoplasia) occur before morphologic expression of dysplasia. OBJECTIVE To summarize the biologic and pathologic features of preneoplastic conditions of the tubal gut that reveal evidence of neoplastic alteration, but without the traditional morphologic features of dysplasia, in order to provide guidance on how to identify these lesions. Particular attention is given to Barrett esophagus, a chronic inflammatory condition in which early molecular and morphologic events that drive carcinogenesis are best understood. DATA SOURCES Selected references and abstracts were obtained by a PubMed (US National Library of Medicine) search by using the search headings neoplasia, preneoplasia, dysplasia, adenoma, serrated polyps, and Barrett's esophagus between the years 1980 and 2009. CONCLUSIONS Many types of lesions throughout the tubal gut fulfill the most basic and classic principles of a neoplastic precursor lesion but lack conventional morphologic evidence of dysplasia and/or maintain the capacity for cell differentiation and maturation. All of these lesions, such as squamous dysplasia of the esophagus, dysplasia in Barrett esophagus, and hyperplastic/serrated polyps of the colon, represent early neoplastic precursor lesions but without conventional histologic features of dysplasia. It is important for pathologists to be aware of these lesions, both for diagnostic and prognostic purposes, but also so that future studies can be performed with regard to risk stratification of patients.
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Affiliation(s)
- Robert D Odze
- Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
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19
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Xie HL, Li ZY, Gan RL, Li XJ, Zhang QL, Hui M, Zhou XT. Differential gene and protein expression in primary gastric carcinomas and their lymph node metastases as revealed by combined cDNA microarray and tissue microarray analysis. J Dig Dis 2010; 11:167-75. [PMID: 20579220 DOI: 10.1111/j.1751-2980.2010.00432.x] [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] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To gain insight into the molecular events of lymph node metastasis of human gastric carcinoma. METHODS The gene expression profile of five matched primary gastric carcinomas and their lymph node metastases was analyzed by complementary DNA (cDNA) microarray. Differential genes were identified in the metastatic and corresponding primary tumor pairs. Among the differentially expressed genes, carbonic anhydrase II (CAII) and insulin-like growth factor binding protein 4 (IGFBP 4) genes were detected by RT-PCR. CTTN protein expression was examined by tissue microarray. RESULTS There was a high expression (over twofold) of 44 genes and a low expression (under twofold) of 32 genes in lymph node metastasis compared with primary gastric carcinoma, respectively. CAII mRNA was downregulated and IGFBP 4 mRNA was upregulated in paired lymph node metastases of gastric carcinomas. The overexpression of CTTN protein was related to the lymph node metastasis and the clinical stage of gastric carcinomas. CONCLUSION This study showed that there is a low expression of genes relative to growth signal and immune response in lymph node metastases, and a high expression of genes relative to growth factor, cell cycle, cell motility and adhesion in lymph node metastases compared with primary gastric carcinomas. The expression of CTTN was related to the invasion and metastasis of gastric cancer.
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Affiliation(s)
- Hai Long Xie
- Cancer Research Institute, Medical College of University of South China, Hengyang, Hunan Province, China
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20
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Kanwar SS, Nautiyal J, Majumdar AP. EGFR(S) inhibitors in the treatment of gastro-intestinal cancers: what's new? Curr Drug Targets 2010; 11:682-98. [PMID: 20298154 PMCID: PMC3915939 DOI: 10.2174/138945010791170851] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2009] [Accepted: 12/18/2009] [Indexed: 01/01/2023]
Abstract
In the past 10 to 15 years, a considerable progress has been made in the treatment of gastrointestinal (GI) related malignancies, as number of agents expanded from only one in 1995 to seven in 2006. Current review describes the recent role of targeted therapies, specifically EGFR inhibitors in the treatment of GI cancers. Importance of dietary agents in the treatment and prevention of GI cancers is also reviewed.
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Affiliation(s)
- Shailender Singh Kanwar
- Veterans Affairs Medical Center, Wayne State University, Detroit, Ml 48201, USA
- Department of Internal Medicine, Wayne State University, Detroit, Ml 48201, USA
| | - Jyoti Nautiyal
- Veterans Affairs Medical Center, Wayne State University, Detroit, Ml 48201, USA
- Department of Internal Medicine, Wayne State University, Detroit, Ml 48201, USA
- Karmanos Cancer Institute, Wayne State University, Detroit, Ml 48201, USA
| | - Adhip P.N. Majumdar
- Veterans Affairs Medical Center, Wayne State University, Detroit, Ml 48201, USA
- Department of Internal Medicine, Wayne State University, Detroit, Ml 48201, USA
- Karmanos Cancer Institute, Wayne State University, Detroit, Ml 48201, USA
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21
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Ku GY, Ilson DH. Esophagogastric cancer: targeted agents. Cancer Treat Rev 2010; 36:235-48. [PMID: 20122806 DOI: 10.1016/j.ctrv.2009.12.009] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2009] [Revised: 12/09/2009] [Accepted: 12/14/2009] [Indexed: 02/07/2023]
Abstract
Because of the poor prognosis for patients with locally advanced and metastatic esophageal, gastroesophageal junction and gastric cancers, increasing attention has focused on the integration of targeted agents into current therapies. The molecular targets of these agents include epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF) or its receptor, cyclooxygenase-2 (COX-2), mammalian target of rapamycin (mTOR) and components and regulators of the cell cycle. In this review article, we briefly discuss pre-clinical data and the rationale for targeting these pathways and summarize the results of clinical trials to-date, including completed and ongoing phase III evaluations.
