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Zhang S, Valenzuela LF, Zatulovskiy E, Mangiante L, Curtis C, Skotheim JM. The G 1-S transition is promoted by Rb degradation via the E3 ligase UBR5. SCIENCE ADVANCES 2024; 10:eadq6858. [PMID: 39441926 PMCID: PMC11498223 DOI: 10.1126/sciadv.adq6858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/26/2024] [Accepted: 09/18/2024] [Indexed: 10/25/2024]
Abstract
Mammalian cells make the decision to divide at the G1-S transition in response to diverse signals impinging on the retinoblastoma protein Rb, a cell cycle inhibitor and tumor suppressor. Passage through the G1-S transition is initially driven by Rb inactivation via phosphorylation and by Rb's decreasing concentration in G1. While many studies have identified the mechanisms of Rb phosphorylation, the mechanism underlying Rb's decreasing concentration in G1 was unknown. Here, we found that Rb's concentration decrease in G1 requires the E3 ubiquitin ligase UBR5. UBR5 knockout cells have increased Rb concentration in early G1, exhibited a lower G1-S transition rate, and are more sensitive to inhibition of cyclin-dependent kinase 4/6 (Cdk4/6). This last observation suggests that UBR5 inhibition can strengthen the efficacy of Cdk4/6 inhibitor-based cancer therapies.
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Affiliation(s)
- Shuyuan Zhang
- Department of Biology, Stanford University, Stanford, CA 94305, USA
| | | | - Evgeny Zatulovskiy
- Department of Biology, Stanford University, Stanford, CA 94305, USA
- Department of Biochemistry, University of Cambridge, Cambridge CB2 1GA, UK
| | | | | | - Jan M. Skotheim
- Department of Biology, Stanford University, Stanford, CA 94305, USA
- Chan Zuckerberg Biohub, San Francisco, CA 94158, USA
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Wang J, Su W, Zhang T, Zhang S, Lei H, Ma F, Shi M, Shi W, Xie X, Di C. Aberrant Cyclin D1 splicing in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis 2023; 14:244. [PMID: 37024471 PMCID: PMC10079974 DOI: 10.1038/s41419-023-05763-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 03/15/2023] [Accepted: 03/21/2023] [Indexed: 04/08/2023]
Abstract
Cyclin D1 (CCND1), a crucial mediator of cell cycle progression, possesses many mutation types with different mutation frequencies in human cancers. The G870A mutation is the most common mutation in CCND1, which produces two isoforms: full-length CCND1a and divergent C-terminal CCND1b. The dysregulation of the CCND1 isoforms is associated with multiple human cancers. Exploring the molecular mechanism of CCND1 isoforms has offer new insight for cancer treatment. On this basis, the alterations of CCND1 gene are described, including amplification, overexpression, and mutation, especially the G870A mutation. Subsequently, we review the characteristics of CCND1 isoforms caused by G870A mutation. Additionally, we summarize cis-regulatory elements, trans-acting factors, and the splice mutation involved in splicing regulation of CCND1. Furthermore, we highlight the function of CCND1 isoforms in cell cycle, invasion, and metastasis in cancers. Importantly, the clinical role of CCND1 isoforms is also discussed, particularly concerning prognosis, chemotherapy, and radiotherapy. Last, emphasis is given to the corrective strategies that modulate the cancerous CCND1 isoforms. Thus, it is highlighting significance of aberrant isoforms of CCND1 as targets for cancer therapy.
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Affiliation(s)
- Jing Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
| | - Wei Su
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Taotao Zhang
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Shasha Zhang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Huiwen Lei
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 101408, China
| | - Fengdie Ma
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Maoning Shi
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Wenjing Shi
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China
| | - Xiaodong Xie
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, 730000, China.
| | - Cuixia Di
- Bio-Medical Research Center, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, 730000, China.
- Key Laboratory of Heavy Ion Radiation Biology and Medicine of Chinese Academy of Sciences, Lanzhou, 730000, China.
- College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 101408, China.
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Sensitization of prostate cancer to radiation therapy: Molecules and pathways to target. Radiother Oncol 2018; 128:283-300. [PMID: 29929859 DOI: 10.1016/j.radonc.2018.05.021] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Revised: 05/01/2018] [Accepted: 05/17/2018] [Indexed: 12/11/2022]
Abstract
Radiation therapy is used to treat cancer by radiation-induced DNA damage. Despite the best efforts to eliminate cancer, some cancer cells survive irradiation, resulting in cancer progression or recurrence. Alteration in DNA damage repair pathways is common in cancers, resulting in modulation of their response to radiation. This article focuses on the recent findings about molecules and pathways that potentially can be targeted to sensitize prostate cancer cells to ionizing radiation, thereby achieving an improved therapeutic outcome.
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Ma M, Zhao J, Wu Q, Xiao K, Li S, Zhu H, Liu C, Xie H, Zuo C. MiRNA-545 negatively regulates the oncogenic activity of EMS1 in gastric cancer. Cancer Med 2018; 7:2452-2462. [PMID: 29733519 PMCID: PMC6010719 DOI: 10.1002/cam4.1520] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Revised: 03/17/2018] [Accepted: 04/03/2018] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer (GC) is a common malignant tumor of the digestive system. In addition, GC metastasis is an extremely complicated process. In this article, high expression levels of EMS1 mRNA and protein were found to be positively correlated with an enhanced malignant potential of GC cells and a poor clinical prognosis of GC patients. Interestingly, the expression levels of EMS1 mRNA and protein in GC cells were inhibited by microRNA-545 (miR-545), which was identified by a bioinformatics analysis. The expression level of miR-545 in carcinoma tissues was significantly lower than that in para-carcinoma tissues. The proliferation and epithelial-mesenchymal transition (EMT) of GC cells were suppressed by exogenous oligonucleotides of miR-545 mimics. In addition, the expression levels of EMT-associated markers were altered with the expression of miR-545. Notably, the growth rates of tumors in nude mice were seriously restrained by an intratumoral injection of oligonucleotides of the miR-545 mimics. These results suggest a negative regulatory role of miR-545 on the oncogenic activity of EMS1. In addition, EMS1 and miR-545 may be potential biomarkers for GC diagnosis. Synthesized oligonucleotides of miR-545 mimics may be developed as important gene medicines for GC therapy in the future.
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Affiliation(s)
- Min Ma
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, Hunan, 410013, China
| | - Juanxia Zhao
- Institute of Cancer Research, School of Medicine, University of South China, Hengyang, Hunan, 421001, China
| | - Qunfeng Wu
- Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, 07103
| | - Ke Xiao
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, Hunan, 410013, China
| | - Shuang Li
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, Hunan, 410013, China
| | - Haizhen Zhu
- Department of Molecular Medicine, College of Biology, State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha, Hunan, 410082, China
| | - Chen Liu
- Department of Pathology and Laboratory Medicine, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, New Jersey, 07103
| | - Hailong Xie
- Institute of Cancer Research, School of Medicine, University of South China, Hengyang, Hunan, 421001, China
| | - Chaohui Zuo
- The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Hunan Cancer Hospital, Changsha, Hunan, 410013, China
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78495111110.3390/cancers9050052" />
Abstract
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation. These EGFR aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These pathways then activate many biological outputs that are beneficial to cancer cell proliferation, including their chronic initiation and progression through the cell cycle. Here, we review the molecular mechanisms that regulate EGFR signal transduction, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression. We focus on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways. We also discuss the successes and challenges of EGFR-targeted therapies, and the potential for their use in combination with CDK4/6 inhibitors.
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Wee P, Wang Z. Epidermal Growth Factor Receptor Cell Proliferation Signaling Pathways. Cancers (Basel) 2017; 9:cancers9050052. [PMID: 28513565 PMCID: PMC5447962 DOI: 10.3390/cancers9050052] [Citation(s) in RCA: 1201] [Impact Index Per Article: 150.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Revised: 05/10/2017] [Accepted: 05/10/2017] [Indexed: 12/12/2022] Open
Abstract
The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is commonly upregulated in cancers such as in non-small-cell lung cancer, metastatic colorectal cancer, glioblastoma, head and neck cancer, pancreatic cancer, and breast cancer. Various mechanisms mediate the upregulation of EGFR activity, including common mutations and truncations to its extracellular domain, such as in the EGFRvIII truncations, as well as to its kinase domain, such as the L858R and T790M mutations, or the exon 19 truncation. These EGFR aberrations over-activate downstream pro-oncogenic signaling pathways, including the RAS-RAF-MEK-ERK MAPK and AKT-PI3K-mTOR pathways. These pathways then activate many biological outputs that are beneficial to cancer cell proliferation, including their chronic initiation and progression through the cell cycle. Here, we review the molecular mechanisms that regulate EGFR signal transduction, including the EGFR structure and its mutations, ligand binding and EGFR dimerization, as well as the signaling pathways that lead to G1 cell cycle progression. We focus on the induction of CYCLIN D expression, CDK4/6 activation, and the repression of cyclin-dependent kinase inhibitor proteins (CDKi) by EGFR signaling pathways. We also discuss the successes and challenges of EGFR-targeted therapies, and the potential for their use in combination with CDK4/6 inhibitors.
