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Markovic M, Mitrovic S, Dagovic A, Jovanovic D, Nikolic T, Ivosevic A, Milosavljevic MZ, Vojinovic R, Petrovic M. Does the Expression of Vascular Endothelial Growth Factor (VEGF) and Bcl-2 Have a Prognostic Significance in Advanced Non-Small Cell Lung Cancer? Healthcare (Basel) 2023; 11:healthcare11030292. [PMID: 36766867 PMCID: PMC9914895 DOI: 10.3390/healthcare11030292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 01/20/2023] Open
Abstract
Lung cancer is the most common cause of mortality from malignant tumors worldwide. The five-year survival rate for people with advanced stages varies considerably, from 35.4% to 6.9%. The angiogenic potential of bcl2 is not well known, nor is the way in which tumor cells with excessive bcl2 expression affect VEGF production. Hypothetically, given that tumor growth, progression and metastasis are dependent on angiogenesis, the antiapoptotic effect is expected to form a link between these two molecules. The aim of this study was to evaluate the relationship between bcl-2 and VEGF expression, clinicopathological features and survival in 216 patients with advanced NSCLC. Archival tumor tissues were examined by immunohistochemistry for the expression of bcl-2 and VEGF. Immunoreactivity for bcl-2 was observed in 41.4% of NSCLCs, 51% of squamous and 34.8% of adenocarcinomas-expressed Bcl-2. There was an inverse correlation of mononuclear stromal reaction and bcl-2 expression in adenocarcinoma (p < 0.0005). A total of 71.8% NSCLCs were VEGF positive, 56% of squamous and 82.2% of adenocarcinomas. High level of VEGF expression was significantly associated with histology type (p = 0.043), low histology grade (p = 0.014), clinical stage IV (p = 0.018), smoking history (p = 0.008) and EGFR mutations (p = 0.026). There was an inverse correlation in the expression of Bcl-2 and VEGF in NSCLC patients (p = 0.039, r = -0.163). Two-year survival of patients with unresectable NSCLC was 39.3%, and 50% of patients were alive at 17 months. Our results demonstrated no difference in survival for patients in advanced NSCLC grouped by bcl-2 and VEGF status. Additionally, we observed an inverse correlation in the expression of Bcl-2 and VEGF in NSCLC and mononuclear reaction and bcl-2 expression in adenocarcinomas.
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Affiliation(s)
- Marina Markovic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
- Department of Medical Oncology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
| | - Slobodanka Mitrovic
- Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
- Department of Pathology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
- Correspondence: ; Tel.: +381-65-808-0877 or +381-34-505-356
| | - Aleksandar Dagovic
- Department of Medical Oncology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
- Department of Oncology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Dalibor Jovanovic
- Department of Pathology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Tomislav Nikolic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
- Clinic for Nephrology and Dyalisis, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
| | - Anita Ivosevic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
- Clinic for Rheumatology and Allergology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
| | - Milos Z. Milosavljevic
- Department of Pathology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
| | - Radisa Vojinovic
- Department of Radiology, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
- Department of Radiology, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
| | - Marina Petrovic
- Department of Internal Medicine, Faculty of Medical Sciences, University of Kragujevac, 34000 Kragujevac, Serbia
- Pulmonology Clinic, University Clinical Center Kragujevac, 34000 Kragujevac, Serbia
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Wu BC, Hsu ATW, Abadchi SN, Johnson CR, Bengali S, Lay F, Melinosky K, Shao C, Chang KH, Born LJ, Abraham J, Evans D, Ha JS, Harmon JW. Potential Role of Silencing Ribonucleic Acid for Esophageal Cancer Treatment. J Surg Res 2022; 278:433-444. [PMID: 35667884 DOI: 10.1016/j.jss.2022.04.029] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/30/2022] [Accepted: 04/04/2022] [Indexed: 11/28/2022]
Abstract
INTRODUCTION Esophageal cancer is an aggressive malignancy with high mortality. Optimal treatment of esophageal cancer remains an elusive goal. Ribonucleic acid (RNA) interference is a novel potential targeted approach to treat esophageal cancer. Targeting oncogenes that can alter critical cellular functions with silencing RNA molecules is a promising approach. The silencing of specific oncogenes in esophageal cancer cells in the experimental setting has been shown to decrease the expression of oncogenic proteins. This has resulted in cell apoptosis, reduction in cell proliferation, reduced invasion, migration, epithelial-mesenchymal transition, decrease in tumor angiogenesis and metastasis, and overcoming drug resistance. The Hedgehog (Hh) signaling pathway has been shown to be involved in esophageal adenocarcinoma formation in a reflux animal model. In addition to Hh, we will focus on other targets with clinical potential in the treatment of esophageal cancer. MATERIALS AND METHODS We searched for articles published from 2005 to August 2020 that studied the siRNA effects on inhibiting esophageal cancer formation in experimental settings. We used combinations of the following terms for searching: "esophageal cancer," "RNA interference," "small interfering RNA," "siRNA," "silencing RNA," "Smoothened (Smo)," "Gli," "Bcl-2," "Bcl-XL," "Bcl-W,″ "Mcl-1," "Bfl-1," "STAT3,"and "Hypoxia inducible factor (HIF)". A total of 21 relevant articles were found. RESULTS AND CONCLUSIONS Several proto-oncogenes/oncogenes including Hh pathway mediators, glioma-associated oncogene homolog 1 (Gli-1), Smoothened (Smo), and antiapoptotic Bcl-2 have potential as targets for silencing RNA in the treatment of esophageal cancer.