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Affiliation(s)
- Geoffrey Y Ku
- Ludwig Center for Cancer Immunotherapy, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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22
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Lysine 269 is essential for cyclin D1 ubiquitylation by the SCF(Fbx4/alphaB-crystallin) ligase and subsequent proteasome-dependent degradation. Oncogene 2010; 28:4317-25. [PMID: 19767775 PMCID: PMC2794935 DOI: 10.1038/onc.2009.287] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
Protein ubiquitylation is a complex enzymatic process that results in the covalent attachment of ubiquitin, via Gly-76 of ubiquitin, to an ε-NH2-group of an internal lysine residue in a given substrate. While E3 ligases frequently utilize lysines adjacent to the degron within the substrate, many substrates can be targeted to the proteasome via polyubiquitylation of any lysine. We have assessed the role of lysine residues proximal to the cyclin D1 phosphodegron for ubiquitylation by the SCFFbx4/αB-crystallin ubiquitin ligase and subsequent proteasome-dependent degradation of cyclin D1. The work described herein reveals a requisite role for Lys-269 (K269) for the rapid, poly-ubiquitin mediated degradation of cyclin D1. Mutation of lysine 269, which is proximal to the phosphodegron sequence surrounding Thr-286 in cyclin D1, not only stabilizes cyclin D1, but also triggers cyclin D1 accumulation within the nucleus thereby promoting cell transformation. In addition, D1-K269R is resistant to genotoxic stress induced degradation, similar to non-phosphorylatable D1-T286A, supporting the critical role for the post-translational regulation of cyclin D1 in the response to DNA damaging agents. Strikingly, while mutation of lysine 269 to arginine inhibits cyclin D1 degradation, it does not inhibit cyclin D1 ubiquitylation in vivo demonstrating that ubiquitylation of a specific lysine can influence substrate targeting to the 26S proteasome.
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23
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Abstract
Carcinoma of the oesophagus including carcinoma of gastro-oesophageal junction are rapidly increasing in incidence. During recent years there have been changes in the knowledge surrounding biology of the disease progression. Identification of dysplasia in mucosal biopsies is the most reliable pathologic indicator of an increased risk of development of squamous cell carcinoma and passes through the sequence of chronic esophagitis, low-grade and high-grade dysplasia and invasive carcinoma. Although Barrett's esophagus is a precursor to esophageal adenocarcinoma and have a well described sequence of carcinogenesis: the Barrett's metaplasia-dysplasia-adenocarcinoma sequence, not all patients with this disorder require intensive surveillance. The natural history of dysplasia is poorly understood, particularly in low-risk regions, and prospective follow-up studies are needed. Adjunctive methods to improve reproducibility, such as immunostaining for alpha-methylacyl-coenzyme A racemase (AMACR), show promise, but require confirmation in larger studies. In addition, several controversial methods such as detection of p16, p53, and DNA content abnormalities may help identify patients at particularly high risk for progression to cancer, but these techniques are not yet widely available for routine clinical application. More studies are needed to define other early nonmorphologic biomarkers for risk of squamous cell carcinoma. Recent evidence regarding the importance of several histopathologically derived prognostic factors, such as circumferential resection margin status and lymph node metastases are evaluated, including lymph node micrometastases and the sentinel node concept. With the rising use of multimodal treatments for oesophageal cancer it is important that the response of the tumour to this therapy can be carefully documented by histopathology.
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24
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Arrington AK, Davydova J, Vickers SM, Yamamoto M. Anti-ERBB2 sh-RNA suppress both cell growth and tumor growth in ERBB2-overexpressing upper gastrointestinal adenocarcinomas. J Gastrointest Surg 2009; 13:1754-61. [PMID: 19813066 PMCID: PMC5093911 DOI: 10.1007/s11605-009-0957-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2009] [Accepted: 06/12/2009] [Indexed: 01/31/2023]
Abstract
INTRODUCTION ERBB2 is overexpressed in 15-25% of upper gastrointestinal adenocarcinomas. We use a stable lentiviral shRNA model to demonstrate that ERBB2 suppression in upper gastrointestinal adenocarcinomas with documented ERBB2 amplification effectively decreases ERBB2 protein levels and decreases cell viability. Further, we evaluate tumor growth of cells treated with the ERBB2 shRNA. METHODS Three upper gastrointestinal adenocarcinoma cells lines with varying ERBB2 levels were treated with one of three separate lentiviral green fluorescent protein (GFP)-labeled ERBB2 shRNA vectors or a nonsilencing control shRNA vector for 6 h. Protein levels on day 6 and cell viability was evaluated on days 3-10. A xenograft in vivo experiment was performed using OE19 cells pretransduced with ERBB2 shRNA to evaluate tumor growth. RESULTS ERBB2 protein levels decreased by 80%. ERBB2 knockdown significantly decreased cell viability in cell lines with high ERBB2 levels. In vivo tumor growth was suppressed in ERBB2-shRNA-treated groups. CONCLUSION ERBB2 suppression based on a stable lentiviral shRNA transfection system effectively decreases cell viability in cell lines with amplification of ERBB2 as compared to cell lines without overexpression. ERBB2 knockdown significantly decreases tumor growth in vivo. ERBB2-directed therapy may be of benefit in the subset of patients with gastrointestinal adenocarcinomas exhibiting overamplification of ERBB2.
