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Shahid A, Santos SG, Lin C, Huang Y. Role of Insulin-like Growth Factor-1 Receptor in Tobacco Smoking-Associated Lung Cancer Development. Biomedicines 2024; 12:563. [PMID: 38540176 PMCID: PMC10967781 DOI: 10.3390/biomedicines12030563] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 02/23/2024] [Accepted: 02/29/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer remains a significant global health concern, with lung cancer consistently leading as one of the most common malignancies. Genetic aberrations involving receptor tyrosine kinases (RTKs) are known to be associated with cancer initiation and development, but RTK involvement in smoking-associated lung cancer cases is not well understood. The Insulin-like Growth Factor 1 Receptor (IGF-1R) is a receptor that plays a critical role in lung cancer development. Its signaling pathway affects the growth and survival of cancer cells, and high expression is linked to poor prognosis and resistance to treatment. Several reports have shown that by activating IGF-1R, tobacco smoke-related carcinogens promote lung cancer and chemotherapy resistance. However, the relationship between IGF-1R and cancer is complex and can vary depending on the type of cancer. Ongoing investigations are focused on developing therapeutic strategies to target IGF-1R and overcome chemotherapy resistance. Overall, this review explores the intricate connections between tobacco smoke-specific carcinogens and the IGF-1R pathway in lung carcinogenesis. This review further highlights the challenges in using IGF-1R inhibitors as targeted therapy for lung cancer due to structural similarities with insulin receptors. Overcoming these obstacles may require a comprehensive approach combining IGF-1R inhibition with other selective agents for successful cancer treatment.
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Affiliation(s)
- Ayaz Shahid
- Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA;
| | - Shaira Gail Santos
- College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA
| | - Carol Lin
- Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA;
| | - Ying Huang
- Department of Pharmaceutical Sciences, College of Pharmacy, Western University of Health Sciences, Pomona, CA 91766, USA;
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2
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Lagou MK, Karagiannis GS. Obesity-induced thymic involution and cancer risk. Semin Cancer Biol 2023; 93:3-19. [PMID: 37088128 DOI: 10.1016/j.semcancer.2023.04.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 04/19/2023] [Accepted: 04/20/2023] [Indexed: 04/25/2023]
Abstract
Declining thymic functions associated either with old age (i.e., age-related thymic involution), or with acute involution as a result of stress, infectious disease, or cytoreductive therapies (e.g., chemotherapy/radiotherapy), have been associated with cancer development. A key mechanism underlying such increased cancer risk is the thymus-dependent debilitation of adaptive immunity, which is responsible for orchestrating immunoediting mechanisms and tumor immune surveillance. In the past few years, a blooming set of evidence has intriguingly linked obesity with cancer development and progression. The majority of such studies has focused on obesity-driven chronic inflammation, steroid/sex hormone and adipokine production, and hyperinsulinemia, as principal factors affecting the tumor microenvironment and driving the development of primary malignancy. However, experimental observations about the negative impact of obesity on T cell development and maturation have existed for more than half a century. Here, we critically discuss the molecular and cellular mechanisms of obesity-driven thymic involution as a previously underrepresented intermediary pathology leading to cancer development and progression. This knowledge could be especially relevant in the context of childhood obesity, because impaired thymic function in young individuals leads to immune system abnormalities, and predisposes to various pediatric cancers. A thorough understanding behind the molecular and cellular circuitries governing obesity-induced thymic involution could therefore help towards the rationalized development of targeted thymic regeneration strategies for obese individuals at high risk of cancer development.
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Affiliation(s)
- Maria K Lagou
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA; Tumor Microenvironment of Metastasis Program, Albert Einstein Cancer Center, Bronx, NY, USA
| | - George S Karagiannis
- Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA; Tumor Microenvironment of Metastasis Program, Albert Einstein Cancer Center, Bronx, NY, USA; Cancer Dormancy and Tumor Microenvironment Institute, Albert Einstein College of Medicine, Bronx, NY, USA; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA; Integrated Imaging Program for Cancer Research, Albert Einstein College of Medicine, Bronx, NY, USA.