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Affiliation(s)
- Bo-Chang Wu
- Bayview Surgical Research Laboratory, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Angela Ting-Wei Hsu
- Bayview Surgical Research Laboratory, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sanaz Nourmohammadi Abadchi
- Bayview Surgical Research Laboratory, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Christopher R Johnson
- Bayview Surgical Research Laboratory, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; Division of Thoracic Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Sameer Bengali
- Bayview Surgical Research Laboratory, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Frank Lay
- Bayview Surgical Research Laboratory, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Kelsey Melinosky
- Bayview Surgical Research Laboratory, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Kai-Hua Chang
- Bayview Surgical Research Laboratory, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Louis J Born
- Department of Bioengineering, University of Maryland, College Park, College Park, Maryland
| | - John Abraham
- Bayview Surgical Research Laboratory, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - Jinny S Ha
- Division of Thoracic Surgery, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - John W Harmon
- Bayview Surgical Research Laboratory, Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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The Establishment of Esophageal Precancerous Lesion Model by Using p53 Conditional Knockout Mouse in Esophageal Epithelium. BIOMED RESEARCH INTERNATIONAL 2020; 2020:4534289. [PMID: 32047812 PMCID: PMC7003290 DOI: 10.1155/2020/4534289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/17/2019] [Revised: 11/26/2019] [Accepted: 12/20/2019] [Indexed: 12/30/2022]
Abstract
Understanding the molecular mechanisms of precancerous lesion of esophageal cancer is beneficial for early diagnosis and early treatment. The deletion of p53 gene is common in esophageal cancer, but its pathogenesis is still unclear. An animal model is urgently needed to study the mechanisms of esophageal cancer and p53 deficiency. KO mice (p53flox/flox.ED-L2-Cre+/−) and the corresponding control Loxp mice (p53flox/flox.ED-L2-Cre−/−) were obtained by crossing between the p53flox/flox mice and ED-L2-Cre+/− mice. Methylbenzylnitrosamine (NMBA) was injected subcutaneously to induce esophageal precancerous lesion of these two groups of mice. Hematoxylin and eosin staining analysis was performed to evaluate the number and extent of esophageal precancerous lesions in KO mice and Loxp mice at the 16th and 48th weeks. Immunohistochemistry analysis was used to detect the change of Ki67, P21, Bcl-2, and Bax proteins. The number and extent of esophageal precancerous lesions in KO mice were significantly increased compared with the control at the 16th and 48th weeks under the induction of NMBA. The Ki67, P21, Bcl-2, and Bax proteins also had cancer-related pathological characteristics. These results suggest that the esophageal precancerous lesion model was established under the combined effect of p53 gene deletion in esophageal epithelium and NMBA, which could provide a new esophageal precancerous lesion model to explore the mechanism of precancerous lesions.
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Wang X, Cheng G, Zhang T, Deng L, Xu K, Xu X, Wang W, Zhou Z, Feng Q, Chen D, Bi N, Wang L. CHST15 promotes the proliferation of TE‑1 cells via multiple pathways in esophageal cancer. Oncol Rep 2019; 43:75-86. [PMID: 31746400 PMCID: PMC6908928 DOI: 10.3892/or.2019.7395] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Accepted: 10/04/2019] [Indexed: 02/06/2023] Open
Abstract
Esophageal squamous cell carcinoma (ESCC) is a common type of esophageal cancer and is prevalent worldwide. Understanding the mechanisms underlying its formation and the search for more effective therapeutic strategies are critical due to the occurrence of chemotherapeutic drug resistance. The aim of the present study was to determine the functional relevance and therapeutic potential of carbohydrate sulfotransferase 15 (CHST15) in ESCC. CHST15 levels were measured in different ESCC cell lines and evaluated in ESCC tissues using tissue chip immunohistochemistry. Cell growth and apoptosis assays, 3‑(4,5‑dimethylthiazol‑2‑yl)‑2,5‑diphenyltetrazolium bromide assays, and clonogenic assays were conducted using TE‑1 cells and lenti‑shCHST15 virus constructs were used to investigate the function of CHST15 in cell proliferation and apoptosis. mRNA microarray analysis was performed to determine the underlying mechanism of CHST15 regulation in TE‑1 cell proliferation and apoptosis. The results showed that knockdown of CHST15 inhibited TE‑1 cell growth and proliferation, but induced cell apoptosis. CHST15 was more frequently detected in ESCC tissue compared with that in normal esophageal tissue. Microarray data analysis indicated that the inhibition of cell proliferation and activation of cell apoptosis in CHST15‑knockdown cells may be caused by altered CHST15/ILKAP/CCND1 and CHST15/RABL6/PMAIP1 signaling axes, respectively.