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Affiliation(s)
- Amanda K Arrington
- Department of Surgery, University of Minnesota, 420 Delaware St SE, MMC195, Minneapolis, MN 55455, USA
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25
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Arrington AK, Dahlberg PS, Davydova J, Vickers SM, Yamamoto M. ERBB2 suppression decreases cell growth via apoptosis in gastrointestinal adenocarcinomas. Surgery 2009; 146:213-9. [PMID: 19628076 DOI: 10.1016/j.surg.2009.04.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2009] [Accepted: 04/06/2009] [Indexed: 02/07/2023]
Abstract
BACKGROUND Although the incidence of adenocarcinoma of the esophageal and gastroesophageal junction has increased at an alarming rate in the past 30 years, little improvement has been made in treatment strategies. Previous studies have demonstrated that many upper gastrointestinal (GI) adenocarcinomas exhibit ERBB2 amplification. In cancers proven to have similar amplification, such as breast, ERBB2-targeted therapies have dramatically improved overall survival and disease-free rates of survival. This study uses siRNA to knockdown ERBB2 in GI adenocarcinoma cell lines to evaluate cell viability, apoptosis, and changes in cell cycle. METHODS A cell line with a baseline amount of ERBB2 (Seg-1) and 2 upper GI adenocarcinoma cell lines with known amplification of ERBB2 (esophageal [OE19] and gastric [MKN45]) were treated with 120 pmol of 1 of 2 independent ERBB2 siRNAs or control siRNA for 6 hours. RESULTS We demonstrate that knockdown of ERBB2 in esophageal and gastric cancer cell lines with known ERBB2 amplification effectively decreases ERBB2 protein levels and decreases cell viability mainly via apoptotic pathways. CONCLUSION ERBB-directed therapy may be of benefit in the subset of patients with GI adenocarcinomas exhibiting amplification of ERBB2.
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Affiliation(s)
- Amanda K Arrington
- Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA
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26
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Wang B, Khachigian LM, Esau L, Birrer MJ, Zhao X, Parker MI, Hendricks DT. A key role for early growth response-1 and nuclear factor-kappaB in mediating and maintaining GRO/CXCR2 proliferative signaling in esophageal cancer. Mol Cancer Res 2009; 7:755-64. [PMID: 19435811 DOI: 10.1158/1541-7786.mcr-08-0472] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Although early growth response-1 (EGR-1) has been shown as a key transcription factor in controlling cell growth, proliferation, differentiation, and angiogenesis, its role in the development of esophageal cancer is poorly understood despite the high frequency of this disease in many parts of the world. Here, immunohistochemistry showed that EGR-1 is overexpressed in 80% of esophageal tumor tissues examined. Furthermore, EGR-1 is constitutively expressed in all esophageal cancer cell lines analyzed. Esophageal squamous carcinoma WHCO1 cells stably transfected with EGR-1 short hairpin RNA displayed a 55% reduction in EGR-1 protein levels, 50% reduction in cell proliferation, a 50% reduction in cyclin-dependent kinase 4 levels, and a 2-fold induction in p27(Kip1) levels associated with a G(2)-M cell cycle arrest. EGR-1 knockdown also caused a marked induction in IkappaBalpha expression, an effect also observed in GRObeta RNA interference-expressing WHCO1 cells, because EGR-1 lies downstream of GRO/CXCR2 signaling. Furthermore, p65 mRNA levels were also reduced in cells treated with either short hairpin RNA EGR-1 or small interfering RNA EGR-1. Immunohistochemical analysis indicated that p65 is elevated in 78% (n = 61) of esophageal tumor sections analyzed. Moreover, nuclear factor-kappaB inhibition with either sodium salicylate or p65 RNA interference led to a significant reduction in GROalpha and GRObeta expression. These results indicate that EGR-1 and nuclear factor-kappaB mediate GRO/CXCR2 proliferative signaling in esophageal cancer and may represent potential target molecules for therapeutic intervention.
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Affiliation(s)
- Bo Wang
- Division of Medical Biochemistry, Institute of Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa
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27
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Cescon DW, Bradbury PA, Asomaning K, Hopkins J, Zhai R, Zhou W, Wang Z, Kulke M, Su L, Ma C, Xu W, Marshall AL, Heist RS, Wain JC, Lynch TJ, Christiani DC, Liu G. p53 Arg72Pro and MDM2 T309G polymorphisms, histology, and esophageal cancer prognosis. Clin Cancer Res 2009; 15:3103-9. [PMID: 19383811 DOI: 10.1158/1078-0432.ccr-08-3120] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
PURPOSE This study aimed to evaluate the prognostic significance of two functional single nucleotide polymorphisms (SNP) in the p53 pathway (p53 Arg72Pro and MDM2 T309G) in patients with esophageal cancer, and to determine the importance of histologic subtype in the SNP-outcome relationships. EXPERIMENTAL DESIGN A cohort of 371 patients with esophageal carcinoma enrolled in Boston, USA from 1999 to 2004 were genotyped for the p53 and MDM2 SNPs. Associations between genotypes and overall survival (OS; the primary outcome) and progression-free survival (PFS) were assessed using the Kaplan-Meier method. Cox proportional hazard models, adjusted for age, stage, performance status, and smoking were developed. Interaction analyses were done for histology (adenocarcinoma versus squamous cell carcinoma). RESULTS At the median follow-up of 33 months, median survival (MS) and PFS were 29.1 and 15.7 months, respectively. p53 Pro/Pro was strongly associated with shorter survival in the entire cohort (MS of 11.8 versus 29.1 months, P < 0.0001; adjusted hazard ratio for death, 2.05; 95% confidence interval, 1.30-3.24; P = 0.002 for Pro/Pro versus Arg/Arg). MDM2 G/G was associated with markedly reduced survival in squamous cell carcinoma (MS of 10.3 versus 49.4 months; adjusted hazard ratio for death, 7.9; 95% confidence interval, 2.4-26.0; P = 0.0007 for G/G versus T/T) but not in adenocarcinoma (SNP-histology interaction P = 0.004). CONCLUSIONS In a large prospective cohort, p53 Arg72Pro Pro/Pro was associated with a 2-fold increased risk of death in all esophageal cancers, whereas MDM2 T309G G/G was associated with a 7-fold increased risk of death in squamous cell carcinoma.