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3
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Zhang Y, Hu Y, Yu J, Xie X, Jiang F, Wu C. Landscape of PCOS co-expression gene and its role in predicting prognosis and assisting immunotherapy in endometrial cancer. J Ovarian Res 2023; 16:129. [PMID: 37393293 DOI: 10.1186/s13048-023-01201-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 06/07/2023] [Indexed: 07/03/2023] Open
Abstract
BACKGROUND Endometrial carcinoma (EC) is the sixth most frequent malignancy in women and is often linked to high estrogen exposure. Polycystic ovarian syndrome (PCOS) is a known risk factor for EC, but the underlying mechanisms remain unclear. METHODS We investigated shared gene signals and potential biological pathways to identify effective therapy options for PCOS- and EC-related malignancies. Weighted gene expression network analysis (WGCNA) was used to identify genes associated with PCOS and EC using gene expression data from the Gene Expression Omnibus (GEO) and Cancer Genome Atlas (TCGA) datasets. Enrichment analysis using Cluego software revealed that the steroid hormone biosynthetic process was a critical feature in both PCOS and EC. A predictive signature encompassing genes involved in steroid hormone production was developed using multivariate and least absolute shrinkage and selection operator (LASSO) regression analysis to predict the prognosis of EC. Then, we conducted further experimental verification. RESULTS Patients in the TCGA cohort with high predictive scores had poorer outcomes than those with low scores. We also investigated the relationship between tumor microenvironment (TME) features and predictive risk rating and found that patients with low-risk scores had higher levels of inflammatory and inhibitory immune cells. Also, we found that immunotherapy against anti-CTLA4 and anti-PD-1/PD-L1 was successful in treating individuals with low risk. Low-risk individuals were more responsive to crizotinib therapy, according to further research performed using the "pRRophetic" R package. We further confirmed that IGF2 expression was associated with tumor cell migration, proliferation, and invasion in EC cells. CONCLUTIONS By uncovering the pathways and genes linking PCOS and EC, our findings may provide new therapeutic strategies for patients with PCOS-related EC.
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Affiliation(s)
- Yun Zhang
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, 210029, China
| | - Yifang Hu
- Department of Geriatric Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Yu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, 210029, China
| | - Xiaoyan Xie
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, 210029, China
| | - Feng Jiang
- Department of Neonatology, Obstetrics and Gynecology Hospital of Fudan University, No.419, Fangxie Road, Shanghai, 200011, China.
| | - Chuyan Wu
- Department of Rehabilitation Medicine, The First Affiliated Hospital of Nanjing Medical University, No.300, Guangzhou Road, Nanjing, 210029, China.
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Fitzgerald GS, Chuchta TG, McNay EC. Insulin‐like growth factor‐2 is a promising candidate for the treatment and prevention of Alzheimer's disease. CNS Neurosci Ther 2023; 29:1449-1469. [PMID: 36971212 PMCID: PMC10173726 DOI: 10.1111/cns.14160] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Revised: 02/06/2023] [Accepted: 02/22/2023] [Indexed: 03/29/2023] Open
Abstract
Alzheimer's disease (AD) is the most common form of dementia. Current AD treatments slow the rate of cognitive decline, but do not restore lost function. One reason for the low efficacy of current treatments is that they fail to target neurotrophic processes, which are thought to be essential for functional recovery. Bolstering neurotrophic processes may also be a viable strategy for preventative treatment, since structural losses are thought to underlie cognitive decline in AD. The challenge of identifying presymptomatic patients who might benefit from preventative treatment means that any such treatment must meet a high standard of safety and tolerability. The neurotrophic peptide insulin-like growth factor-2 (IGF2) is a promising candidate for both treating and preventing AD-induced cognitive decline. Brain IGF2 expression declines in AD patients. In rodent models of AD, exogenous IGF2 modulates multiple aspects of AD pathology, resulting in (1) improved cognitive function; (2) stimulation of neurogenesis and synaptogenesis; and, (3) neuroprotection against cholinergic dysfunction and beta amyloid-induced neurotoxicity. Preclinical evidence suggests that IGF2 is likely to be safe and tolerable at therapeutic doses. In the preventative treatment context, the intranasal route of administration is likely to be the preferred method for achieving the therapeutic effect without risking adverse side effects. For patients already experiencing AD dementia, routes of administration that deliver IGF2 directly access the CNS may be necessary. Finally, we discuss several strategies for improving the translational validity of animal models used to study the therapeutic potential of IGF2.