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Affiliation(s)
- Xin Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Guowei Cheng
- Department of Radiotherapy, Huanxing Tumor Hospital, Beijing 100023, P.R. China
| | - Tao Zhang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Lei Deng
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Kunpeng Xu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Xin Xu
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Wenqing Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Zongmei Zhou
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Qinfu Feng
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Dongfu Chen
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Nan Bi
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, P.R. China
| | - Luhua Wang
- Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital and Shenzhen Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Shenzhen, Guangdong 518116, P.R. China
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Wang C, Wang J, Chen Z, Gao Y, He J. Immunohistochemical prognostic markers of esophageal squamous cell carcinoma: a systematic review. CHINESE JOURNAL OF CANCER 2017; 36:65. [PMID: 28818096 PMCID: PMC5561640 DOI: 10.1186/s40880-017-0232-5] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/12/2016] [Accepted: 04/17/2017] [Indexed: 12/18/2022]
Abstract
BACKGROUND Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy, with a high incidence and poor prognosis. In the past several decades, hundreds of proteins have been reported to be associated with the prognosis of ESCC, but none has been widely accepted to guide clinical care. This study aimed to identify proteins with great potential for predicting prognosis of ESCC. METHODS We conducted a systematic review on immunohistochemical (IHC) prognostic markers of ESCC according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Guidelines. Literature related to IHC prognostic markers of ESCC were searched from PubMed, Embase, Web of Science, and Cochrane Library until January 30th, 2017. The risk of bias of these original studies was evaluated using the Quality in Prognosis Studies (QUIPS) tool. RESULTS We identified 11 emerging IHC markers with reproducible results, including eight markers [epidermal growth factor receptor (EGFR), Cyclin D1, vascular endothelial growth factor (VEGF), Survivin, Podoplanin, Fascin, phosphorylated mammalian target of rapamycin (p-mTOR), and pyruvate kinase M2 (PKM2)] indicating unfavorable prognosis and 3 markers (P27, P16, and E-cadherin) indicating favorable prognosis of ESCC. CONCLUSION Strong evidence supports that these 11 emerging IHC markers or their combinations may be useful in predicting prognosis and aiding personalized therapy decision-making for ESCC patients.
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Affiliation(s)
- Chunni Wang
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Science Building, No.17 Panjiayuan Nanli, Chaoyang District, PO Box 2258, Beijing, 100021 P. R. China
| | - Jingnan Wang
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Science Building, No.17 Panjiayuan Nanli, Chaoyang District, PO Box 2258, Beijing, 100021 P. R. China
| | - Zhaoli Chen
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Science Building, No.17 Panjiayuan Nanli, Chaoyang District, PO Box 2258, Beijing, 100021 P. R. China
| | - Yibo Gao
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Science Building, No.17 Panjiayuan Nanli, Chaoyang District, PO Box 2258, Beijing, 100021 P. R. China
| | - Jie He
- Department of Thoracic Surgery, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Science Building, No.17 Panjiayuan Nanli, Chaoyang District, PO Box 2258, Beijing, 100021 P. R. China
- Center for Cancer Precision Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021 P. R. China
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Bachmann K, Neumann A, Hinsch A, Nentwich MF, El Gammal AT, Vashist Y, Perez D, Bockhorn M, Izbicki JR, Mann O. Cyclin D1 is a strong prognostic factor for survival in pancreatic cancer: analysis of CD G870A polymorphism, FISH and immunohistochemistry. J Surg Oncol 2014; 111:316-23. [PMID: 25470788 DOI: 10.1002/jso.23826] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Accepted: 09/30/2014] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND OBJECTIVE Cyclin D1 is an important regulator protein for the G1-S cell cycle phase transition. The aim of this trial was to evaluate the impact of the CCND1 polymorphism G870A and corresponding protein expression and CCND1 amplification on the survival of the patients. METHODS 425 patients with ductal pancreatic adenocarcinoma who underwent resection were included after histopathological confirmation. DNA was analyzed for Cyclin D1 polymorphisms, immunhistochemical examination and fluorescence in situ hybridization analysis of the tumor were performed. RESULTS Overall, the mean survival was 22.9 months (20.5-25.3). The survival in patients with Cyclin D1 G870A polymorphism Adenine/Adenine was 15.1 months (95% CI 11.3-18.9), 21.5 months (17.4-25.6) for Adenine/Guanine, and 29.4 months (95% CI 23.8-35.0) for Guanine/Guanine (P = 0.003). A shorter survival was associated with strong/moderate protein expression in immunohistochemistry (IHC) compared to weak/no expression (P = 0.028). Additionally, a significant coherency between unfavourable polymorphism (AA/AG) and increased protein expression was detected (P = 0.005). CONCLUSIONS A strong impact on survival of Cyclin D1 G870A polymorphism and the detected corresponding protein expression was found. The biological mechanism of CCND1 in carcinogenesis has not been fully examined; but at present Cyclin D1 seems to be an interesting biomarker for the prognosis of ductal adenocarcinoma.
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Affiliation(s)
- Kai Bachmann
- Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Yan W, Wistuba II, Emmert-Buck MR, Erickson HS. Squamous Cell Carcinoma - Similarities and Differences among Anatomical Sites. Am J Cancer Res 2014. [PMID: 21938273 DOI: 10.1158/1538-7445.am2011-275] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
Squamous cell carcinoma (SCC) is an epithelial malignancy involving many anatomical sites and is the most common cancer capable of metastatic spread. Development of early diagnosis methods and novel therapeutics are important for prevention and mortality reduction. In this effort, numerous molecular alterations have been described in SCCs. SCCs share many phenotypic and molecular characteristics, but they have not been extensively compared. This article reviews SCC as a disease, including: epidemiology, pathology, risk factors, molecular characteristics, prognostic markers, targeted therapy, and a new approach to studying SCCs. Through this comparison, several themes are apparent. For example, HPV infection is a common risk factor among the four major SCCs (NMSC, HNSC, ESCC, and NSCLC) and molecular abnormalities in cell-cycle regulation and signal transduction predominate. These data reveal that the molecular insights, new markers, and drug targets discovered in individual SCCs may shed light on this type of cancer as a whole.