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Affiliation(s)
- Ping Wee
- Department of Medical Genetics and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
| | - Zhixiang Wang
- Department of Medical Genetics and Signal Transduction Research Group, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
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Identification of epidermal growth factor receptor and its inhibitory microRNA141 as novel targets of Krüppel-like factor 8 in breast cancer. Oncotarget 2016; 6:21428-42. [PMID: 26025929 PMCID: PMC4673276 DOI: 10.18632/oncotarget.4077] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2015] [Accepted: 05/14/2015] [Indexed: 01/22/2023] Open
Abstract
Krüppel-like factor 8 (KLF8) is a dual transcriptional factor critical for breast cancer progression. Epidermal growth factor receptor (EGFR) is frequently overexpressed in aggressive such as triple-negative breast cancer and associated with poor clinical outcomes. Here we report a novel KLF8-EGFR signaling axis in breast cancer. We identified a highly correlated co-overexpression between KLF8 and EGFR in invasive breast cancer cells and patient tumor samples. Overexpression of KLF8 in the non-tumorigenic MCF-10A cells induced the expression of EGFR, whereas knockdown of KLF8 from the MDA-MB-231 cells decreased it. Promoter activation and binding assays indicated that KLF8 promotes the EGFR expression by directly binding its gene promoter. We also revealed that KLF8 directly represses the promoter of miR141 and miR141 targets the 3′-untranslational region of EGFR transcript to inhibit EGFR translation. Treatment with the EGFR inhibitor AG1478 or overexpression of miR141 blocked the activity of ERK downstream of EGFR and inhibited KLF8-depndent cell invasiveness, proliferation and viability in cell culture and invasive growth and lung metastasis in nude mice. Conversely, overexpression of an inhibitory sponge of miR141 led to the opposite phenotypes. Taken together, these findings demonstrate a novel KLF8 to miR141/EGFR signaling pathway potentially crucial for breast cancer malignancy.
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Codony-Servat J, Rosell R. Cancer stem cells and immunoresistance: clinical implications and solutions. Transl Lung Cancer Res 2016; 4:689-703. [PMID: 26798578 DOI: 10.3978/j.issn.2218-6751.2015.12.11] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Tumor cells can be contained, but not eliminated, by traditional cancer therapies. A cell minor subpopulation is able to evade attack from therapies and may have cancer stem cell (CSC) characteristics, including self-renewal, multiple differentiation and tumor initiation (tumor initiating cells, or TICs). Thus, CSCs/TICs, aided by the microenvironment, produce more differentiated, metastatic cancer cells which the immune system detects and interacts with. There are three phases to this process: elimination, equilibrium and escape. In the elimination phase the immune system recognizes and destroys most of the tumor cells. Then the latency phase begins, consisting of equilibrium between immunological elimination and tumor cell growth. Finally, a minor attack-resistant subpopulation escapes and forms a clinically detectable tumor mass. Herein we review current knowledge of immunological characterization of CSCs/TICs. Due to the correlation between CTCs/TICs and drug resistance and metastasis, we also comment on the crucial role of key molecules involved in controlling CSCs/TICs properties; such molecules are essential to detect and destroy CSCs/TICs. Monoclonal antibodies, antibody constructs and vaccines have been designed to act against CSCs/TICs, with demonstrated efficacy in human cancer xenografts and some antitumor activity in human clinical studies. Therefore, therapeutic strategies that selectively target CSCs/TICs warrant further investigation. Better understanding of the interaction between CSCs and tumor immunology may help to identify strategies to eradicate the minor subpopulation that escapes conventional therapy attack, thus providing a solution to the problem of drug resistance and metastasis.
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Affiliation(s)
- Jordi Codony-Servat
- 1 Pangaea Biotech S.L., Quirón-Dexeus University Hospital, Barcelona, Spain ; 2 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain ; 3 Instituto Oncológico Dr Rosell, Quirón-Dexeus University Hospital, Barcelona, Spain ; 4 Fundación Molecular Oncology Research, Barcelona, Spain
| | - Rafael Rosell
- 1 Pangaea Biotech S.L., Quirón-Dexeus University Hospital, Barcelona, Spain ; 2 Cancer Biology and Precision Medicine Program, Catalan Institute of Oncology, Hospital Germans Trias i Pujol, Badalona, Spain ; 3 Instituto Oncológico Dr Rosell, Quirón-Dexeus University Hospital, Barcelona, Spain ; 4 Fundación Molecular Oncology Research, Barcelona, Spain
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Association of CCND1 overexpression with KRAS and PTEN alterations in specific subtypes of non-small cell lung carcinoma and its influence on patients' outcome. Tumour Biol 2015; 36:8773-80. [PMID: 26055143 DOI: 10.1007/s13277-015-3620-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2015] [Accepted: 05/27/2015] [Indexed: 01/12/2023] Open
Abstract
Cyclin D1 is one of the major cellular oncogenes, overexpressed in number of human cancers, including non-small cell lung carcinoma (NSCLC). However, it does not exert tumorigenic activity by itself, but rather cooperates with other altered oncogenes and tumor suppressors. Therefore, in the present study, we have examined mutual role of cyclin D1, KRAS, and PTEN alterations in the pathogenesis of NSCLC and their potential to serve as multiple molecular markers for this disease. CCND1 gene amplification and gene expression were analyzed in relation to mutational status of KRAS gene as well as to PTEN alterations (loss of heterozygosity and promoter hypermethylation) in NSCLC patient samples. Moreover, the effect of these co-alterations on patient survival was examined. Amplified CCND1 gene was exclusively associated with increased gene expression. Statistical analyses also revealed significant association between CCND1 overexpression and KRAS mutations in the whole group and in the groups of patients with adenocarcinoma, grade 1/2, and stage I/II. In addition, CCND1 overexpression was significantly related to PTEN promoter hypermethylation in the whole group and in the group of patients with squamous cell carcinoma and lymph node invasion. These joint alterations also significantly shortened patients' survival and were shown to be an independent factor for adverse prognosis. Overall results point that cyclin D1 expression cooperates with KRAS and PTEN alterations in pathogenesis of NSCLC, and they could serve as potential multiple molecular markers for specific subgroups of NSCLC patients as well as prognostic markers for this type of cancer.
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Szyszka-Barth K, Ramlau K, Goździk-Spychalska J, Spychalski Ł, Bryl M, Gołda-Gocka I, Kopczyńska A, Barinow-Wojewódzki A, Ramlau R. Actual status of therapeutic vaccination in non-small cell lung cancer. Contemp Oncol (Pozn) 2014; 18:77-84. [PMID: 24966788 PMCID: PMC4068811 DOI: 10.5114/wo.2014.42724] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2014] [Revised: 04/02/2014] [Accepted: 04/17/2014] [Indexed: 12/16/2022] Open
Abstract
Lung cancer is the leading cause of cancer-related death worldwide. Although treatment methods such as surgery, radiotherapy and/or chemotherapy have improved, prognosis remains unsatisfactory, and developing new therapeutic strategies is still an urgent matter. Immunotherapy is a novel therapeutic approach wherein activated immune cells can specifically kill tumour cells. Several lung cancer vaccines have demonstrated prolonged survival time in phase II and III trials, and several clinical trials are under investigation. However, many clinical trials involving cancer vaccination with defined tumour antigens have shown this method to work only in a small number of patients. Cancer immunotherapy is not completely effective in eradicating tumour cells because they evade host immune control.
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Affiliation(s)
- Katarzyna Szyszka-Barth
- Department of Clinical Oncology with the Subdepartment of Diurnal Chemotherapy, Wielkopolska Center of Pulmonology and Thoracosurgery of Eugenia and Janusz Zeyland, Poznan, Poland
| | | | - Joanna Goździk-Spychalska
- Department of Pulmonology, Allergology and Lung Oncology, Poznan University of Medical Sciences, Poland
| | - Łukasz Spychalski
- Department of Clinical Oncology with the Subdepartment of Diurnal Chemotherapy, Wielkopolska Center of Pulmonology and Thoracosurgery of Eugenia and Janusz Zeyland, Poznan, Poland
| | - Maciej Bryl
- Department of Clinical Oncology with the Subdepartment of Diurnal Chemotherapy, Wielkopolska Center of Pulmonology and Thoracosurgery of Eugenia and Janusz Zeyland, Poznan, Poland
| | - Iwona Gołda-Gocka
- Department of Clinical Oncology with the Subdepartment of Diurnal Chemotherapy, Wielkopolska Center of Pulmonology and Thoracosurgery of Eugenia and Janusz Zeyland, Poznan, Poland
| | - Anna Kopczyńska
- Department of Chemotherapy, Poznan University of Medical Sciences, Poland
| | - Aleksander Barinow-Wojewódzki
- Adult Pulmonary-Rehabilitation Department, Wielkopolska Center of Pulmonology and Thoracosurgery of Eugenia and Janusz Zeyland, Poznan, Poland
| | - Rodryg Ramlau
- Department of Clinical Oncology with the Subdepartment of Diurnal Chemotherapy, Wielkopolska Center of Pulmonology and Thoracosurgery of Eugenia and Janusz Zeyland, Poznan, Poland
- Thoracosurgery Clinic, Poznan University of Medical Sciences, Poland
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Lung cancer. Mol Oncol 2013. [DOI: 10.1017/cbo9781139046947.044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
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Hegde GV, de la Cruz CC, Chiu C, Alag N, Schaefer G, Crocker L, Ross S, Goldenberg D, Merchant M, Tien J, Shao L, Roth L, Tsai SP, Stawicki S, Jin Z, Wyatt SK, Carano RAD, Zheng Y, Sweet-Cordero EA, Wu Y, Jackson EL. Blocking NRG1 and Other Ligand-Mediated Her4 Signaling Enhances the Magnitude and Duration of the Chemotherapeutic Response of Non-Small Cell Lung Cancer. Sci Transl Med 2013; 5:171ra18. [DOI: 10.1126/scitranslmed.3004438] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Winter H, van den Engel NK, Rusan M, Schupp N, Poehlein CH, Hu HM, Hatz RA, Urba WJ, Jauch KW, Fox BA, Rüttinger D. Active-specific immunotherapy for non-small cell lung cancer. J Thorac Dis 2012; 3:105-14. [PMID: 22263073 DOI: 10.3978/j.issn.2072-1439.2010.12.06] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2010] [Accepted: 12/24/2010] [Indexed: 12/28/2022]
Abstract
Non-small cell lung cancer constitutes about 85% of all newly diagnosed cases of lung cancer and continues to be the leading cause of cancer-related deaths worldwide. Standard treatment for this devastating disease, such as systemic chemotherapy, has reached a plateau in effectiveness and comes with considerable toxicities. For all stages of disease fewer than 20% of patients are alive 5 years after diagnosis; for metastatic disease the median survival is less than one year. Until now, the success of active-specific immunotherapy for all tumor types has been sporadic and unpredictable. However, the active-specific stimulation of the host's own immune system still holds great promise for achieving non-toxic and durable antitumor responses. Recently, sipuleucel-T (Provenge(®); Dendreon Corp., Seattle, WA) was the first therapeutic cancer vaccine to receive market approval, in this case for advanced prostate cancer. Other phase III clinical trials using time-dependent endpoints, e.g. in melanoma and follicular lymphoma, have recently turned out positive. More sophisticated specific vaccines have now also been developed for lung cancer, which, for long, was not considered an immune-sensitive malignancy. This may explain why advances in active-specific immunotherapy for lung cancer lag behind similar efforts in renal cell cancer, melanoma or prostate cancer. However, various vaccines are now being evaluated in controlled phase III clinical trials, raising hopes that active-specific immunotherapy may become an additional effective therapy for patients with lung cancer. This article reviews the most prominent active-specific immunotherapeutic approaches using protein/peptide, whole tumor cells, and dendritic cells as vaccines for lung cancer.