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Affiliation(s)
- David W Cescon
- Department of Medical Biophysics, Princess Margaret Hospital, University of Toronto, Canada
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Morisawa T, Marusawa H, Ueda Y, Iwai A, Okazaki IM, Honjo T, Chiba T. Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression. Int J Cancer 2009; 123:2735-40. [PMID: 18781563 DOI: 10.1002/ijc.23853] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Various molecular changes characterizing organ-specific carcinogenesis have been identified in human tumors; however, the molecular mechanisms of the genomic changes specific for each cancer are not well defined. A transgenic (Tg) mouse model with constitutive expression of the nucleotide-editing enzyme, activation-induced cytidine deaminase (AID), develops tumors in various organs as a result of the mutagenic activities of AID. This phenotypic character of AID Tg mice allowed us to analyze the organ-specific genetic changes in tumor-related genes commonly triggered by AID-mediated mutagenesis. Among the 80 AID Tg mice analyzed, 11 mice developed hepatocellular carcinomas, and 7 developed lung cancers. In addition, 1 developed the gastric cancer and 3 developed gastric adenomas. Organ-specific preferences for nucleotide changes were observed in some of the tumor-related genes in each epithelial tissue of the AID Tg mice. Of note, the c-myc and K-ras genes were the preferential targets of the mutagenic activity of AID in lung and stomach cancers, respectively, whereas mutations in the p53 and beta-catenin genes were commonly observed in all 3 organs. Quantitative RT-PCR analyses revealed that alpha-fetoprotein, insulin-like growth factor-2 and cyclin D1 genes were specifically upregulated in HCC, whereas upregulation of the matrix metalloproteinase-7 gene was more marked in lung cancer. Our findings suggest that AID, a DNA mutator that plays a critical role linking inflammation to human cancers, might be involved in the generation of organ-specific genetic diversity in oncogenic pathways during cancer development.
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Affiliation(s)
- Toshiyuki Morisawa
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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29
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Paulson TG, Galipeau PC, Xu L, Kissel HD, Li X, Blount PL, Sanchez CA, Odze RD, Reid BJ. p16 mutation spectrum in the premalignant condition Barrett's esophagus. PLoS One 2008; 3:e3809. [PMID: 19043591 PMCID: PMC2585012 DOI: 10.1371/journal.pone.0003809] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2008] [Accepted: 11/06/2008] [Indexed: 02/08/2023] Open
Abstract
Background Mutation, promoter hypermethylation and loss of heterozygosity involving the tumor suppressor gene p16 (CDKN2a/INK4a) have been detected in a wide variety of human cancers, but much less is known concerning the frequency and spectrum of p16 mutations in premalignant conditions. Methods and Findings We have determined the p16 mutation spectrum for a cohort of 304 patients with Barrett's esophagus, a premalignant condition that predisposes to the development of esophageal adenocarcinoma. Forty seven mutations were detected by sequencing of p16 exon 2 in 44 BE patients (14.5%) with a mutation spectrum consistent with that caused by oxidative damage and chronic inflammation. The percentage of patients with p16 mutations increased with increasing histologic grade. In addition, samples from 3 out of 19 patients (15.8%) who underwent esophagectomy were found to have mutations. Conclusions The results of this study suggest the environment of the esophagus in BE patients can both generate and select for clones with p16 mutations.
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Affiliation(s)
- Thomas G Paulson
- Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America.
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Shimizu M, Ban S, Odze RD. Squamous dysplasia and other precursor lesions related to esophageal squamous cell carcinoma. Gastroenterol Clin North Am 2007; 36:797-811, v-vi. [PMID: 17996791 DOI: 10.1016/j.gtc.2007.08.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Squamous cell carcinoma is the most common tumor of the esophagus worldwide, and it is believed to develop through a sequence of dysplastic precursor lesions, which can be detected both endoscopically and microscopically. There are no published guidelines regarding treatment for dysplasia; however, most authorities recommend increased endoscopic surveillance, with biopsies, for patients with flat low-grade dysplasia and endoscopic mucosal resection, endoscopic submucosal dissection, or esophagectomy for patients with high-grade dysplasia. Future studies are needed to define appropriate endoscopic surveillance frequencies for patients with premalignant lesions of the esophagus. This article discusses squamous dysplasia in detail, which is the most important and well-described risk factor for squamous cell carcinoma of the esophagus.
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Affiliation(s)
- Michio Shimizu
- Department of Pathology, Saitama Medical University International Medical Center, 1397-1 Yamane, Hidaka City, Saitama 350-1298, Japan.
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Abstract
New growth in the vascular network is important since the proliferation, as well as metastatic spread, of cancer cells depends on an adequate supply of oxygen and nutrients and the removal of waste products. New blood and lymphatic vessels form through processes called angiogenesis and lymphangiogenesis, respectively. Angiogenesis is regulated by both activator and inhibitor molecules. More than a dozen different proteins have been identified as angiogenic activators and inhibitors. Levels of expression of angiogenic factors reflect the aggressiveness of tumor cells. The discovery of angiogenic inhibitors should help to reduce both morbidity and mortality from carcinomas. Thousands of patients have received antiangiogenic therapy to date. Despite their theoretical efficacy, antiangiogeic treatments have not proved beneficial in terms of long-term survival. There is an urgent need for a new comprehensive treatment strategy combining antiangiogenic agents with conventional cytoreductive treatments in the control of cancer.