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Affiliation(s)
- Wusheng Yan
- Pathogenetics Unit, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
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Zhang Y, Zhang Y, Yun H, Lai R, Su M. Correlation of STAT1 with apoptosis and cell-cycle markers in esophageal squamous cell carcinoma. PLoS One 2014; 9:e113928. [PMID: 25438156 PMCID: PMC4250046 DOI: 10.1371/journal.pone.0113928] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2014] [Accepted: 11/03/2014] [Indexed: 02/05/2023] Open
Abstract
We recently found evidence that STAT1 in esophageal squamous carcinoma (ESCC) cells exerts tumor suppressor function, and it regulates five key regulators of apoptosis or cell-cycle progression, including Bcl-2, Bcl-xL, survivin, cyclin D1 and p21. In this study, we confirmed these findings in four ESCC cell lines. Using immunohistochemistry, we also assessed the expression of these proteins in 62 primary tumors. The expression of these markers was heterogeneous, ranging 39 to 69% of the cohort. Significant correlation was found between STAT1 and three proteins (p21, Bcl-xL and survivin), whereas only a trend was identified for cyclin D1 and Bcl-2. We then correlated the expression of these proteins with several clinicopathologic parameters including lymph node metastasis, depth of invasion, clinical stage and overall survival. Significant correlations were found between Bcl-2 and deep invasion (p = 0.033), survivin and lymph node metastasis (p = 0.006), as well as cyclin D1 and clinical stage (p = 0.014). Patients with p21-positive tumors had a significantly longer survival compared to those with p21-negative tumors (p = 0.031). To conclude, our findings support the concept that STAT1 exerts its tumor suppressor effects in ESCC via modulating the expression of key regulators of apoptosis and cell-cycle progression.
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Affiliation(s)
- Ying Zhang
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong Province, China
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
| | - Yaozhong Zhang
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Hailong Yun
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong Province, China
| | - Raymond Lai
- Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
- Department of Oncology, University of Alberta, Edmonton, Alberta, Canada
- * E-mail: (RL); (MS)
| | - Min Su
- Department of Pathology, Shantou University Medical College, Shantou, Guangdong Province, China
- * E-mail: (RL); (MS)
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Wu P, Tang Y, He J, Qi L, Jiang W, Zhao S. ARC is highly expressed in nasopharyngeal carcinoma and confers X-radiation and cisplatin resistance. Oncol Rep 2013; 30:1807-13. [PMID: 23877130 DOI: 10.3892/or.2013.2622] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 06/12/2013] [Indexed: 11/05/2022] Open
Abstract
Apoptosis repressor with caspase recruitment domain (ARC), an inhibitor of apoptosis, is primarily expressed in terminally differentiated tissues. Recent studies have revealed that ARC is highly expressed in a variety of human cancer cell lines and epithelial-derived cancers, which suggests that ARC plays an important role in the process of carcinogenesis. However, whether ARC is involved in the development of nasopharyngeal carcinoma (NPC) and the various roles it plays in NPC remain unclear. In the present study, we examined the expression of ARC in NPC cell lines and NPC tissues and the relationship between its subcellular expression and clinicopathological grade; moreover, we explored the effect of this protein on radiation resistance and chemoresistance in NPC cells. We found that cytoplasmic ARC was expressed at high levels in NPC tissues, at moderate levels in severe atypical hyperplasia and at low levels in benign nasopharyngeal tissues. High expression of cytoplasmic and nuclear ARC was correlated with advanced local invasion. However, only a small amount of nuclear ARC was expressed in NPC in contrast to cytoplasmic ARC. We also found that attenuation of ARC expression by miRNA resulted in decreased X-radiation and cisplatin resistance in NPC CNE-2 cells. In contrast, overexpression of ARC resulted in increased X-radiation and cisplatin resistance in NPC 6-10B cells. Furthermore, we demonstrated that ARC appears to be critical for blocking the activation of casapse-8 and casapse-2 in NPC cells subjected to X-radiation or cisplatin. These results suggest that high expression of ARC plays an important role in the pathogenesis of NPC and leads to X-radiation and cisplatin resistance in NPC.
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Affiliation(s)
- Ping Wu
- Department of Otolaryngology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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Vallböhmer D, Brabender J, Metzger R, Hölscher AH. Genetics in the pathogenesis of esophageal cancer: possible predictive and prognostic factors. J Gastrointest Surg 2010; 14 Suppl 1:S75-80. [PMID: 19756878 DOI: 10.1007/s11605-009-1021-5] [Citation(s) in RCA: 37] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2009] [Accepted: 08/25/2009] [Indexed: 01/31/2023]
Abstract
INTRODUCTION Esophageal adenocarcinoma is the most rapidly increasing cancer in Western countries. Like esophageal squamous-cell carcinoma, these tumors are often detected at an advanced stage, requiring a multimodal concept. Despite improvements in detection, surgical resection, and (neo-) adjuvant therapy, the overall survival of esophageal cancer remains lower than other solid tumors. In fact, just 30-40% of the patients with advanced esophageal cancer benefit from a neoadjuvant therapy. Therefore, predictive/prognostic markers are needed to allow tailored multimodality therapy with increased efficacy. DISCUSSION In recent years, there has been an exponential growth in our understanding of the cellular and molecular events associated with cell cycle regulation, programmed cell death, angiogenesis, and tumor growth. In this review, the classification of Hanahan and Weinberg is used concerning the six essential changes in carcinogenesis, i.e., the six hallmarks of cancer: (1) self-sufficiency in growth signals; (2) insensitivity to antigrowth signals; (3) avoidance of apoptosis; (4) limitless replicative potential; (5) sustained angiogenesis; and (6) tissue invasion and metastasis. CONCLUSIONS According to these six steps, this review provides an update of the most recent data about predictive/prognostic molecular markers in patients with esophageal cancer.