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Affiliation(s)
- Hauke Winter
- Department of Surgery-Campus Grosshadern, Thoracic Surgery Center Munich, Laboratory of Clinical and Experimental Tumor Immunology, Ludwig-Maximilians-University, Munich, Germany
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Vijayalakshmi R, Krishnamurthy A. Targetable "driver" mutations in non small cell lung cancer. Indian J Surg Oncol 2011; 2:178-88. [PMID: 22942608 DOI: 10.1007/s13193-011-0108-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2011] [Accepted: 11/23/2011] [Indexed: 12/12/2022] Open
Abstract
Lung cancer remains the leading cause of cancer-related mortality in the world despite advances in the field of cancer therapeutics. Traditional treatment with empirically chosen cytotoxic chemotherapeutic agents, have given small, but real survival benefits. Recent advances and insights into molecular pathogenesis of lung cancers have provided some novel molecular targets, offering newer strategies and agents that are tumor specific. Studies have identified mutations in specific genes that are involved in driving the development of lung cancer and so it is important to subsequently target them with specific drugs thus changing paradigms of management of this type of cancer. Recently, Lung Cancer Mutation Consortium (LCMC) has identified at least one of the many recognized "driver mutations" in nearly two thirds of the patients with advanced cancer. This study suggests that identification of driver mutations can help in molecular targeted therapeutics and in addition supplant tumor histology in guiding treatment decisions, identifying subset of patients who may benefit therapy. This review focuses on these mutations identified in specific genes serving as "drivers" of lung tumorigenesis and suggests that clear promise for the future of lung cancer treatment is indeed personalized therapy with drugs chosen according to the patient mutation profile. Most clinically relevant translational advances made in genes involved in lung tumorigenesis namely EML4-ALK fusions, HER2, PIK3CA, AKT, BRAF, MAP2K1, MET mutations and amplifications along with the well established EGFR and KRAS mutations are discussed in the context of NSCLCs. These studies emphasize the need for treatment management based on mutation profile along with routine histology based classification of these tumors in future for a directed therapy and thus a better therapeutic outcome.
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Abstract
Lung cancer is a heterogeneous disease clinically, biologically, histologically, and molecularly. Understanding the molecular causes of this heterogeneity, which might reflect changes occurring in different classes of epithelial cells or different molecular changes occurring in the same target lung epithelial cells, is the focus of current research. Identifying the genes and pathways involved, determining how they relate to the biological behavior of lung cancer, and their utility as diagnostic and therapeutic targets are important basic and translational research issues. This article reviews current information on the key molecular steps in lung cancer pathogenesis, their timing, and clinical implications.
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Affiliation(s)
- Jill E Larsen
- Hamon Center for Therapeutic Oncology Research, Simmons Cancer Center, 6000 Harry Hines Boulevard, University of Texas Southwestern Medical Center, Dallas, TX 75390-8593, USA
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Esposito L, Conti D, Ailavajhala R, Khalil N, Giordano A. Lung Cancer: Are we up to the Challenge? Curr Genomics 2011; 11:513-8. [PMID: 21532835 PMCID: PMC3048313 DOI: 10.2174/138920210793175903] [Citation(s) in RCA: 83] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2010] [Revised: 06/08/2010] [Accepted: 07/26/2010] [Indexed: 12/31/2022] Open
Abstract
Lung cancer is the leading cause of cancer deaths worldwide among both men and women, with more than 1 million deaths annually. Non–small cell lung cancer (NSCLC) accounts for about 80% of all lung cancers. Although recent advances have been made in diagnosis and treatment strategies, the prognosis of NSCLC patients is poor and it is basically due to a lack of early diagnostic tools. However, in the last years genetic and biochemical studies have provided more information about the protein and gene’s mutations involved in lung tumors. Additionally, recent proteomic and microRNA’s approaches have been introduced to help biomarker discovery. Here we would like to discuss the most recent discoveries in lung cancer pathways, focusing on the genetic and epigenetic factors that play a crucial role in malignant cell proliferation, and how they could be helpful in diagnosis and targeted therapy.
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Affiliation(s)
- Luca Esposito
- Oncology Research Centre of Mercogliano, Avellino, Italy
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Andrew AS, Mason RA, Memoli V, Duell EJ. Arsenic activates EGFR pathway signaling in the lung. Toxicol Sci 2009; 109:350-7. [PMID: 19168569 PMCID: PMC2683921 DOI: 10.1093/toxsci/kfp015] [Citation(s) in RCA: 52] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2008] [Accepted: 01/17/2009] [Indexed: 12/21/2022] Open
Abstract
Arsenic is an established lung carcinogen, however, the carcinogenic mechanisms are currently under investigation. Phosphorylation of the epidermal growth factor receptor (EGFR) has been reported with arsenic exposure in bladder cells. EGFR is a tyrosine kinase transmembrane receptor that regulates important processes in carcinogenesis, including cell survival, cell cycle progression, tumor invasion, and angiogenesis. We investigated the mechanisms of EGFR pathway activation by levels of arsenic relevant to human exposure scenarios both in vitro using cultured lung epithelial cells, and in lung tumors samples from New England Lung Cancer Study participants. Toenail arsenic levels were used as an internal biomarker of arsenic exposure. Our in vitro data suggest that arsenic increases levels of the EGFR ligand, heparin binding-EGF, and activate EGFR phosphorylation in the lung. Downstream of EGFR, arsenic exposure increased pERK and cyclin D1 levels. These effects were inhibited by treatment of cultured cells with the EGFR tyrosine kinase inhibitor, Tarceva (erlotinib). In a consecutive series of human lung tumor specimens, pEGFR protein levels were higher in subjects with elevated toenail arsenic levels compared to those with low exposure (odds ratio adjusted for other factors, OR 4.1 (95% confidence interval 1.1-15.6) (p = 0.04). These data suggest that arsenic exposure may stimulate EGFR pathway activation in the lung. Moreover, the tumors that arise in arsenic-exposed individuals also exhibit signs of EGFR pathway dysregulation. Further work is needed to assess the clinical utility of targeting the EGFR pathway in subgroups of lung cancer patients who have been exposed to elevated levels of arsenic.
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Affiliation(s)
- Angeline S Andrew
- Department of Community and Family Medicine, Dartmouth Medical School, Dartmouth College, Hanover, New Hampshire 03756, USA.
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19
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Campbell JM, Lockwood WW, Buys TPH, Chari R, Coe BP, Lam S, Lam WL. Integrative genomic and gene expression analysis of chromosome 7 identified novel oncogene loci in non-small cell lung cancer. Genome 2009; 51:1032-9. [PMID: 19088816 DOI: 10.1139/g08-086] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Lung cancer accounts for over a quarter of cancer deaths, with non-small cell lung cancer (NSCLC) accounting for approximately 80% of cases. Several genome studies have been undertaken in both cell models of NSCLC and clinical samples to identify alterations underlying disease behaviour, and many have identified recurring aberrations of chromosome 7. The presence of recurring chromosome 7 alterations that do not span the well-studied oncogenes EGFR (at 7p11.2) and MET (at 7q31.2) has raised the hypothesis of additional genes on this chromosome that contribute to tumourigenesis. In this study, we demonstrated that multiple loci on chromosome 7 are indeed amplified in NSCLC, and through integrative analysis of gene dosage alterations and parallel gene expression changes, we identified new lung cancer oncogene candidates, including FTSJ2, NUDT1, TAF6, and POLR2J. Activation of these key genes was confirmed in panels of clinical lung tumour tissue as compared with matched normal lung tissue. The detection of gene activation in multiple cohorts of samples strongly supports the presence of key genes involved in lung cancer that are distinct from the EGFR and MET loci on chromosome 7.
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Affiliation(s)
- Jennifer M Campbell
- Department of Cancer Genetics and Developmental Biology, British Columbia Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC V5Z1L3 Canada
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Sasaki H, Shimizu S, Okuda K, Kawano O, Yukiue H, Yano M, Fujii Y. Epidermal growth factor receptor gene amplification in surgical resected Japanese lung cancer. Lung Cancer 2008; 64:295-300. [PMID: 19058870 DOI: 10.1016/j.lungcan.2008.10.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2008] [Revised: 08/04/2008] [Accepted: 10/06/2008] [Indexed: 11/17/2022]
Abstract
To evaluate the epidermal growth factor receptor (EGFR) protein expression and increased copy number as predictors of clinical outcome in patients with non-small-cell lung cancer (NSCLC), we have performed fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). We investigated the EGFR increased copy number and EGFR protein expression statuses in 109 surgically treated NSCLC cases. The presence or absence of EGFR mutations of kinase domains was analyzed by genotyping analysis and sequences, and already reported. EGFR increased copy number was defined as Cappuzzo et al. criteria. FISH positive was found from 36/109 (33.0%) lung cancer patients, including 30 high polysomy cases and 6 gene amplification cases. FISH-positive cases were significantly correlated with worse prognosis (log-rank test p=0.0097). Within EGFR-mutant patients (n=55), FISH-positive cases were also correlated with poor prognosis (p=0.0255). FISH-negative tumors were found to be more frequently well-differentiated histology. Smoking status (never smoker vs. smoker, p=0.1510), and gender (p=0.5248) did not correlated with FISH positive. EGFR IHC results were correlated with FISH results (p=0.004), but not correlated with prognosis (p=0.2815). Although EGFR FISH-positive rate did not correlated with EGFR mutation (p=0.1973), EGFR polysomy or amplification cases were correlated with EGFR mutations (p=0.0023). In conclusion, the EGFR FISH-positive rate in Japanese patients with NSCLC was similar to rates in Western populations, unlike the higher frequencies of EGFR mutation in East Asians. A high EGFR gene copy number might have shorter survival in NSCLC.