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Affiliation(s)
| | | | - E C McNay
- University at Albany, Albany, New York, USA
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IGF2: A Role in Metastasis and Tumor Evasion from Immune Surveillance? Biomedicines 2023; 11:biomedicines11010229. [PMID: 36672737 PMCID: PMC9855361 DOI: 10.3390/biomedicines11010229] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2022] [Revised: 01/12/2023] [Accepted: 01/13/2023] [Indexed: 01/19/2023] Open
Abstract
Insulin-like growth factor 2 (IGF2) is upregulated in both childhood and adult malignancies. Its overexpression is associated with resistance to chemotherapy and worse prognosis. However, our understanding of its physiological and pathological role is lagging behind what we know about IGF1. Dysregulation of the expression and function of IGF2 receptors, insulin receptor isoform A (IR-A), insulin growth factor receptor 1 (IGF1R), and their downstream signaling effectors drive cancer initiation and progression. The involvement of IGF2 in carcinogenesis depends on its ability to link high energy intake, increase cell proliferation, and suppress apoptosis to cancer risk, and this is likely the key mechanism bridging insulin resistance to cancer. New aspects are emerging regarding the role of IGF2 in promoting cancer metastasis by promoting evasion from immune destruction. This review provides a perspective on IGF2 and an update on recent research findings. Specifically, we focus on studies providing compelling evidence that IGF2 is not only a major factor in primary tumor development, but it also plays a crucial role in cancer spread, immune evasion, and resistance to therapies. Further studies are needed in order to find new therapeutic approaches to target IGF2 action.
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Unraveling the IGF System Interactome in Sarcomas Exploits Novel Therapeutic Options. Cells 2021; 10:cells10082075. [PMID: 34440844 PMCID: PMC8392407 DOI: 10.3390/cells10082075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Revised: 08/06/2021] [Accepted: 08/10/2021] [Indexed: 12/15/2022] Open
Abstract
Aberrant bioactivity of the insulin-like growth factor (IGF) system results in the development and progression of several pathologic conditions including cancer. Preclinical studies have shown promising anti-cancer therapeutic potentials for anti-IGF targeted therapies. However, a clear but limited clinical benefit was observed only in a minority of patients with sarcomas. The molecular complexity of the IGF system, which comprises multiple regulators and interactions with other cancer-related pathways, poses a major limitation in the use of anti-IGF agents and supports the need of combinatorial therapeutic strategies to better tackle this axis. In this review, we will initially highlight multiple mechanisms underlying IGF dysregulation in cancer and then focus on the impact of the IGF system and its complexity in sarcoma development and progression as well as response to anti-IGF therapies. We will also discuss the role of Ephrin receptors, Hippo pathway, BET proteins and CXCR4 signaling, as mediators of sarcoma malignancy and relevant interactors with the IGF system in tumor cells. A deeper understanding of these molecular interactions might provide the rationale for novel and more effective therapeutic combinations to treat sarcomas.
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Liu M, Zhong YB, Shao J, Zhang C, Shi C. Tumor-associated macrophages promote human hepatoma Huh-7 cell migration and invasion through the Gli2/IGF-II/ERK1/2 axis by secreting TGF-β1. Cancer Biol Ther 2020; 21:1041-1050. [PMID: 33081566 DOI: 10.1080/15384047.2020.1824478] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
AIM In this study, we explored the ability of TAMs to affect the malignant phenotype of human hepatoma Huh-7 cells through the Gli2/IGF-II/ERK1/2 pathway. METHODS The TAMs were characterized by flow cytometry and ELISA assays. Huh-7 cells were treated with conditioned medium of TAMs (TAMs-CM), and the proliferation, migration and invasion abilities were measured by CCK-8, Transwell and scratch assays. The levels of TGF-β1, Gli2, IGF-II and related proteins in the ERK1/2 pathway and the epithelial-mesenchymal transition (EMT) process were examined by RT-qPCR and western blot. Huh-7 cells were injected subcutaneously into nude mice with TAMs to explore the role of TAMs in tumor growth. RESULTS The expression levels of TGF-β1, Gli2 and IGF-II and the cell proliferation, migration and invasion abilities were elevated in Huh-7 cells treated with TAMs-CM. TGF-β1 was upregulated in the conditioned medium and was found to be involved in the promotion of migration, invasion and the EMT of Huh-7 cells. The activation of TGF-β1 signaling increased the expression of Gli2. Knockdown of Gli2 decreased the expression of IGF-II and also reversed the promotional effect of the conditioned medium on migration, invasion and the EMT of Huh-7 cells. TGF-β1/Gli2/IGF-II signaling was shown to promote the malignant phenotype of Huh-7 cells by activating the ERK1/2 signaling pathway. Further, TGF-β1 knockdown attenuated the influence of TAMs on tumor growth in mouse model. CONCLUSION The TGF-β1 secreted by TAMs promotes the migration, invasion and EMT of human hepatoma Huh-7 cells through the Gli2/IGF-II/ERK1/2 pathway.