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Affiliation(s)
- Daniel Vallböhmer
- Department of General, Visceral and Cancer Surgery, University of Cologne, Cologne, Germany.
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Takikita M, Hu N, Shou JZ, Wang QH, Giffen C, Taylor PR, Hewitt SM. Biomarkers of apoptosis and survival in esophageal squamous cell carcinoma. BMC Cancer 2009; 9:310. [PMID: 19728877 PMCID: PMC2745431 DOI: 10.1186/1471-2407-9-310] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2009] [Accepted: 09/03/2009] [Indexed: 11/10/2022] Open
Abstract
Background Cancer of the esophagus is a deadly malignancy, and development of biomarkers that predict survival is an urgent need. The apoptotic pathways have been hypothesized as important in progression of esophageal squamous cell carcinoma (ESCC). We investigated a panel of proteins that regulate apoptosis as candidate of biomarkers of prognosis in ESCC. Methods Tissue microarray (TMA) including 313 surgically-resected cases of ESCC specimens was built for immunohistochemical interrogation. We evaluated seven genes in the FasL-Fas apoptotic pathway - FasL, Fas, FAS-associated death domain protein (FADD), phosphorylated-FADD, and caspase 8 and 10, and the antiapoptotic protein bcl-2. We studied pathway integrity and relations to risk and clinical factors, and determined the prognostic significance of each marker. Results Five markers showed strong inter-marker correlations (r ≥ 0.28, p < 0.001), including FasL, Fas, FADD, and caspases 8 and 10. FasL and FADD also showed modest correlations with one or more cancer risk factors, but none of the markers was significantly associated with either tumor stage or lymph node metastasis, the only two clinical factors that predicted survival in these ESCC cases. Multivariate-adjusted proportional hazard regression models showed no association between protein expression and risk of death for any of the seven markers examined. Conclusion Individual biomarkers in the apoptosis pathway do not appear to predict survival of patients with ESCC.
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Affiliation(s)
- Mikiko Takikita
- Tissue Array Research Program, Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, MD, USA.
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12
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Sakaeda T, Yamamori M, Kuwahara A, Nishiguchi K. Pharmacokinetics and pharmacogenomics in esophageal cancer chemoradiotherapy. Adv Drug Deliv Rev 2009; 61:388-401. [PMID: 19135108 DOI: 10.1016/j.addr.2008.10.005] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2008] [Accepted: 10/30/2008] [Indexed: 12/15/2022]
Abstract
Esophageal cancer is one of the most lethal malignancies. Surgical resection of the tumor from the primary site has been the standard treatment, especially for localized squamous cell carcinoma, but considerable clinical efforts during the last decade have resulted in novel courses of treatment. These options include chemoradiotherapy, consisting of a continuous infusion of 5-fluorouracil (5-FU), cisplatin (CDDP), and concurrent radiation. Given the substantial inter- and/or intra-individual variation in clinical outcome, future improvements will likely require the incorporation of a novel anticancer drug, pharmacokinetically guided administration of CDDP or 5-FU, and identification of potential responders by patient genetic profiling prior to treatment. In this review, the latest information on incidence, risk factors, biomarkers, therapeutic strategies, and the pharmacokinetically guided or genotype-guided administration of CDDP and 5-FU is summarized for future individualization of esophageal cancer treatment.
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Affiliation(s)
- Toshiyuki Sakaeda
- Center for Integrative Education of Pharmacy Frontier, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
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13
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Bachmann K, Shahmiri S, Kaifi J, Schurr P, Mann O, Rawnaq T, Block S, Kalinin V, Izbicki JR, Strate T. Polymorphism Arg290Arg in esophageal-cancer-related gene 1 (ECRG1) is a prognostic factor for survival in esophageal cancer. J Gastrointest Surg 2009; 13:181-7. [PMID: 19052822 DOI: 10.1007/s11605-008-0766-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2008] [Accepted: 11/12/2008] [Indexed: 01/31/2023]
Abstract
BACKGROUND Esophageal cancer is one of the most frequent cancers worldwide and is associated with poor outcome. Besides clinicopathological data, few prognostic molecular markers exist. Esophageal-cancer-related gene1 (ECRG1) short tandem repeats are associated with higher risk for developing esophageal squamous cell carcinoma. The aim of the present study was to evaluate the impact of DNA polymorphisms in the coding region of ECRG1 in esophageal carcinoma. METHODS Genomic DNA of 107 patients with esophageal cancer that underwent complete surgical resection between 1997 and 2005 was extracted. DNA was analyzed for ECRG1 polymorphisms Arg290Arg, Arg290Gln, and Gln290Gln by PCR and gel electrophoresis. Polymorphisms were correlated with survival data by the Kaplan-Meier method, multivariate Cox regression analysis, and odds ratio were determined. For all variables, cross tables were generated, followed by calculation of the p value by using the chi-square test/Fisher-exact test. RESULTS Follow-up data of 102 patients with esophageal cancer were available after complete surgical resection for a median follow-up time of 24.3 months. Polymorphism Arg290Arg was found in 47 patients (46.1%), Arg290Gln in 48 patients (47.0%), and Gln290Gln in seven cases (6.9%). Arg290Arg polymorphism was significantly associated with reduced overall survival (p = 0.01) and tumor-free survival (p = 0.01) by the log-rank test. Multivariate regression analysis by Cox revealed polymorphism Arg290Arg to be a significant prognostic factor for survival (p = 0.012). CONCLUSIONS Polymorphism Arg290Arg in ECRG1 is associated with poor clinical outcome after complete surgical resection in patients with esophageal cancer.