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Affiliation(s)
- Naoyo Nishida
- Department of Pathology, Research Center of Innovative Cancer Therapy of the 21 Century, COE Program for Medical Science, Kurume University School of Medicine, Fukuoka, Japan.
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32
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Carneiro F, Chaves P. Pathologic Risk Factors of Adenocarcinoma of the Gastric Cardia and Gastroesophageal Junction. Surg Oncol Clin N Am 2006; 15:697-714. [PMID: 17030268 DOI: 10.1016/j.soc.2006.07.012] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Available evidence supports the existence of two major pathways of neoplastic development in the gastroesophageal region: the Barrett pathway, related to gastroesophageal reflux disease, and the gastric pathway, related to Helicobacter pylori infection. The existence of an independent junctional pathway is questionable, and gastroesophageal junction adenocarcinomas share features of esophageal and gastric adenocarcinomas. It has been impossible to accommodate all data that are provided by different levels and tools of observation in tumors that develop in the gastroesophageal region in a single, coherent classification. That is why the stratification of pathologic risk in such tumors, and their respective precursors, incorporates features from topography, histology, immunohistochemistry, and molecular pathology.
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Affiliation(s)
- Fátima Carneiro
- Medical Faculty of the University of Porto and Hospital S.João, Alameda Prof. Hernâni Monteiro, 4200-319 Porto, Portugal.
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33
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Langer R, Von Rahden BHA, Nahrig J, Von Weyhern C, Reiter R, Feith M, Stein HJ, Siewert JR, Höfler H, Sarbia M. Prognostic significance of expression patterns of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor in oesophageal adenocarcinoma: a tissue microarray study. J Clin Pathol 2006; 59:631-4. [PMID: 16731604 PMCID: PMC1860401 DOI: 10.1136/jcp.2005.034298] [Citation(s) in RCA: 77] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
AIMS To correlate immunohistochemical expression patterns and prognosis in oesophageal adenocarcinoma. METHODS The expression of c-erbB-2, p53, p16INK4A, p27KIP1, cyclin D1 and epidermal growth factor receptor (EGFR) was studied in a series of 137 primarily resected oesophageal adenocarcinoma samples. The expression analysis on protein level was performed on routine paraffin wax-embedded material, with immunohistochemical staining of the samples, assembled on a tissue microarray. The results were correlated with clinicopathological features (pT, pN and G) and survival. RESULTS 22 (16%) tumours showed an overexpression of the c-erbB-2 oncoprotein. Expression of EGFR was observed in 72 (55%) cases, accumulation of p53 in 68 (52%) cases and of cyclin D1 in 102 (77%) cases. Loss of p16INK4A expression was observed in 101 (76%) cases and low expression of p27KIP1 in 91 (71%) cases. Expression of these proteins did not correlate with tumour stage, grade, Lauren's or World Health Organization classification or lymph node status. On univariate survival analysis, more advanced tumour stage (p = 0.002), lymph node involvement (p = 0.003), high tumour grade (p = 0.017) and lack of EGFR expression (p = 0.034) were found to be associated with poorer survival. On multiple regression analysis, only tumour stage (p = 0.03) and lymph node involvement (p = 0.004) were shown to have an association with the survival of the patient. CONCLUSION The immunohistochemical expression of c-erbB-2 oncoprotein, cylin D1, p16INK4A, p27KIP1, p53 and EGFR in most oesophageal adenocarcinomas suggests their implication in the pathogenesis of this entity. None of the molecular markers assessed, however, was of prognostic value. Identification of any marker superior to or even approaching the prognostic value of conventional histopathological markers (pT and pN) was therefore not possible.
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Affiliation(s)
- R Langer
- Institut für Pathologie, Technical University, München, Germany.
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Shukla SD, Aroor AR. Epigenetic effects of ethanol on liver and gastrointestinal injury. World J Gastroenterol 2006; 12:5265-71. [PMID: 16981253 PMCID: PMC4088190 DOI: 10.3748/wjg.v12.i33.5265] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2006] [Revised: 05/28/2006] [Accepted: 07/07/2006] [Indexed: 02/06/2023] Open
Abstract
Alcohol consumption causes cellular injury. Recent developments indicate that ethanol induces epigenetic alterations, particularly acetylation, methylation of histones, and hypo- and hypermethylation of DNA. This has opened up a new area of interest in ethanol research and is providing novel insight into actions of ethanol at the nucleosomal level in relation to gene expression and patho-physiological consequences. The epigenetic effects are mainly attributable to ethanol metabolic stress (Emess), generated by the oxidative and non-oxidative metabolism of ethanol, and dysregulation of methionine metabolism. Epigenetic changes are important in ethanol-induced hepatic steatosis, fibrosis, carcinoma and gastrointestinal injury. This editorial highlights these new advances and its future potential.