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Affiliation(s)
- Hidefumi Sasaki
- Department of Surgery II, Nagoya City University Medical School, Nagoya 467-8601, Japan.
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21
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Campos SM. Anti-epidermal growth factor receptor strategies for advanced breast cancer. Cancer Invest 2008; 26:757-68. [PMID: 18853311 DOI: 10.1080/07357900801971040] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Susana M Campos
- Department of Breast and Gynecology, Dana Farber Cancer Institute, Harvard University, Boston, Massachusetts, USA
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22
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Stevens KL, Reno MJ, Alberti JB, Price DJ, Kane-Carson LS, Knick VB, Shewchuk LM, Hassell AM, Veal JM, Davis ST, Griffin RJ, Peel MR. Synthesis and evaluation of pyrazolo[1,5-b]pyridazines as selective cyclin dependent kinase inhibitors. Bioorg Med Chem Lett 2008; 18:5758-62. [PMID: 18835709 DOI: 10.1016/j.bmcl.2008.09.069] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2008] [Revised: 09/16/2008] [Accepted: 09/19/2008] [Indexed: 11/15/2022]
Abstract
A novel series of pyrazolo[1,5-b]pyridazines have been synthesized and identified as cyclin dependant kinase inhibitors potentially useful for the treatment of solid tumors. Modification of the hinge-binding amine or the C(2)- and C(6)-substitutions on the pyrazolopyridazine core provided potent inhibitors of CDK4 and demonstrated enzyme selectivity against VEGFR-2 and GSK3beta.
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Affiliation(s)
- Kirk L Stevens
- Department of Oncology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA.
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Abstract
Lung cancer is the leading cause of cancer-related death and thus a major health problem. The efficiency of current treatment modalities for lung cancer depends strongly on the time of diagnosis, with better chances of survival if a tumor has been detected at an early stage. Thus, there is an urgent need for rapid and efficient early detection methods. Biomarkers represent a possible alternative to current, rather expensive, screening tools such as spiral computer tomography (CT), or may allow the identification of high risk groups for whom screening would be cost efficient. Although most lung cancers are the consequence of smoking, a substantial fraction of molecular-epidemiological studies point to high-prevalence, low-penetrance genetic polymorphisms as modifiers of environmental lung cancer risk. In the past the genomics field has also made significant advances in identifying genetic lesions that can now be harvested with the goal of identifying novel biomarkers for lung cancer. Furthermore, the importance of epigenetic changes that occur during lung cancer development has been reported, but has been underestimated in the past. Novel high-throughput, quantitative assays for the detection of DNA methylation or histone tail modifications are now applied, to search for alterations in the lung cancer genome and will identify novel cancer-related genes that may become attractive targets for treatment, provide new insight into the biology of lung cancers, and could also become useful biomarkers for the early detection of lung cancer in sputum, or may be used as prognostic markers. Thus, an integrative approach in lung cancer research combining epidemiological, genetic and epigenetic information becomes an important concept for the future.
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Affiliation(s)
- Angela Risch
- German Cancer Research Center, Division of Epigenomics and Cancer Risk Factors, Heidelberg, Germany
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Erythropoietin receptor transcription is neither elevated nor predictive of surface expression in human tumour cells. Br J Cancer 2008; 98:1059-67. [PMID: 18349818 PMCID: PMC2275479 DOI: 10.1038/sj.bjc.6604220] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Erythropoietin receptor (EpoR) has been reported to be overexpressed in tumours and has raised safety concerns regarding the use of erythropoiesis-stimulating agents (ESAs) to treat anaemia in cancer patients. To investigate the potential for EpoR to be overexpressed in tumours, we have evaluated human tumours for amplification of the EPOR locus, levels of EPOR transcripts, and expression of surface EpoR protein. Gene amplification analysis of 1083 solid tumours found that amplification of the EPOR locus was rare with frequencies similar to other non-oncogenes. EPOR transcript levels in tumours and tumour cell lines were low in comparison with bone marrow and were equivalent to, or lower than, levels in normal tissues of tumour origin. Although EpoR mRNA was detected in some tumour lines, no EpoR could be detected on the cell surface using (125)I-Epo binding studies. This may be due to the lack of EpoR protein expression or lack of cell-surface-trafficking factors, such as Jak2. Taken together, we have found no evidence that EpoR is overexpressed in tumours or gets to the surface of tumour cells. This suggests that there is no selective advantage for tumours to overexpress EpoR and questions the functional relevance of EpoR gene transcription in tumours.
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25
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de La Motte Rouge T, Valent A, Ambrosetti D, Vielh P, Lacroix L. [Clinical and molecular predictors of response to EGFR tyrosine kinase inhibitors in non-small cell lung cancer]. Ann Pathol 2008; 27:353-63. [PMID: 18185470 DOI: 10.1016/s0242-6498(07)78274-3] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Up to 10% of patients with non-small cell lung carcinoma (NSCLC) achieve an objective response to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as erlotinib or gefitinib. This rate of response is related to non-smoker status, female gender, adenocarcinoma subtype, and Asian ethnicity. Molecular analysis showed that EGFR tyrosine kinase domain somatic mutations appear to be a strong predictor of response to EGFR-TKI. The L858R point mutation and the E746-A750 deletion represent 90% of the mutations encountered in responding patients. The amplification of EGFR gene also seems to be predictive of the response to EGFR-TKI, whereas T790M point mutation induces secondary resistance to EGFR-TKI. Nevertheless, objective responses or strong long-term stabilizations are observed in patients without any EGFR abnormality. Thus, the assessment of the EGFR status in patients with NSCLC remains controversial for clinical practice. The assessment of EGFR abnormalities should be targeted to identify reliable biomarkers of the NSCLC response to EGFR-TKI. This review presents the current knowledge on predictive biomarkers of NSCLC response to EGFR-TKI and the methods available for the assessment of EGFR status.
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Sasaki H, Okuda K, Endo K, Kawano O, Yukiue H, Yokoyama T, Yano M, Fujii Y. CCND1 messenger RNA expression is correlated with EGFR mutation status in lung cancer. Clin Lung Cancer 2007; 8:493-6. [PMID: 17922974 DOI: 10.3816/clc.2007.n.034] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND Epidermal growth factor receptor (EGFR) stimulation markedly increases cyclin D1 protein expression. Recently, it has been reported that cyclin D1 expression was increased in EGFR mutant cell lines; however, the expression status of CCND1 in EGFR mutant lung cancer tissues has not been reported. PATIENTS AND METHODS We have investigated the CCND1 messenger RNA (mRNA) levels and other clinicopathologic data in 74 lung cancers. The CCND1 mRNA levels were quantified by real-time reverse-transcriptase polymerase chain reaction using LightCycler. RESULTS The CCND1/GAPDH mRNA levels were significantly higher in adenocarcinoma (35.125 +/- 37.387) than in non-adenocarcinoma (15.2 +/- 24.699; P = .0158), and CCND1/GAPDH mRNA levels were not significantly different among smoking status, sex, or pathologic stage. The CCND1/GAPDH mRNA levels were significantly higher in lung cancer with EGFR mutation (39.713 +/- 41.265) than in lung cancer without EGFR mutation (21.805 +/- 29.152; P = .0338). CCND/GAPDH mRNA expression did not correlate with prognosis of lung cancer. CONCLUSION Using the LightCycler real-time reverse-transcriptase polymerase chain reaction assay, CCND1 gene expression might correlate with EGFR mutation in lung cancer. However, further studies are needed to confirm the impact of cyclin D1 for a molecular target of lung cancer.
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Affiliation(s)
- Hidefumi Sasaki
- Department of Surgery II, Nagoya City University Medical School, Nagoya, Japan.
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Rüttinger D, Hatz RA, Jauch KW, Fox BA. Current Immunotherapeutic Strategies in Lung Cancer. Surg Oncol Clin N Am 2007; 16:901-18, x. [DOI: 10.1016/j.soc.2007.07.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Hu L, Sham JST, Xie D, Wen JM, Wang WS, Wang Y, Guan XY. Up-regulation of fibroblast growth factor 3 is associated with tumor metastasis and recurrence in human hepatocellular carcinoma. Cancer Lett 2007; 252:36-42. [PMID: 17215076 DOI: 10.1016/j.canlet.2006.12.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2006] [Revised: 11/29/2006] [Accepted: 12/01/2006] [Indexed: 11/19/2022]
Abstract
Recently, we established a hepatocellular carcinoma (HCC) cell line (named H4-M) from a metastatic HCC tumor. In H4-M, a marker chromosome containing a homogeneously staining region (hsr) was identified by cytogenetic analysis. The hsr was characterized by chromosome microdissection and the result showed that the hsr was composed of DNA sequence from 11q13. Oncogenes CCND1 and FGF3 were localized within the complicon and overexpressions of CCND1 and FGF3 were confirmed by Northern blot analysis. Clinical significance of FGF3 overexpression was studied by immunohistochemistry (IHC) using an HCC tissue microarray (TMA) containing 60 pairs of primary/metastatic HCCs and 30 pairs of primary/recurrent HCCs. TMA study showed that overexpression of FGF3 was significantly associated with HCC metastasis and recurrence (p<0.01), suggesting that up-regulation of FGF3 may play an important role in HCC metastasis and recurrence.