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Affiliation(s)
- Kai Bachmann
- Department of General, Visceral, and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
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14
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Zhang J, Zhang YW, Chen ZW, Zhou XY, Lu S, Luo QQ, Hu H, Miao LS, Ma LF, Xiang JQ. Adjuvant chemotherapy of cisplatin, 5-fluorouracil and leucovorin for complete resectable esophageal cancer: a case-matched cohort study in east China. Dis Esophagus 2008; 21:207-13. [PMID: 18430100 DOI: 10.1111/j.1442-2050.2007.00748.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
It is still controversial whether adjuvant chemotherapy of cisplatin, 5-fluorouracil and leucovorin can increase the overall survival of esophageal cancer patients, and which subgroup of patients get most benefits from it. Between 1998 and 2004, 66 esophageal cancer patients with adjuvant chemotherapy and 160 well-matched patients without chemotherapy were included in this study. Nine markers were measured in the protein level to analyze prognostic significance. In the whole group, adjuvant chemotherapy did not improve the survival of esophageal cancer patients. There was also no significant difference for survival in stage I (P=0.59 and P=0.59), stage II (P=0.28 and P=0.28) and stage III patients (P=0.144 and P=0.06) between the observation and the chemotherapy group. Chemotherapy was most effective for the patients who had metastases in cervical and/or celiac lymph nodes (IV subgroup). One and 3-year disease-free survival and overall survival were significantly better than for those who did not receive the chemotherapy(P=0.038, and 0.016, respectively). Bcl-2 expression was a bad prognostic factor, and was more predictive in the adjuvant chemotherapy group than in the no-chemotherapy group. Adjuvant chemotherapy significantly improved the treatment result of stage IV patients compared with the observation group. Bcl-2 could be used to analyze prognosis and guide the adjuvant treatment.
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Affiliation(s)
- J Zhang
- Department of Thoracic Surgery, Shanghai Cancer Hospital, Fudan University, Shanghai, China.
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15
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Wang R, Lin F, Wang X, Gao P, Dong K, Wei SH, Cheng SY, Zhang HZ. Suppression of Bcl-xL expression by a novel tumor-specific RNA interference system inhibits proliferation and enhances radiosensitivity in prostatic carcinoma cells. Cancer Chemother Pharmacol 2007; 61:943-52. [PMID: 17653717 DOI: 10.1007/s00280-007-0548-y] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2007] [Accepted: 06/08/2007] [Indexed: 10/23/2022]
Abstract
Bcl-xL, a novel member of anti-apoptotic Bcl-2 family that play important roles in regulating cell survival and apoptosis, is frequently overexpressed in various kinds of human cancers, including prostatic carcinoma. To explore its possibility as a therapeutic target for prostatic carcinoma, we developed a novel tumor-specific RNA interference system by using survivin promoter and employed it to suppress exogenous reporters (LUC and EGFP) and endogenous gene Bcl-xL expression and analyzed its phenotypes. We found that expression of exogenous reporters (LUC and EGFP) was specifically inhibited in tumor cells but not in normal cells. We also observed that the specific inhibition of Bcl-xL in human prostatic carcinoma cells (PC3) strongly suppressed in vitro cell proliferation and in vivo tumorigenicity. We observed significant apoptosis induction and radiosensitivity enhancement in PC3 cells by the RNA interference-mediated suppression of Bcl-xL expression. All these results indicate that inhibition of Bcl-xL expression can result in potent antitumor activity and radiosensitization in human prostatic carcinoma.
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Affiliation(s)
- Rui Wang
- Research Center, Tangdu Hospital, Fourth Military Medical University, Xinsi Road, 710038 Xi'an, Shaanxi Province, China
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16
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Xie YE, Tang EJ, Zhang DR, Ren BX. Down-regulation of Bcl-X L by RNA interference suppresses cell growth and induces apoptosis in human esophageal cancer cells. World J Gastroenterol 2006; 12:7472-7. [PMID: 17167836 PMCID: PMC4087593 DOI: 10.3748/wjg.v12.i46.7472] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the inhibitory effect of the vector-generated small interfering RNAs (siRNAs) on the expression of the Bcl-XL gene in established human esophageal cancer cells, and to investigate the effect of the Bcl-XL siRNAs on cell growth and apoptosis in esophageal cancer cells.