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Benzeno S, Lu F, Guo M, Barbash O, Zhang F, Herman JG, Klein PS, Rustgi A, Diehl JA. Identification of mutations that disrupt phosphorylation-dependent nuclear export of cyclin D1. Oncogene 2006; 25:6291-303. [PMID: 16732330 DOI: 10.1038/sj.onc.1209644] [Citation(s) in RCA: 108] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Although cyclin D1 is overexpressed in a significant number of human cancers, overexpression alone is insufficient to promote tumorigenesis. In vitro studies have revealed that inhibition of cyclin D1 nuclear export unmasks its neoplastic potential. Cyclin D1 nuclear export depends upon phosphorylation of a C-terminal residue, threonine 286, (Thr-286) which in turn promotes association with the nuclear exportin, CRM1. Mutation of Thr-286 to a non-phosphorylatable residue results in a constitutively nuclear cyclin D1 protein with significantly increased oncogenic potential. To determine whether cyclin D1 is subject to mutations that inhibit its nuclear export in human cancer, we have sequenced exon 5 of cyclin D1 in primary esophageal carcinoma samples and in cell lines derived from esophageal cancer. Our work reveals that cyclin D1 is subject to mutations in primary human cancer. The mutations identified specifically disrupt phosphorylation of cyclin D1 at Thr-286, thereby enforcing nuclear accumulation of cyclin D1. Through characterization of these mutants, we also define an acidic residue within the C-terminus of cyclin D1 that is necessary for recognition and phosphorylation of cyclin D1 by glycogen synthase kinase-3 beta. Finally, through construction of compound mutants, we demonstrate that cell transformation by the cancer-derived cyclin D1 alleles correlates with their ability to associate with and activate CDK4. Our data reveal that cyclin D1 is subject to mutations in primary human cancer that specifically disrupt phosphorylation-dependent nuclear export of cyclin D1 and suggest that such mutations contribute to the genesis and progression of neoplastic growth.
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Affiliation(s)
- S Benzeno
- Department of Cancer Biology, The Leonard and Madlyn Abramson Family Cancer Research Institute and Cancer Center, University of Pennsylvania, Philadelphia, PA 19104, USA
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Kim MS, Yamashita K, Baek JH, Park HL, Carvalho AL, Osada M, Hoque MO, Upadhyay S, Mori M, Moon C, Sidransky D. N-methyl-D-aspartate receptor type 2B is epigenetically inactivated and exhibits tumor-suppressive activity in human esophageal cancer. Cancer Res 2006; 66:3409-18. [PMID: 16585162 DOI: 10.1158/0008-5472.can-05-1608] [Citation(s) in RCA: 87] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Promoter hypermethylation accompanied by gene silencing is a common feature of human cancers. We identified previously several new tumor suppressor genes based on pharmacologic unmasking of the promoter region and detection of reexpression on microarray analysis. In this study, we modified the selection of candidates from our previous microarray data by excluding genes that showed basal expression in cancer cell lines. With the new method, we found novel methylated genes with 90% accuracy. Among these 33 novel methylated genes that we identified in esophageal squamous cell carcinoma (ESCC) cell lines, N-methyl-D-aspartate receptor type 2B (NMDAR2B) was of particular interest. NMDAR2B was methylated in 95% of primary human ESCC tissue specimens and 12 ESCC cell lines by sequence analysis. NMDAR2B expression was silenced in all 12 ESCC cell lines and was reactivated by the demethylating agent 5-aza-2'-deoxycytidine. Moreover, reintroduction of the gene was accompanied by marked Ca(2+)-independent apoptosis in ESCC cell lines, suggesting that NMDAR2B can suppress tumor growth. Thus, NMDAR2B promoter methylation is common in ESCC, abrogating gene transcription and leading to cellular resistance to apoptosis.
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Affiliation(s)
- Myoung Sook Kim
- Department of Otolaryngology, Head and Neck Cancer Research Division, Institute of Cell Engineering, Johns Hopkins University School of Medicine, 818 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196, USA
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Abstract
Gastric cancer is the fourth most commonly diagnosed cancer and is the second leading cause of cancer death worldwide. More than 50% of patients undergo surgery, but even after a curative resection, 60% of patients relapse locally or with distant metastases. Despite the fact that many advances have occurred in the management of gastric cancer, it continues to carry a poor prognosis, amplifying the importance of palliative chemotherapy. When compared with best supportive care alone, combination chemotherapy yields a significant advantage in the management of advanced gastric cancer. However, no single regimen has emerged or been accepted as clearly superior over another. Numerous phase II studies have demonstrated promising results with newer agents including irinotecan, docetaxel, capecitabine, S-1, and oxaliplatin. Recently reported phase III results with these agents now demonstrate positive developments in the treatment options for patients with advanced gastric cancer.
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Affiliation(s)
- Jaffer A Ajani
- University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Box 426, Houston, Texas 77030, USA.