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Affiliation(s)
- Liang Hu
- Department of Clinical Oncology, The University of Hong Kong, Pokfulam, Hong Kong, China
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29
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Koutsopoulos AV, Mavroudis D, Dambaki KI, Souglakos J, Tzortzaki EG, Drositis J, Delides GS, Georgoulias V, Stathopoulos EN. Simultaneous expression of c-erbB-1, c-erbB-2, c-erbB-3 and c-erbB-4 receptors in non-small-cell lung carcinomas: correlation with clinical outcome. Lung Cancer 2007; 57:193-200. [PMID: 17442448 DOI: 10.1016/j.lungcan.2007.03.009] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2006] [Revised: 02/14/2007] [Accepted: 03/07/2007] [Indexed: 11/16/2022]
Abstract
The expression of c-erbB receptors was immunohistochemically examined in paraffin embedded specimens from non-small-cell lung carcinomas. A total of 209 patients were enrolled [squamous-cell carcinomas (n=59), adenocarcinomas (n=130), large-cell carcinomas (n=15) and giant-cell carcinomas (n=5)]. The HercepTest kit scoring guidelines were used for the interpretation of positivity. C-erbB-1 was overexpressed in older patients, in squamous-cell carcinomas and in poorly-differentiated tumours, whereas c-erbB-2 overexpression with adenocarcinomas and poorly-differentiated tumours. C-erbB-4 overexpression correlated with advanced disease stage. The c-erbB-1/4 pair was the most commonly overexpressed and significantly correlated with female gender, while the c-erbB-1/2 pair with older age. Response to chemotherapy was significantly reduced in patients with tumours overexpressing c-erbB-1 receptor as well as the c-erbB-1/2 and c-erbB-3/4 receptor pairs. Patients' overall survival was significantly correlated with the co-expression of c-erbB-1 and c-erbB-4 receptors. These findings clearly suggest that specific receptors overexpression or co-overexpression is correlated with patients' disease control rate and outcome. A better understanding of the overexpression of the heterodimerized partners of c-erbB family receptors may provide a useful predictive indicator of response to molecular targeted therapies with c-erbB inhibitors.
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MESH Headings
- Adenocarcinoma/metabolism
- Adenocarcinoma/mortality
- Adult
- Aged
- Aged, 80 and over
- Carcinoma, Non-Small-Cell Lung/diagnosis
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/mortality
- Carcinoma, Non-Small-Cell Lung/pathology
- Carcinoma, Non-Small-Cell Lung/surgery
- Female
- Humans
- Immunohistochemistry
- Lung Neoplasms/diagnosis
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/mortality
- Lung Neoplasms/pathology
- Lung Neoplasms/surgery
- Male
- Middle Aged
- Multivariate Analysis
- Neoplasm Staging
- Proto-Oncogene Proteins/metabolism
- Receptor, ErbB-2/analysis
- Receptor, ErbB-2/immunology
- Receptor, ErbB-2/metabolism
- Retrospective Studies
- Survival Analysis
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Affiliation(s)
- Anastassios V Koutsopoulos
- Department of Pathology, University General Hospital of Heraklion, P.O. Box 1352, Heraklion 71110, Crete, Greece.
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Yang D, Schneider S, Azuma M, Iqbal S, El-Khoueiry A, Groshen S, Agafitei D, Danenberg KD, Danenberg PV, Ladner RD, Lenz HJ. Gene expression levels of epidermal growth factor receptor, survivin, and vascular endothelial growth factor as molecular markers of lymph node involvement in patients with locally advanced rectal cancer. Clin Colorectal Cancer 2007; 6:305-11. [PMID: 17241515 DOI: 10.3816/ccc.2006.n.049] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Patients diagnosed with locally advanced rectal cancer usually receive surgical resection and adjuvant chemoradiation therapy. Lymph node involvement is an important clinical prognostic factor affecting recurrence and survival. Few studies have explored molecular markers associated with lymph node involvement of rectal cancer. PATIENTS AND METHODS Tissue was obtained from 59 patients with locally advanced rectal cancer who were treated with adjuvant chemoradiation therapy. We assessed messenger RNA (mRNA) levels of genes involved in pathways of angiogenesis (vascular endothelial growth factor [VEGF], cyclooxygenase-2), apoptosis (survivin), tumor growth and epidermal growth factor receptor (EGFR), DNA repair (ERCC1, Rad51), and the DNA synthesis in tumor tissue and tumor-adjacent normal tissue from paraffin-embedded samples using laser-capture microdissection methods. RESULTS Twenty-four patients had no involvement of regional lymph nodes and 35 had lymph node metastases. In univariate analysis, patients with lymph node involvement had higher mRNA levels of VEGF and survivin in tumor tissue and EGFR in tumor-adjacent normal tissue compared with patients with no lymph node involvement (P < 0.1; t test). Multivariate analysis using recursive partitioning showed that mRNA levels of EGFR, survivin, and Rad51 are primarily responsible for delineating node positive from node negative. CONCLUSION Gene expression of VEGF, survivin, and EGFR could be associated with lymph node involvement in patients with locally advanced rectal cancer. Further independent studies of those gene expression levels and lymph node involvement are warranted to better characterize the associations.
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Affiliation(s)
- Dongyun Yang
- Department of Preventive Medicine, Humboldt-University, Berlin, Germany
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van der Woning SP, van Rotterdam W, Nabuurs SB, Venselaar H, Jacobs-Oomen S, Wingens M, Vriend G, Stortelers C, van Zoelen EJJ. Negative Constraints Underlie the ErbB Specificity of Epidermal Growth Factor-like Ligands. J Biol Chem 2006; 281:40033-40. [PMID: 17032651 DOI: 10.1074/jbc.m603168200] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Epidermal growth factor (EGF)-like growth factors bind their ErbB receptors in a highly selective manner, but the molecular basis for this specificity is poorly understood. We have previously shown that certain residues in human EGF (Ser(2)-Asp(3)) and TGFalpha (Glu(26)) are not essential for their binding to ErbB1 but prevent binding to ErbB3 and ErbB4. In the present study, we have used a phage display approach to affinity-optimize the C-terminal linear region of EGF-like growth factors for binding to each ErbB receptor and thereby shown that Arg(45) in EGF impairs binding to both ErbB3 and ErbB4. By omitting all these so-called negative constraints from EGF, we designed a ligand designated panerbin that binds ErbB1, ErbB3, and ErbB4 with similarly high affinity as their wild-type ligands. Homology models, based on the known crystal structure of TGFalpha-bound ErbB1, showed that panerbin is able to bind ErbB1, ErbB3, and ErbB4 in a highly similar manner with respect to position and number of interaction sites. Upon in silico introduction of the experimentally known negative constraints into panerbin, we found that Arg(45) induced local charge repulsion and Glu(26) induced steric hindrance in a receptor-specific manner, whereas Ser(2)-Asp(3) impaired binding due to a disordered conformation. Furthermore, radiolabeled panerbin was used to quantify the level of all three receptors on human breast cancer cells in a single radioreceptor assay. It is concluded that the ErbB specificity of EGF-like growth factors primarily results from the presence of a limited number of residues that impair the unintended interaction with other ErbB receptors.
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Affiliation(s)
- Sebastian P van der Woning
- Department of Cell Biology and Centre for Molecular and Biomolecular Informatics, Radboud University Nijmegen, Faculty of Science, Toernooiveld 1, 6525 ED Nijmegen, The Netherlands.
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Kettunen E, Salmenkivi K, Vuopala K, Toljamo T, Kuosma E, Norppa H, Knuutila S, Kaleva S, Huuskonen MS, Anttila S. Copy number gains on 5p15, 6p11-q11, 7p12, and 8q24 are rare in sputum cells of individuals at high risk of lung cancer. Lung Cancer 2006; 54:169-76. [PMID: 16935392 DOI: 10.1016/j.lungcan.2006.07.009] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2006] [Revised: 07/02/2006] [Accepted: 07/15/2006] [Indexed: 11/21/2022]
Abstract
UNLABELLED Lung cancer specimens display recurrent copy number aberrations in distinguished chromosomal regions as compared with normal lung cells. Such alterations have been utilized in design of fluorescence in situ hybridization (FISH) probe sets in attempts to improve the cytological diagnosis of lung cancer. One of such probe sets, LAVysion, detects copy number changes in the centromeric region of chromosome 6 (CEP6), and regions 5p15, 8q24, and 7p12, often gained in lung cancer. METHODS We evaluated the feasibility of the LAVysion multi-color probe set in detection of individuals at high risk of lung cancer by applying the FISH probe set on smears prepared of induced sputa obtained from 20 lung cancer patients, 43 asbestos-exposed workers, 21 heavy tobacco smokers, and 15 healthy never-smokers. The hybridized sputum smears were examined using fluorescence microscopy and the number of signals in epithelial cells was examined throughout the hybridized area. Additionally, we review here the previous studies using LAVysion probe set. RESULTS The FISH probe set was slightly more sensitive than cytology alone in detecting lung cancer. No significant differences in copy number gain were found between high-risk individuals and healthy never-smokers. The proportions of individuals with copy number gains in sputa among the lung cancer patients, asbestos-exposed workers, tobacco smokers, and never-smokers were 50, 20, 12, and 27%, respectively, when three or more cells with a copy number gain detected by at least two different probes was used as the cut-off point. In comparison, the sensitivity of cytology in detecting lung cancer was 44%. In the lung cancer patients the number of abnormal cells by FISH correlated well with the cytologic atypia class (Spearman rank correlation coefficient 0.77, p<0.01). Using multivariant variance analysis, gains in CEP6, 5p15, 8q24 and 7p12 were not associated with smoking or asbestos exposure. CONCLUSIONS FISH did not significantly exceed the sensitivity of sputum cytology in finding lung cancers. Significant differences were not found between sputa of asbestos-exposed individuals, heavy-smokers and never-smokers. More sensitive methods are needed for the follow-up of populations at high risk of contracting lung cancer.