METHODS: Three siRNA-expressing vectors targeting different sites of the Bcl-XL gene were constructed from pTZ-U6+1 vector. Cultured esophageal cancer cells were transfected with the siRNA-expressing vector (or the control vector) using lipofectamine 2000. Bcl-XL gene expression was determined with semiquantitative RT-PCR assay and Western blotting. Among the three siRNA-expressing vectors, the most highly functional vector and its effect on cell growth and apoptosis in esophageal cancer cells was further analyzed.
RESULTS: Of the three siRNA-expressing vectors, siRNA-expressing vector No.1 was the most potent one which suppressed Bcl-XL mRNA production to 32.5% of that in the untreated esophageal cancer cells. Western blotting analysis showed that siRNA-expressing vector No.1 markedly down-regulated the expression of Bcl-XL in human esophageal cancer cells. Treatment of esophageal cancer cells with siRNA-expressing vector No.1 resulted in inhibition of cell growth and induction of apoptosis.
CONCLUSION: Down-regulation of Bcl-XL by vector-generated small interfering RNAs can suppress cell growth and induce apoptosis in human esophageal cancer cells.
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Affiliation(s)
- Yong-En Xie
- The Institute of Immunology and Molecular Biology, North Sichuan Medical College, No.234, Fujiang Road, Nanchong 637007, Sichuan Province, China.
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17
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Abstract
Despite improvements in detection, surgical resection and (neo-) adjuvant therapy, the overall survival in esophageal cancer remains lower than in other solid tumors. In fact, less than 20% of patients with advanced esophageal cancer benefit from a neoadjuvant therapy. Therefore predictive/prognostic markers are needed to allow tailored (radio-) chemotherapy with increased efficacy and decreased toxicity. Recently potential predictive/prognostic factors have been characterized by innovative molecular-based technologies. These factors include growth-factor receptors, enzymes of angiogenesis, tumor suppressor genes, cell cycle regulators, enzymes involved in the DNA repair system, in apoptosis and in the degradation of extracellular matrix. The results of these mostly retrospective studies are promising but prospective studies are needed to validate those markers in the multimodal therapy of esophageal cancer.
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Affiliation(s)
- D Vallböhmer
- Department of Visceral and Vascular Surgery, University of Cologne, Medical Center, Germany
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18
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Reszec J, Sulkowska M, Koda M, Kanczuga-Koda L, Sulkowski S. Expression of Cell Proliferation and Apoptosis Markers in Papillomas and Cancers of Conjunctiva and Eyelid. Ann N Y Acad Sci 2004; 1030:419-26. [PMID: 15659825 DOI: 10.1196/annals.1329.052] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Cell proliferation and programmed cell death are considered to be important events in carcinogenesis. The object of our study was to evaluate the expression of the Bcl-2 protein family (Bcl-2, Bak, Bax), p53, proliferating cell nuclear antigen (PCNA), and Ki-67 protein immunoexpression as well as the correlation between the examined markers and some clinicopathological features in papillomas and cancers of conjunctiva and eyelid. Forty-five squamous cell papillomas (SCP), 11 squamous cell cancers (SCC), and 27 basal cell cancers (BCC) were estimated. In the SCP group, p53 protein expression was observed in 30 cases (66.6%), Ki-67 in 14 (31.1%), PCNA in 44 (97.8%), Bcl-2 in 24 (53.3%), Bak in 28 (62.2%), Bax in 31 (68.9%), and Bcl-xl in 11 (100%). In the SCC group, p53 protein expression was evaluated in 8 cases (72.8%), Ki-67 in 2 (18.2%), PCNA in 8 (72.7%), Bcl-2 in 5 (45.4%), Bax and Bak both in 10 (90.9%), and Bcl-xl in 100%. In the BCC group, p53 protein expression was estimated in 23 cases (85.1%), Ki-67 in 13 (48.1%), PCNA in 26 (96.2%), Bcl-2 in 13 (48.1%), Bak in 21 (77.8%), Bax in 22 (81.5%), and Bcl-xl in 23 (85.2%). We observed a correlation between some clinicopathological features and the examined markers of apoptosis and cell proliferation, which seemed to be important events in cancer development.
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Affiliation(s)
- Joanna Reszec
- Department of Clinical Pathology, Medical University of Bilaystok, Waszyngtona 13 str., 15-269 Bialystok, Poland.
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Watanabe J, Kushihata F, Honda K, Sugita A, Tateishi N, Mominoki K, Matsuda S, Kobayashi N. Prognostic significance of Bcl-xL in human hepatocellular carcinoma. Surgery 2004; 135:604-12. [PMID: 15179366 DOI: 10.1016/j.surg.2003.11.015] [Citation(s) in RCA: 84] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND Proliferation and apoptosis of liver cancer cells are closely related phenomena. We investigated the correlation between overexpression of Bcl-xL, an anti-apoptosis-related protein of the Bcl-2 family, and the clinical course of hepatocellular carcinoma (HCC). METHODS Specimens from 7 HCC patients were used for Western blotting and immunoelectron microscopy tests. Samples from 33 HCC patients who had undergone hepatectomies were used for immunohistochemical staining. The degrees of expression of Bcl-xL and Ki-67, as an index of HCC mitosis severity, were each classified into 2 groups. RESULTS With the use of Western blot analysis, enhanced immunoreactivity of Bcl-xL was found in cancerous specimens. Bcl-xL overexpression was found in cancer specimens in 21 of 33 patients (63.6%). The overall survival (P=.019) and disease-free survival (P=.030) rates of the group overexpressing Bcl-xL were definitely poorer. The Ki-67 higher labeling index LI > 10) group had a poorer survival rate (P=.016). There were significant correlations between Bcl-xL and overall survival and disease-free survival. Multivariate analyses revealed that Bcl-xL, tumor size, histologic portal invasion, and histologic metastatic foci were independent prognostic factors for overall survival and disease-free survival. CONCLUSIONS These results showed Bcl-xL in HCC specimens, suggesting that Bcl-xL was a significant prognostic factor for disease progression in human HCC.