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Powell EL, Leoni LM, Canto MI, Forastiere AA, Iocobuzio-Donahue CA, Wang JS, Maitra A, Montgomery E. Concordant loss of MTAP and p16/CDKN2A expression in gastroesophageal carcinogenesis: evidence of homozygous deletion in esophageal noninvasive precursor lesions and therapeutic implications. Am J Surg Pathol 2006; 29:1497-504. [PMID: 16224217 DOI: 10.1097/01.pas.0000170349.47680.e8] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The gene that encodes methylthioadenosine phosphorylase (MTAP), an enzyme involved in adenine and methionine salvage pathways, is located on chromosome 9p21 telomeric to the p16INK4A/CDKN2A tumor suppressor gene. Inactivation of the p16INK4A/CDKN2A gene occurs by three different mechanisms: hypermethylation of the gene promoter, intragenic mutation coupled with loss of the second allele, and homozygous deletion. Immunohistochemical labeling for the p16INK4A/CDKN2A gene product parallels gene status but does not elucidate the mechanism of gene inactivation. Since the MTAP gene is often co-deleted with p16INK4A/CDKN2A, concurrent immunolabeling for both proteins can identify cases with homozygous p16INK4A/CDKN2A gene deletion. MTAP loss itself has therapeutic implications since it may confer selective sensitivity to inhibitors of de novo purine biosynthesis, such as L-alanosine. Twelve tissue microarrays were constructed from 92 cases of Barrett-associated adenocarcinomas and precursor lesions and 112 cases of gastric adenocarcinoma and precursor lesions comprising 1161 individual cores. Multiple cores were arrayed from any given case, and when available, included the entire histologic spectrum of intestinal metaplasia-dysplasia-carcinoma. Tissue microarrays were labeled with monoclonal antibodies against MTAP protein (clone 6.9, Salmedix, Inc) and p16 (clone 16P07, Neomarkers). Complete loss of labeling was considered negative, while any labeling (p16: nuclear; MTAP: cytoplasmic and nuclear) was considered positive. Loss of MTAP labeling occurred exclusively in conjunction with loss of p16 labeling, confirming that the previous findings from this group that concurrent loss of MTAP and p16 labeling is a surrogate marker of 9p21 homozygous deletions. Complete loss of MTAP and p16 was seen in 4 of 25 (16%) patients with Barrett's esophagus, 4 of 18 (22%) with low-grade dysplasia, 5 of 39 (13%) with high-grade dysplasia, 17 of 78 (22%) with invasive adenocarcinoma, and 8 of 36 (22%) of metastases. There were 7 cases of esophageal adenocarcinoma with loss of both MTAP and p16 for which precursor lesions were available. In 6 on these 7 cases (85%), the precursor lesion(s) had loss of both MTAP and p16. Lack of MTAP and p16 expression was seen in 11 of 106 (10%) cases of gastric adenocarcinoma. All metaplastic (30 biopsies from 20 cases) and dysplastic (15 biopsies from 13 cases) gastric tissues had both intact MTAP and p16INK4A/CDKN2A gene products. No precursor lesions were available from the gastric cancers that had loss of both MTAP and p16. Two benign gastric hyperplastic polyps also had intact p16 and MTAP. Concurrent MTAP and p16 loss detected by immunohistochemistry can serve as a convenient surrogate for p16INK4A/CDKN2A gene homozygous deletion in archival tissues. Inactivation of p16INK4A/CDKN2A by homozygous deletion appears to be an early event in Barrett carcinogenesis, occurring in noninvasive precursor lesions, including nondysplastic Barrett mucosa, in subsets of cases. In the absence of MTAP, cells depend exclusively on the de novo synthesis pathway for production of adenosine. This loss of MTAP during 9p21 homozygous deletion might be exploited therapeutically using de novo purine synthesis antimetabolites to treat a subset of invasive gastroesophageal adenocarcinomas and esophageal precursor lesions.
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Affiliation(s)
- Eric L Powell
- Department of Pathology, Johns Hopkins University, Baltimore, MD, USA
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Forshaw MJ, Gossage JA, Mason RC. Neoadjuvant chemotherapy for oesophageal cancer: The need for accurate response prediction and evaluation. Surgeon 2005; 3:373-82, 422. [PMID: 16353857 DOI: 10.1016/s1479-666x(05)80047-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Primary surgical resection for locally advanced oesophageal cancer is associated with systemic failure and poor survival due to presence of micrometastatic disease at the time of diagnosis. Neoadjuvant chemotherapy prior to surgical resection aims to downstage these locally advanced tumours. A review of reported randomised controlled trials has shown only one sufficiently powered trial with a survival advantage for cisplatin-based chemotherapy. Published meta-analyses of neoadjuvant chemotherapy trials have shown little or no overall survival benefit. A subgroup of patients with biologically favourable tumours who respond to this treatment have been consistently shown to have a survival advantage. These patients need to be differentiated from non-responders preferably at an early stage of this potentially toxic treatment. Current clinical, endoscopic and radiological methods of response evaluation are all unreliable. Response evaluation with 18FDG-PET has been shown to accurately assess the pathological response and also to predict the risk of local recurrence and overall survival. The development of integrated PET/CT imaging may enhance the accuracy of this response evaluation. In the future, molecular markers of response prediction prior to initiation of treatment may allow the development of individualised treatment strategies. New emerging chemotherapeutic agents may prove to be more effective in eradicating micrometastatic disease.
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Affiliation(s)
- M J Forshaw
- Department of General Surgery, Guy's and St Thomas' NHS Foundation Trust, St Thomas' Hospital, London, UK.
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Geddert H, Kiel S, Zotz RB, Zhang J, Willers R, Gabbert HE, Sarbia M. Polymorphism of p16 INK4A and cyclin D1 in adenocarcinomas of the upper gastrointestinal tract. J Cancer Res Clin Oncol 2005; 131:803-8. [PMID: 16163549 DOI: 10.1007/s00432-005-0021-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2005] [Accepted: 06/30/2005] [Indexed: 01/10/2023]
Abstract
PURPOSE We investigated the prevalence of single nucleotide polymorphisms in the p16 gene (C540G) and the cyclin D1 gene (G870A), both known to regulate function in G1 arrest and therefore, may play an important role in carcinogenesis. METHODS Using PCR based restriction fragment length polymorphism and single strand conformational polymorphism, we determined single nucleotide exchanges in the p16 and cyclin D1 genes among 56 esophageal adenocarcinomas (ADC) arising in Barrett's esophagus, 95 cardiac gastric ADC, and in 191 distal gastric ADC. The allelic frequencies were compared to a control group of 253 healthy blood donors. RESULTS The C/G genotype of p16 was identified in 10.4% of esophageal carcinomas, 13.3% of cardiac carcinomas, and in 14.1% of gastric carcinomas, compared to 17.4% in the healthy control group. All other cases showed the C/C wildtype, as no homozygous G/G nucleotide exchange was detected in the group of cancer patients or in the control group. In esophageal cancer, cyclin D1 G/G genotype was found 28.6%, A/G in 46.4%, and A/A in 25.0%. In cardiac carcinoma, frequency of cyclin D1 genotype was 27.4% for G/G, 57.9% for A/G, and 14.7% for AA. In distal gastric carcinoma, both homozygous genotypes (G/G and A/A) had a frequency of 15.2% each, while the heterozygous A/G genotype occurred in 69.6% of patients. The control group displayed 24.9% G/G, 53.8% A/G, and 21.3% A/A genotype. CONCLUSIONS Our results show that frequencies of p16 or cyclin D1 polymorphisms in gastric and esophageal ADC do not differ significantly from the healthy control group. Therefore, these polymorphisms are unlikely to be associated with risk of ADC of the upper gastrointestinal tract.