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Affiliation(s)
- Eeva Kettunen
- Finnish Institute of Occupational Health, Centre of Expertise for Health and Work Ability, Topeliuksenkatu 41 a A, FI-00250 Helsinki, Finland
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Gautschi O, Ratschiller D, Gugger M, Betticher DC, Heighway J. Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation. Lung Cancer 2006; 55:1-14. [PMID: 17070615 DOI: 10.1016/j.lungcan.2006.09.024] [Citation(s) in RCA: 188] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2006] [Revised: 09/25/2006] [Accepted: 09/26/2006] [Indexed: 01/10/2023]
Abstract
PURPOSE To review the evidence implicating the deregulation of cyclin D1 in the pathogenesis of non-small cell lung cancer (NSCLC), and to discuss the opportunities for targeted clinical intervention. METHODS Data published until June 2006 are summarized, and previously unpublished results from our own research are included. RESULTS In normal cells, cyclin D1 complexes with and activates cyclin-dependent kinases (CDK) and acts as a transcriptional regulator. The protein is frequently overexpressed in a wide range of cancers, sometimes coincident with CCND1 (cyclin D1) gene amplification (5-20% of tumours). A low level of somatic mutations have been seen in certain tumours. CCND1 is amplified in NSCLC and cyclin D1 is frequently overexpressed in tumours and pre-invasive bronchial lesions, generally from one parental allele. Mutation analyses revealed a frequent CCND1 gene polymorphism (A870G) that modulates alternative splicing and allows expression of an alternative cyclin D1 transcript (transcript cyclin D1b). The encoded cyclin D1b protein lacks a specific phosphorylation site required for nuclear export. Genotype has been correlated with the risk and/or severity of disease or drug response across a range of malignancies, including lung cancer. Together, these findings suggest a strong pathological role for cyclin D1 deregulation in bronchial neoplasia. CONCLUSION Current data indicate that cyclin D1 overexpression is not a consequence of, but rather a pivotal element in the process of malignant transformation in the lung and other tissues. This understanding may open new avenues for lung cancer diagnosis, treatment and prevention.
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Affiliation(s)
- Oliver Gautschi
- University of California Davis Cancer Center, Sacramento 95817, USA, and Clinic of Medical Oncology, University Hospital Bern, Bern, Switzerland.
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Yokoyama T, Kondo M, Goto Y, Fukui T, Yoshioka H, Yokoi K, Osada H, Imaizumi K, Hasegawa Y, Shimokata K, Sekido Y. EGFR point mutation in non-small cell lung cancer is occasionally accompanied by a second mutation or amplification. Cancer Sci 2006; 97:753-9. [PMID: 16863509 PMCID: PMC11158750 DOI: 10.1111/j.1349-7006.2006.00233.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
Activating mutations of EGFR are found frequently in a subgroup of patients with non-small cell lung cancer (NSCLC) and are highly correlated with the response to gefitinib and erlotinib. In the present study, we searched for mutations of EGFR, HER2 and KRAS in 264 resected primary NSCLC from Japanese patients and determined whether there is a correlation between genetic alterations of these genes and clinicopathological factors, together with 85 tumors that we reported previously. EGFR mutations were found in 102 of the total 349 tumors, and seven tumors had two missense mutations. Reverse transcription-polymerase chain reaction of EGFR and subsequent subcloning analyses identified that the double mutations occurred in the same allele. Furthermore, in 202 NSCLC analyzed by Southern blotting, we identified 11 tumors with gene amplification of EGFR, with eight tumors containing a mutation in EGFR. Sequence analysis detected only weak or no signals of the wild-type allele in the eight tumors, strongly suggesting that the mutated allele was amplified selectively. These findings indicate that a dual genetic change of EGFR can occur in the same allele either with a possible second-hit mutation or with amplification, which may imply a more selective growth advantage in a cancer cell. Meanwhile, HER2 mutations and amplifications were found in six of 349 tumors and three of 202 tumors, respectively, and KRAS mutations in 21 of 349 tumors. Mutations of the EGFR and HER2 genes were more frequently found in female never or light-smoking patients with adenocarcinoma, and there were no tumors that had two or more mutations simultaneously among EGFR, HER2 and KRAS. The current study further demonstrates that a double genetic event in EGFR can occasionally occur in lung cancer, thus providing new clues for understanding the involvement of epidermal growth factor receptor signaling cascades in the pathogenesis of NSCLC.
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Affiliation(s)
- Toshihiko Yokoyama
- Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya 464-0021
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Abstract
Although cell-lineage and differentiation models dominate tumour classification and treatment, the recognition that cancer is also a genomic disease has prompted a reconfiguration of cancer taxonomies according to molecular criteria. Recent evidence indicates that a synthesis of lineage-based and genetic paradigms might offer new insights into crucial and therapeutically pliable tumour dependencies. For example, MITF (microphthalmia-associated transcription factor), which is a master regulator of the melanocyte lineage, might become a melanoma oncogene when deregulated in certain genetic contexts. MITF and other lineage-survival genes therefore implicate lineage dependency (or lineage addiction) as a newly recognized mechanism that is affected by tumour genetic alterations.
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Affiliation(s)
- Levi A Garraway
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
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Wikman H, Kettunen E. Regulation of the G1/S phase of the cell cycle and alterations in the RB pathway in human lung cancer. Expert Rev Anticancer Ther 2006; 6:515-30. [PMID: 16613540 DOI: 10.1586/14737140.6.4.515] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
The retinoblastoma (RB)-Cyclin (CCN)D1-p16 cell cycle pathway has a crucial role in lung tumorigenesis. Impairment of the RB pathway has been shown to occur in almost all lung tumors. A deregulation at any level of this core RB pathway seems to make cells insensitive to the mitogenic signaling that is required for cell cycle progression. To date, almost all participants in this pathway have been shown to be altered to a various degree in lung tumors. Some of the alterations are mutually exclusive, including RB and p16INK4A . In small cell lung cancer, the RB tumor suppressor gene is inactivated in almost 90% of the tumors, whereas in non-small cell lung cancer, the cyclin-dependent kinase (CDK)4 inhibitor p16INK4A is inactivated in 40-60% of the tumors. Many mechanisms may be responsible for activating the RB-Cyclin D1 pathway, including activating (CDK4) and inactivating mutations (p16INK4A ), deletions (RB and p16INK4A ), amplifications (CCND1 and CDK4), silencing methylation (p16INK4A and RB), and hyper-phosphorylation (RB). As some of these alterations, such as p16INK4A methylation, can also be detected in bronchial lavage and serum, they could potentially serve as useful markers for the early detection of lung cancer. This review summarizes recent experiments describing the variable roles of key-player molecules of the RB pathway and different mechanisms by which the RB pathway can be altered in lung cancer.
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Affiliation(s)
- Harriet Wikman
- Institute of Tumor Biology, Center of Experimental Medicine, University Medical Center Hamburg-Eppendorf Martinistrasse 52, D-20246 Hamburg, Germany.
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Dacic S, Flanagan M, Cieply K, Ramalingam S, Luketich J, Belani C, Yousem SA. Significance of EGFR protein expression and gene amplification in non-small cell lung carcinoma. Am J Clin Pathol 2006; 125:860-865. [PMID: 16690485 DOI: 10.1309/h5uw-6cpc-wwc9-2241] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
We evaluated epidermal growth factor receptor (EGFR) protein expression by immunohistochemical analysis and EGFR gene amplification by fluorescence in situ hybridization in 199 consecutive newly diagnosed and surgically treated patients with primary non-small cell lung carcinoma (NSCLC) and correlated results with clinicopathologic findings. EGFR protein expression was more common in squamous cell carcinoma (SCC; 17 [26.2%]) than in adenocarcinoma (14 [11.1%]; (P = .0076) and more frequently associated with EGFR amplification (8 [14.5%] vs 4 [3.6%] cases; P = .0208). Poor differentiation was associated with a higher average number of EGFR gene copies per cell (mean, 4.18; P = .0322) and a higher EGFR/chromosome 7 ratio (mean, 1.84; P = .0324). N0 disease showed a higher number of EGFR gene copies (mean, 4.196; P = .0163). SCCs demonstrated a higher EGFR/chromosome 7 ratio than adenocarcinomas (mean, 1.95 vs 1.47; P = .0324), particularly T1 tumors (mean, 1.79; P = .0243). Statistical analysis failed to show correlation between outcome and EGFR protein expression and gene amplification in early NSCLC. EGFR protein expression was uncoupled from gene amplification in most cases, although good correlation occurred in a subset of SCCs.