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Affiliation(s)
- Mei Liu
- Department of Oncology, The First Affiliated Hospital of Nanchang University , Nanchang, Jiangxi Province, P. R China
| | - Yuan-Bin Zhong
- Department of Infectious Diseases & Key Laboratory of Liver Regenerative Medicine of Jiangxi Province, The First Affiliated Hospital of Nanchang University , Nanchang, Jiangxi Province, P. R China
| | - Jia Shao
- Department of Assisted Reproductive, The First Affiliated Hospital of Nanchang University , Nanchang, Jiangxi Province, P. R China
| | - Cheng Zhang
- School of Basic Medical Sciences, Nanchang University , Nanchang, Jiangxi Province, P. R China
| | - Chao Shi
- Department of Oncology, The First Affiliated Hospital of Nanchang University , Nanchang, Jiangxi Province, P. R China
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Abstract
The insulin and insulin-like growth factor (IGF) family of proteins are part of a complex network that regulates cell proliferation and survival. While this system is undoubtedly important in prenatal development and postnatal cell growth, members of this family have been implicated in several different cancer types. Increased circulating insulin and IGF ligands have been linked to increased risk of cancer incidence. This observation has led to targeting the IGF system as a therapeutic strategy in a number of cancers. This chapter aims to describe the well-characterized biology of the IGF1R system, outline the rationale for targeting this system in cancer, summarize the clinical data as it stands, and discuss where we can go from here.
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9
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Chiu YF, Wu CC, Kuo MH, Miao CC, Zheng MY, Chen PY, Lin SC, Chang JL, Wang YH, Chou YT. Critical role of SOX2-IGF2 signaling in aggressiveness of bladder cancer. Sci Rep 2020; 10:8261. [PMID: 32427884 PMCID: PMC7237425 DOI: 10.1038/s41598-020-65006-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2019] [Accepted: 04/27/2020] [Indexed: 02/07/2023] Open
Abstract
Signaling elicited by the stem cell factors SOX2, OCT4, KLF4, and MYC not only mediates reprogramming of differentiated cells to pluripotency but has also been correlated with tumor malignancy. In this study, we found SOX2 expression signifies poor recurrence-free survival and correlates with advanced pathological grade in bladder cancer. SOX2 silencing attenuated bladder cancer cell growth, while its expression promoted cancer cell survival and proliferation. Under low-serum stress, SOX2 expression promoted AKT phosphorylation and bladder cancer cells' spheroid-forming capability. Furthermore, pharmacological inhibition of AKT phosphorylation, using MK2206, inhibited the SOX2-mediated spheroid formation of bladder cancer cells. Gene expression profiling showed that SOX2 expression, in turn, induced IGF2 expression, while SOX2 silencing inhibited IGF2 expression. Moreover, knocking down IGF2 and IGF1R diminished bladder cancer cell growth. Lastly, pharmacological inhibition of IGF1R, using linsitinib, also inhibited the SOX2-mediated spheroid formation of bladder cancer cells under low-serum stress. Our findings indicate the SOX2-IGF2 signaling affects the aggressiveness of bladder cancer cell growth. This signaling could be a promising biomarker and therapeutic target for bladder cancer intervention.