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Affiliation(s)
- Jota Watanabe
- Department of Surgery, Ehime University School of Medicine, Onsen-gun, Japan
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20
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Krecicki T, Fraczek M, Kozlak J, Zatonski T, Jelen M, Dus D. Bcl-Xl protein expression in laryngeal squamous cell carcinoma. ACTA ACUST UNITED AC 2004; 29:55-8. [PMID: 14961853 DOI: 10.1111/j.1365-2273.2004.00780.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The Bcl-2 family of proteins regulate one of the steps in an evolutionary conserved apoptotic pathway. The long splice variant of Bcl-X (Bcl-Xl) is a potent antagonist of apoptosis. The aim of the study was to evaluate the relation between the presence of immunohistochemically detectable Bcl-Xl protein in laryngeal squamous cell carcinomas (LSCCs) and clinicopathological data, as well as DNA ploidy status and proliferative activity. In 50 specimens of LSCC, Bcl-Xl protein expression was evaluated immunohistochemically. Proliferative activity (SG2M-phase index) and DNA ploidy were measured by flow cytometry. In our study, Bcl-Xl protein expression decreased with decreasing tumour differentiation (P = 0.04). The majority of patients with Bcl-Xl protein immunoreactivity had no metastatic lymph node involvement (P = 0.01). Other factors such as age, gender, primary tumour size (pT) and type of cancer (keratinizing/non-keratinizing) were not associated with Bcl-Xl protein level. There was no correlation between Bcl-Xl protein and SG2M-phase index or DNA ploidy status. Our findings show that expression of Bcl-Xl protein is increased in a great fraction of laryngeal cancers. Further studies, however, are needed to clarify association between Bcl-Xl protein expression and clinical course of patients.
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Affiliation(s)
- T Krecicki
- Department of Otolaryngology, Wroclaw Medical University, Wroclaw, Poland.
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21
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N/A. N/A. Shijie Huaren Xiaohua Zazhi 2003; 11:1665-1669. [DOI: 10.11569/wcjd.v11.i11.1665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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22
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Abstract
Tumors frequently acquire resistance to apoptosis that is expected to contribute to malignant phenotype and reduce sensitivity to treatment. In fact, inactivation of p53 tumor suppressor gene resulting in suppression of apoptosis serves as a negative prognostic marker. Surprisingly, expression of a strong anti-apoptotic protein Bcl-2, another mechanism to avoid apoptosis, was found to be associated with a favorable prognosis. This paradoxical anti-progressor function of Bcl-2 has been explained in literature based on the negative effect of Bcl-2 on cell proliferation. Here, by analyzing accumulated experimental and clinical data, we provide evidence supporting another hypothesis that defines apoptosis as an accelerator of tumor progression. The mechanism of anti-progressor function of Bcl-2 is based on creation of tumors that maintain control of genomic stability by eliminating selective advantages for the cells that acquire resistance to apoptosis through loss of p53. Thus, inhibition of apoptosis does not lead to loss of genomic stability and creates tumor environment that no longer supports further tumor progression and inhibitors of apoptosis can be considered as factors suppressing tumor progression.
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Affiliation(s)
- Katerina V Gurova
- Department of Molecular Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA
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23
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Lau CL, Moore MBH, Brooks KR, D'Amico TA, Harpole DH. Molecular staging of lung and esophageal cancer. Surg Clin North Am 2002; 82:497-523. [PMID: 12371582 DOI: 10.1016/s0039-6109(02)00024-5] [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] [Indexed: 01/13/2023]
Abstract
In both esophageal and NSCLC, the TNM stage at diagnosis remains the most important determinant of survival. Significant research to investigate the biology of NSCLC and esophageal carcinoma is ongoing, and the roles of proto-oncogenes, tumor suppressor genes, angiogenic factors, extracellular matrix proteases, and adhesion molecules are being elucidated. While evidence is accumulating that various markers are involved in NSCLC and esophageal tumor virulence, the current studies are compromised by small sample sizes, heterogeneous populations, and variations in techniques. Large prospective studies with homogenous groups designed to evaluate the role of these various markers should clarify their potential involvement in NSCLC and esophageal cancer. Identification of occult micrometastases in lymph nodes and bone marrow using immunohistochemical techniques and rt-PCR is intriguing. These techniques are promising as a method to more accurately stage patients, and therefore to predict outcomes and to determine therapies. Perhaps the most promising area of research is the development of novel drugs whose mechanism of action targets the pathways of various molecular markers. Molecular biologic substaging offers an opportunity to individualize a chemotherapeutic regimen based on the molecular profile of the tumor, thus providing the potential for improved outcomes with less morbidity in patients with both NSCLC and esophageal cancer.
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Affiliation(s)
- Christine L Lau
- General and Thoracic Surgery, Duke University Medical Center, Durham, NC 27710, USA
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