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MESH Headings
- Adenocarcinoma/genetics
- Adenocarcinoma/metabolism
- Adenocarcinoma/secondary
- Adult
- Aged
- Aged, 80 and over
- Biomarkers, Tumor/metabolism
- Carcinoma, Large Cell/genetics
- Carcinoma, Large Cell/metabolism
- Carcinoma, Large Cell/secondary
- Carcinoma, Non-Small-Cell Lung/genetics
- Carcinoma, Non-Small-Cell Lung/metabolism
- Carcinoma, Non-Small-Cell Lung/secondary
- Carcinoma, Squamous Cell/genetics
- Carcinoma, Squamous Cell/metabolism
- Carcinoma, Squamous Cell/secondary
- Chromosomes, Human, Pair 7
- Disease-Free Survival
- ErbB Receptors/genetics
- ErbB Receptors/metabolism
- Gene Amplification
- Gene Dosage
- Humans
- Immunohistochemistry
- In Situ Hybridization, Fluorescence
- Lung Neoplasms/genetics
- Lung Neoplasms/metabolism
- Lung Neoplasms/pathology
- Middle Aged
- Neoplasm Staging
- Prospective Studies
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Affiliation(s)
- Sanja Dacic
- Department of Pathology, Division of Anatomic Pathology, University of Pittsburgh Medical Center, Presbyterian University Hospital, Pittsburgh, PA 15213, USA
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38
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Dacic S, Flanagan M, Cieply K, Ramalingam S, Luketich J, Belani C, Yousem SA. Significance of EGFR Protein Expression and Gene Amplification in Non–Small Cell Lung Carcinoma. Am J Clin Pathol 2006. [DOI: 10.1309/h5uw6cpcwwc92241] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
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Egri G, Takáts A. Monoclonal antibodies in the treatment of lung cancer. Eur J Surg Oncol 2006; 32:385-94. [PMID: 16504454 DOI: 10.1016/j.ejso.2006.01.007] [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: 08/15/2005] [Accepted: 01/18/2006] [Indexed: 02/09/2023] Open
Abstract
BACKGROUND Lung cancer is an aggressive disease and its conventional therapy is far from success. There is a strong need for new, better approaches to improve survival, symptom control and quality of life. METHODS The authors searched the literature for indexed articles published over the past 30 years from Pubmed concentrating on all possibilities of monoclonal antibodies in the therapy of tumours and especially of lung cancer. RESULTS The search resulted in more then 200 published articles. Important major reports of the pre-clinical/clinical investigations of monoclonal antibodies in the therapy of tumours, with an emphasis on lung cancer were reviewed, screened and tracked for other relevant publications and the yielded data were summarized and systematized. CONCLUSION It is concluded, that immunotherapy and the reviewed use of monoclonal antibodies in the therapy of tumours (including lung cancer) certainly carries a hope. However, studies of this topic are in a wide range of phases, from experiments to clinical trials, thereby their results are not comparable with each other. Based on the data available though the authors feel that active immunization with monoclonal antibodies as anti-idiotype vaccines, and antibody targeting with immunoconjugates (immunotoxins, radioimmunoconjugates and chemoimmunoconjugates) are the most promising methods. Radioimmunoguided surgery and immunoguided focal ablation are also valuable. Anti-growth factor monoclonal antibodies are the most evaluated agents so far. They certainly have an objective effect, though they are still not the 'magic bullets', waited for by many clinicians. The use of monoclonal antibodies against the escape mechanisms of tumours can be a good auxiliary method. There are too little data on the value of antibodies directly targeting tumour cells and on combined passive immunotherapy. Due to constant research, other modalities, such as prodrug activation, T cell activation, the use of intrabodies, T bodies, and conjugated antibody fragments might also prove to be valuable.
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Affiliation(s)
- G Egri
- Department of Thoracic Surgery, Bajcsy-Zsilinszky Hospital, 89-91 Maglódi Street, Budapest 1106, Hungary.
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40
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Tai ALS, Sham JST, Xie D, Fang Y, Wu YL, Hu L, Deng W, Tsao GSW, Qiao GB, Cheung ALM, Guan XY. Co-overexpression of fibroblast growth factor 3 and epidermal growth factor receptor is correlated with the development of nonsmall cell lung carcinoma. Cancer 2006; 106:146-55. [PMID: 16329133 DOI: 10.1002/cncr.21581] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Lung cancer is a prevalent cancer with a poor prognosis. To develop a useful in vitro cell model, a cell line of lung squamous cell carcinoma (SCC-35) was established. METHODS The SCC-35 cell was characterized by comparative genomic hybridization (CGH) and spectral karyotyping (SKY). Chromosome microdissection, fluorescence in situ hybridization (FISH), and Southern and Northern blots analyses were used to study target genes. RESULTS Two amplicons were found at chromosomes 7p12 and 11q13. Amplification and overexpression of epidermal growth factor receptor (EGFR) at 7p12 and fibroblast growth factor 3 (FGF3) at 11q13 were found. To understand the correlation between these two genes in nonsmall cell lung carcinoma (NSCLC) more comprehensively, overexpression of FGF3 and EGFR was investigated by immunohistochemistry with a tissue microarray containing 406 NSCLC samples. Cytoplasmic overexpression of FGF3 and EGFR was detected in 61% and 69% NSCLC cases, respectively. More interestingly, a significant correlation between overexpression of FGF3 and EGFR was found in NSCLC. CONCLUSION These results suggest that co-overexpression of FGF3 and EGFR may play an important role in the pathogenesis of lung carcinoma.
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Affiliation(s)
- Amy L S Tai
- Department of Clinical Oncology, the University of Hong Kong, Hong Kong, China
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41
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Yu Q, Sicinska E, Geng Y, Ahnström M, Zagozdzon A, Kong Y, Gardner H, Kiyokawa H, Harris LN, Stål O, Sicinski P. Requirement for CDK4 kinase function in breast cancer. Cancer Cell 2006; 9:23-32. [PMID: 16413469 DOI: 10.1016/j.ccr.2005.12.012] [Citation(s) in RCA: 301] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2005] [Revised: 11/18/2005] [Accepted: 12/09/2005] [Indexed: 02/08/2023]
Abstract
Cyclin D1 is overexpressed in the majority of human breast cancers. We previously found that mice lacking cyclin D1 are resistant to mammary carcinomas triggered by the ErbB-2 oncogene. In this study, we investigated which function of cyclin D1 is required for ErbB-2-driven mammary oncogenesis. We report that the ability of cyclin D1 to activate cyclin-dependent kinase CDK4 underlies the critical role for cyclin D1 in breast cancer formation. We also found that the continued presence of CDK4-associated kinase activity is required to maintain breast tumorigenesis. We analyzed primary human breast cancers and found high cyclin D1 levels in a subset (approximately 25%) of ErbB-2-overexpressing tumors. We propose that this subset of breast cancer patients might benefit from inhibiting CDK4 kinase.
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Affiliation(s)
- Qunyan Yu
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
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42
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Breuer RHJ, Postmus PE, Smit EF. Molecular pathology of non-small-cell lung cancer. Respiration 2005; 72:313-30. [PMID: 15942304 DOI: 10.1159/000085376] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2003] [Accepted: 07/29/2004] [Indexed: 01/22/2023] Open
Abstract
The molecular basis of lung carcinogenesis must be understood more fully and exploited to enhance survival rates of patients suffering from lung cancer. In this review we will discuss the major molecular alterations that occur in lung cancer. Emphasis is placed on alterations that occur early during carcinogenesis since they might be relevant for future screening programs. Finally we will shortly review new approaches that are used to study the molecular pathology of lung cancer and how they can be applied in a clinical setting.
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Affiliation(s)
- R H J Breuer
- Department of Pulmonology, Free University Medical Center, Amsterdam, The Netherlands
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43
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Zhao X, Weir BA, LaFramboise T, Lin M, Beroukhim R, Garraway L, Beheshti J, Lee JC, Naoki K, Richards WG, Sugarbaker D, Chen F, Rubin MA, Jänne PA, Girard L, Minna J, Christiani D, Li C, Sellers WR, Meyerson M. Homozygous deletions and chromosome amplifications in human lung carcinomas revealed by single nucleotide polymorphism array analysis. Cancer Res 2005; 65:5561-70. [PMID: 15994928 DOI: 10.1158/0008-5472.can-04-4603] [Citation(s) in RCA: 281] [Impact Index Per Article: 14.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
Genome-wide copy number changes were analyzed in 70 primary human lung carcinoma specimens and 31 cell lines derived from human lung carcinomas, with high-density arrays representing approximately 115,000 single nucleotide polymorphism loci. In addition to previously characterized loci, two regions of homozygous deletion were found, one near the PTPRD locus on chromosome segment 9p23 in four samples representing both small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) and the second on chromosome segment 3q25 in one sample each of NSCLC and SCLC. High-level amplifications were identified within chromosome segment 8q12-13 in two SCLC specimens, 12p11 in two NSCLC specimens and 22q11 in four NSCLC specimens. Systematic copy number analysis of tyrosine kinase genes identified high-level amplification of EGFR in three NSCLC specimens, FGFR1 in two specimens and ERBB2 and MET in one specimen each. EGFR amplification was shown to be independent of kinase domain mutational status.
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Affiliation(s)
- Xiaojun Zhao
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA
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44
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Shibata T, Uryu S, Kokubu A, Hosoda F, Ohki M, Sakiyama T, Matsuno Y, Tsuchiya R, Kanai Y, Kondo T, Imoto I, Inazawa J, Hirohashi S. Genetic Classification of Lung Adenocarcinoma Based on Array-Based Comparative Genomic Hybridization Analysis: Its Association with Clinicopathologic Features. Clin Cancer Res 2005; 11:6177-85. [PMID: 16144918 DOI: 10.1158/1078-0432.ccr-05-0293] [Citation(s) in RCA: 92] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
The array-based comparative genomic hybridization using microarrayed bacterial artificial chromosome clones allows high-resolution analysis of genome-wide copy number changes in tumors. To analyze the genetic alterations of primary lung adenocarcinoma in a high-throughput way, we used laser-capture microdissection of cancer cells and array comparative genomic hybridization focusing on 800 chromosomal loci containing cancer-related genes. We identified a large number of chromosomal numerical alterations, including frequent amplifications on 7p12, 11q13, 12q14-15, and 17q21, and two homozygous deletions on 9p21 and one on 8p23. Unsupervised hierarchical clustering analysis of multiple alterations revealed three subgroups of lung adenocarcinoma that were characterized by the accumulation of distinct genetic alterations and associated with smoking history and gender. The mutation status of the epidermal growth factor receptor (EGFR) gene was significantly associated with specific genetic alterations and supervised clustering analysis based on EGFR gene mutations elucidated a subgroup including all EGFR gene mutated tumors, which showed significantly shorter disease-free survival. Our results suggest that there exist multiple molecular carcinogenesis pathways in lung adenocarcinoma that may associate with smoking habits and gender, and that genetic cancer profiling will reveal previously uncharacterized genetic heterogeneity of cancer and be beneficial in estimating patient prognosis and discovering novel cancer-related genes including therapeutic targets.