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Affiliation(s)
- Yu-Fan Chiu
- Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Chia-Chang Wu
- Department of Urology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan
- Department of Urology, School of Medicine, College of Medicine, and TMU Research Center of Urology and Kidney (TMU-RCUK), Taipei Medical University, Taipei, Taiwan
| | - Ming-Han Kuo
- Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Chia-Cheng Miao
- Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Ming-Yi Zheng
- Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Pei-Yu Chen
- Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan
| | - Sheng-Chieh Lin
- Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan
- Graduate Institute of Integrated Medicine, China Medical University, Taichung, Taiwan
| | - Junn-Liang Chang
- Department of Pathology and Laboratory Medicine, Taoyuan Armed Forces General Hospital, Taoyuan, Taiwan
- Department of Biomedical Engineering, Ming Chuan University, Taoyuan, Taiwan
| | - Yuan-Hung Wang
- Department of Medical Research, Shuang Ho Hospital, New Taipei City, Taiwan.
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.
| | - Yu-Ting Chou
- Institute of Biotechnology, College of Life Science, National Tsing Hua University, Hsinchu, Taiwan.
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10
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Gray ME, Meehan J, Sullivan P, Marland JRK, Greenhalgh SN, Gregson R, Clutton RE, Ward C, Cousens C, Griffiths DJ, Murray A, Argyle D. Ovine Pulmonary Adenocarcinoma: A Unique Model to Improve Lung Cancer Research. Front Oncol 2019; 9:335. [PMID: 31106157 PMCID: PMC6498990 DOI: 10.3389/fonc.2019.00335] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 04/11/2019] [Indexed: 12/20/2022] Open
Abstract
Lung cancer represents a major worldwide health concern; although advances in patient management have improved outcomes for some patients, overall 5-year survival rates are only around 15%. In vitro studies and mouse models are commonly used to study lung cancer and their use has increased the molecular understanding of the disease. Unfortunately, mouse models are poor predictors of clinical outcome and seldom mimic advanced stages of the human disease. Animal models that more accurately reflect human disease are required for progress to be made in improving treatment outcomes and prognosis. Similarities in pulmonary anatomy and physiology potentially make sheep better models for studying human lung function and disease. Ovine pulmonary adenocarcinoma (OPA) is a naturally occurring lung cancer that is caused by the jaagsiekte sheep retrovirus. The disease is endemic in many countries throughout the world and has several features in common with human lung adenocarcinomas, including histological classification and activation of common cellular signaling pathways. Here we discuss the in vivo and in vitro OPA models that are currently available and describe the advantages of using pre-clinical naturally occurring OPA cases as a translational animal model for human lung adenocarcinoma. The challenges and options for obtaining these OPA cases for research purposes, along with their use in developing novel techniques for the evaluation of chemotherapeutic agents or for monitoring the tumor microenvironment in response to treatment, are also discussed.
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Affiliation(s)
- Mark E. Gray
- The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
- Cancer Research UK Edinburgh Centre and Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - James Meehan
- Cancer Research UK Edinburgh Centre and Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
- School of Engineering and Physical Sciences, Institute of Sensors, Signals and Systems, Heriot-Watt University, Edinburgh, United Kingdom
| | - Paul Sullivan
- School of Engineering, Institute for Integrated Micro and Nano Systems, The King's Buildings, Edinburgh, United Kingdom
| | - Jamie R. K. Marland
- School of Engineering, Institute for Integrated Micro and Nano Systems, The King's Buildings, Edinburgh, United Kingdom
| | - Stephen N. Greenhalgh
- The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Rachael Gregson
- The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Richard Eddie Clutton
- The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Carol Ward
- Cancer Research UK Edinburgh Centre and Division of Pathology Laboratories, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
| | - Chris Cousens
- Moredun Research Institute, Pentlands Science Park, Midlothian, United Kingdom
| | - David J. Griffiths
- Moredun Research Institute, Pentlands Science Park, Midlothian, United Kingdom
| | - Alan Murray
- School of Engineering, Institute for Integrated Micro and Nano Systems, The King's Buildings, Edinburgh, United Kingdom
| | - David Argyle
- The Royal (Dick) School of Veterinary Studies and Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
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Huo X, Zhang X, Liu Y, Sun Y, Ren Y, Li C, Du X, Chen Z. Instability of microsatellites linked to targeted genes in CRISPR/Cas9-edited and traditional gene knockout mouse strains. J Genet Genomics 2018; 45:553-556. [PMID: 30352733 DOI: 10.1016/j.jgg.2018.07.010] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 05/24/2018] [Accepted: 07/04/2018] [Indexed: 10/28/2022]
Affiliation(s)
- Xueyun Huo
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China
| | - Xiulin Zhang
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China
| | - Yihan Liu
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China
| | - Yizhu Sun
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China
| | - Yu Ren
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China
| | - Changlong Li
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China
| | - Xiaoyan Du
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China.