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Affiliation(s)
- Helene Geddert
- Institute of Pathology, Heinrich-Heine-University, Postfach 101007, 40001, Duesseldorf, Germany
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Aoki M, Yamamoto K, Ohyama S, Yamamura Y, Takenoshita S, Sugano K, Minamoto T, Kitajima M, Sugimura H, Shimada S, Noshiro H, Hiratsuka M, Sairenji M, Ninomiya I, Yano M, Uesaka K, Matsuno S, Maehara Y, Aikou T, Sasazuki T. A genetic variant in the gene encoding the stress70 protein chaperone family member STCH is associated with gastric cancer in the Japanese population. Biochem Biophys Res Commun 2005; 335:566-74. [PMID: 16087163 DOI: 10.1016/j.bbrc.2005.07.110] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2005] [Accepted: 07/21/2005] [Indexed: 01/09/2023]
Abstract
Association analysis, based on linkage disequilibrium between specific alleles in the candidate loci and nearby genetic markers, has been proposed to identify genes conferring susceptibility to multifactorial diseases. Using the affected sib-pair method, we previously mapped four candidate chromosomal regions, 1p32, 2q33-q35, 11p13-p14, and 21q21, for gastric cancer by linkage analysis. To identify genes involved in the disease, we performed a gene-based association analysis of 66 genes, located on 21p11-21q22, using 126 single nucleotide polymorphisms (SNPs) as genetic markers in 373 patients with 250 controls. We found a significant association of five SNPs in the stress70 protein chaperon family member STCH gene with gastric cancer, especially with the non-cardia localization subgroup (P=0.0005-0.02, odds ratio=1.44-1.72). Comparisons of haplotype frequency showed significant association between TTGGC haplotype and gastric cancer (P=0.0001, odds ratio=1.59). These results suggest that, in the Japanese population, STCH might be a new candidate for conferring susceptibility to this disease.
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Affiliation(s)
- Masayuki Aoki
- Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
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Kopp R, Diebold J, Dreier I, Cramer C, Glas J, Baretton G, Jauch KW. Prognostic relevance of p53 and bcl-2 immunoreactivity for early invasive pT1/pT2 gastric carcinomas: indicators for limited gastric resections? Surg Endosc 2005; 19:1507-12. [PMID: 16177872 DOI: 10.1007/s00464-005-0043-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2005] [Accepted: 04/24/2005] [Indexed: 01/28/2023]
Abstract
BACKGROUND Laparoscopic or endoscopic limited resection is intended to be an additional therapeutic option for the treatment of early gastric cancer. However, tumorbiologic markers to predict the outcome for patients after limited resections are missing. This study therefore investigated the prognostic relevance of p53 and bcl-2 immunoreactivity as well as the percentage of apoptotic tumor cells in early invasive pT1/pT2 tumors managed with standard operations for gastric adenocarcinoma. METHODS Histologic slides of 65 pT1/pT2 gastric carcinomas were investigated for bcl-2 and p53 immunoreactivity. For 35 patients, DNA fragmentation of tumor cell nuclei was determined by the terminal uridine 5'-triphosphate (UTP) nick end-labeling (TUNEL) method. Follow-up evaluation of the patients was prospectively documented for 53.4 +/- 4.1 months. RESULTS Findings showed that bcl-2 immunoreactivity was associated with tumors of the intestinal type according to Lauren s classification (p = 0.042), and that p53 immunoreactivity was increased in more invasive tumors (pT1 vs pT2 tumors; p = 0.047). Mean survival time was significantly longer for patients with bcl-2-negative tumors (74.3 +/- 6.8 months) than for patients with bcl-2-positive tumors (50.8 +/- 7.6 months; p = 0.024). The percentage of apoptotic tumor cell nuclei did not have prognostic relevance in the population studied and was not associated with several histopathologic parameters or bcl-2 and p53 immunoreactivity. Subgroup analysis indicated that the survival of patients with differentiated G2 and bcl-2-negative/p53-negative tumors was significantly longer (82 +/- 6 months) than the survival of patients with G2 bcl-2- and/or p53-positive tumors (41.8 +/- 12.5 months; p = 0.005), with independent prognostic relevance determined by multivariate analysis (p = 0.024). CONCLUSION The data reported indicate that the analysis of bcl-2 and p53 immunoreactivity seems to have prognostic implications for early invasive (pT1/pT2) gastric adenocarcinomas and may subclassify patients for minimally invasive laparoscopic or endoscopic gastric resections.
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Affiliation(s)
- R Kopp
- Department of Surgery, Klinikum Grosshadern, University of Munich, Marchioninistrasse 15, D-81377 Munich, Germany
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Bouché O. [How can the prognosis of gastric cancer be improved in France?]. GASTROENTEROLOGIE CLINIQUE ET BIOLOGIQUE 2005; 29:7-10. [PMID: 15738889 DOI: 10.1016/s0399-8320(05)80687-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/01/2023]
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