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Affiliation(s)
- Tatsuhiro Shibata
- Pathology Division, National Cancer Center Research Institute, Tsukjii, Tokyo, Japan
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45
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Abstract
The retinoblastoma tumour suppressor protein (Rb) has come a long way since its initial discovery in 1986. Encoded by the first candidate tumour suppressor gene it has emerged a versatile and context-dependent modulator of cell behaviour. Its activity is managed by signalling networks sensing intra- and extracellular cues. These cues are relayed to hold or permit inactivation of Rb by phosphorylation. Loss or mutation of the retinoblastoma gene is rare in sporadic cancers but defects in the pathways that license inactivation of Rb are found in the majority of them, suggesting that loss of Rb control is central to tumour development and arguing that its reinstatement might reverse tumour formation. Furthermore, mouse models with engineered defects in the Rb-phosphorylating kinases provide evidence that moderation of Rb inactivation may be a strategy for the prevention of tumour formation. The rationale behind these arguments, their underlying molecular concepts and strategies towards therapeutic application will be discussed.
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Affiliation(s)
- Sibylle Mittnacht
- Cancer Research UK Centre for Cell and Molecular Biology, ICR, 237 Fulham Road, London SW3 6JB, UK.
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46
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Meert AP, Martin B, Verdebout JM, Noël S, Ninane V, Sculier JP. Is there a relationship between c-erbB-1 and c-erbB-2 amplification and protein overexpression in NSCLC? Lung Cancer 2005; 47:325-36. [PMID: 15713516 DOI: 10.1016/j.lungcan.2004.07.047] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2004] [Revised: 07/05/2004] [Accepted: 07/14/2004] [Indexed: 11/17/2022]
Abstract
In order to analyse the genetic abnormalities and protein expression of c-erbB-1 and -2, we have performed fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in resected non-small cell lung carcinoma (NSCLC). By IHC (106 patients), 11% of the patients were positive both for c-erbB-1 and -2 protein expression and 47% negative for both proteins. FISH (69 patients) showed a balanced disomy for both c-erbB-1 and -2 in 38%, all other cases had genetic abnormalities in at least one of both genes. c-erbB-2 gene was amplified in less than 10% of the tumours and c-erbB-1 gene was never amplified. c-erbB-2 protein overexpression was observed in only three out of the six cases showing c-erbB-2 amplification. The negative predictive value (NPV) of IHC for gene abnormalities was high for both markers. Median survival time (MST) was respectively of 76 and 174 weeks for patients with or without c-erbB-2 overexpression. Patients with c-erbB-2 amplification had a shorter survival: 125 weeks versus 165 weeks. MST was respectively of 109 and 196 weeks for patients with or without EGFR overexpression and patients with EGFR gene abnormalities had also a shorter survival with MST 136 weeks versus 189 weeks. These differences were not significant. In conclusion, if the majority of NSCLC showed genetic abnormalities in the c-erbB-1 and/or c-erbB-2 gene receptor, amplification could be observed only in a few tumours and was not strictly correlated with protein expression. Finally, survival of patients expressing EGFR and/or c-erbB-2 was slightly shorter.
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Affiliation(s)
- Anne-Pascale Meert
- Service des Soins Intensifs et Cancérologie Pulmonaire et Laboratoire d'Investigation Clinique et d'Oncologie Expérimentale HJ Tagnon, Institut Jules Bordet, 1 rue Héger Bordet, Bruxelles, Belgique.
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47
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Haas-Kogan DA, Prados MD, Tihan T, Eberhard DA, Jelluma N, Arvold ND, Baumber R, Lamborn KR, Kapadia A, Malec M, Berger MS, Stokoe D. Epidermal growth factor receptor, protein kinase B/Akt, and glioma response to erlotinib. J Natl Cancer Inst 2005; 97:880-7. [PMID: 15956649 DOI: 10.1093/jnci/dji161] [Citation(s) in RCA: 351] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND The epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib (also known as Tarceva or OSI-774) has shown promising response rates in malignant gliomas. We investigated the association between expression of EGFR and downstream signaling components and the response of malignant gliomas to erlotinib in a phase I trial of erlotinib administered either alone or with the alkylating agent temozolomide. METHODS Expression of EGFR and ligand-independent EGFRvIII mutant proteins and of phosphorylated protein kinase B (PKB)/Akt in specimens from glioma patients were assessed by immunohistochemistry. EGFR gene amplification was evaluated by fluorescence in situ hybridization. Mutations in PTEN and EGFR were assessed by polymerase chain reaction amplification and sequencing. Response was evaluated by sequential magnetic resonance imaging every 2 months. The Cochran-Mantel-Haenzel test was used to assess associations between biomarker status and response. All statistical tests were two-sided. RESULTS Of 41 glioma patients, eight responded to treatment. Response to erlotinib was associated with EGFR expression (P = .07) and EGFR amplification (P = .08). These associations were stronger and statistically significant among the 29 patients initially diagnosed with glioblastoma multiforme (P = .03 and P = .02, respectively). Among six responders with sufficient tumor tissue, none had EGFRvIII mutations. None of the 22 tumors with high levels of phosphorylated PKB/Akt responded to erlotinib treatment, whereas eight of the 18 tumors with low levels of phosphorylated PKB/Akt responded to erlotinib treatment (P < .001). The level of phosphorylated PKB/Akt was also associated with time to progression (P < .001). CONCLUSIONS Among glioma patients, those with glioblastoma multiforme tumors who have high levels of EGFR expression and low levels of phosphorylated PKB/Akt had better response to erlotinib treatment than those with low levels of EGFR expression and high levels of phosphorylated PKB/Akt.
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Affiliation(s)
- Daphne A Haas-Kogan
- Department of Neurosurgery, Brain Tumor Research Center, University of California-San Francisco, 1600 Divisadero Street, Suite H1031, San Francisco, CA 94143, USA.
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48
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Choong NW, Ma PC, Salgia R. Therapeutic targeting of receptor tyrosine kinases in lung cancer. Expert Opin Ther Targets 2005; 9:533-59. [PMID: 15948672 DOI: 10.1517/14728222.9.3.533] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Lung cancer is a difficult illness with a poor overall survival. Even though combination strategies with chemotherapy, radiation therapy and surgery have all been utilised, the overall outcome for this disease continues to be relatively disappointing. In order to make a difference in the treatment of lung cancer, novel therapeutics will have to be developed. Through basic biological studies, a number of receptor tyrosine kinases have been implicated in the pathogenesis and progression of lung cancer. In this review, the authors summarise the mechanisms of several major receptor tyrosine kinases in lung cancer, especially epidermal growth factor receptor, Her2/neu, MET, vascular endothelial growth factor and KIT. The biology associated with these receptors is described, and the various novel therapeutic inhibitory strategies that are ongoing in preclinical and clinical studies for lung cancer are detailed. Through understanding of receptor tyrosine kinases and the utilisation of specific inhibitors, it is hopeful that a dramatic impact will be made on the biology and therapy for lung cancer.
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Affiliation(s)
- Nicholas W Choong
- University of Chicago Medical Center, Pritzker School of Medicine, MC 2115, 5841, S. Maryland Avenue, Chicago, IL 60615, USA
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49
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Abstract
Lung cancer is one of the most frequent causes of cancer-related death in the United States. For patients with advanced non-small cell lung cancer (NSCLC), chemotherapy, alone or in combination with radiation therapy, is considered the standard treatment. Although this treatment may result in a modest improvement in patient survival, overall prognosis of these patients remains dismal, and the treatment is nonspecific, nonselective, and toxic. Therefore, new therapeutic strategies are needed. During the past decade, several molecules that contribute to lung cancer progression and metastasis have been identified. Growth factors and proangiogenic factors have been the focus of intense research in cancer since therapeutic approaches for their inhibition do exist. The role of these factors was studied in different organs and tumors and was found to be phenotypically distinct. Several molecular targeted therapies have shown efficacy and had been approved for treatment of specific cancers. Most advanced in clinical research for lung cancer are targeted therapies that inhibit the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor (VEGF) signaling pathways. Others are signaling pathway inhibitors. The first targeted therapy for lung cancer is gefitinib, an EGFR inhibitor, which was approved in several countries in 2003. Goals of molecular targeted therapy studies include the following: better understanding of the exact role of particular growth factors in specific tumors; establishment of new clinical study designs for biological agents; and tailoring appropriate combinations of conventional chemotherapy and/or radiotherapy with biological therapy for specific patients. Achievement of these goals will hopefully lead to incorporation of biological therapy into the current anticancer arsenal, for the benefit of lung cancer patients.
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Affiliation(s)
- Takeshi Isobe
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030, USA
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50
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Abstract
A fundamental aspect of cancer is dysregulated cell cycle control. Unlike normal cells that only proliferate when compelled to do so by developmental or other mitogenic signals in response to tissue growth needs, the proliferation of cancer cells proceeds essentially unchecked. This does not mean that cancer cell cycles are necessarily different from those found in normal cycling cells, but rather implies that cancer cells proliferate because they are no longer subject to proliferation-inhibitory influences arising from the stroma or from gene expression pattern changes consequent to 'terminal' differentiation, nor do they necessarily require extrinsic growth factors to recruit them into or maintain their proliferative state. Finally, cancer cells have also often avoided normal controls linked to cell cycle progression that halt proliferation in the presence of damaged DNA or other physiological insults. The result of these alterations is the inappropriate proliferation commonly associated with cancerous tumor formation. This review will summarize the current understanding of dysregulation of the G0/G1-to-S-phase transition in cancer cells, with particular emphasis on recent in vivo studies that suggest a need to rethink existing models of cell cycle control in development and tumorigenesis.
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Affiliation(s)
- Amit Deshpande
- Department of Radiation Oncology, Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, MA 02111, USA
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