| | - Zhenwen Chen
- School of Basic Medical Sciences, Capital Medical University, Beijing Key Laboratory of Cancer Invasion & Metastasis Research, Beijing 100069, China
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12
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Vishwamitra D, George SK, Shi P, Kaseb AO, Amin HM. Type I insulin-like growth factor receptor signaling in hematological malignancies. Oncotarget 2018; 8:1814-1844. [PMID: 27661006 PMCID: PMC5352101 DOI: 10.18632/oncotarget.12123] [Citation(s) in RCA: 37] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 09/12/2016] [Indexed: 12/19/2022] Open
Abstract
The insulin-like growth factor (IGF) signaling system plays key roles in the establishment and progression of different types of cancer. In agreement with this idea, substantial evidence has shown that the type I IGF receptor (IGF-IR) and its primary ligand IGF-I are important for maintaining the survival of malignant cells of hematopoietic origin. In this review, we discuss current understanding of the role of IGF-IR signaling in cancer with a focus on the hematological neoplasms. We also address the emergence of IGF-IR as a potential therapeutic target for the treatment of different types of cancer including plasma cell myeloma, leukemia, and lymphoma.
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Affiliation(s)
- Deeksha Vishwamitra
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Suraj Konnath George
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ping Shi
- State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, Shanghai, China
| | - Ahmed O Kaseb
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Hesham M Amin
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA
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13
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Damaschke NA, Yang B, Bhusari S, Avilla M, Zhong W, Blute ML, Huang W, Jarrard DF. Loss of Igf2 Gene Imprinting in Murine Prostate Promotes Widespread Neoplastic Growth. Cancer Res 2017; 77:5236-5247. [PMID: 28775169 PMCID: PMC9741865 DOI: 10.1158/0008-5472.can-16-3089] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2016] [Revised: 05/12/2017] [Accepted: 07/28/2017] [Indexed: 02/07/2023]
Abstract
Loss of imprinting (LOI) is an epigenetic event that relaxes an allele-specific restriction on gene expression. One gene that experiences LOI is the paracrine insulin-like growth factor IGF2, which occurs commonly in human prostate tissues during aging and tumorigenesis. However, the relationship between IGF2 LOI and prostate tumorigenesis has not been established functionally. In this study, we created a mouse model with CTCF-binding site mutations at the Igf2-H19 imprint control region that abolishes CTCF insulator activity, resulting in biallelic Igf2 expression that mimics increased levels seen with aging-induced LOI. We found that Igf2 LOI increased the prevalence and severity of prostatic intraepithelial neoplasia (PIN), a premalignant lesion. Engineering Nkx3.1 deficiency into our model increased the frequency of PIN lesions in an additive fashion. Prostates harboring LOI displayed increased MAPK signaling and epithelial proliferation. In human prostate tissue arrays, we documented a positive correlation in benign tissues of IGF2 levels with phospho-ERK and phospho-AKT levels. Overall, our results establish that Igf2 LOI is sufficient on its own to increase rates of neoplastic development in the prostate by upregulating critical cancer-associated signaling pathways. Cancer Res; 77(19); 5236-47. ©2017 AACR.
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Affiliation(s)
- Nathan A. Damaschke
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Bing Yang
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Sachin Bhusari
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Mele Avilla
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Weixiong Zhong
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA
| | - Michael L. Blute
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA
| | - Wei Huang
- Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA
| | - David F. Jarrard
- Department of Urology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA, Department of Surgery, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA, University of Wisconsin Carbone Comprehensive Cancer Center, Madison, WI, USA, Environmental and Molecular Toxicology, University of Wisconsin, Madison, WI, USA Madison, WI, USA,Corresponding author: D.F. Jarrard, M.D, 7037 Wisconsin Institute for Medical Research, 1111 Highland Avenue, Madison, WI 53792. Phone 608-252-0937, Fax (608)265-0614,
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14
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The long non-coding RNA 91H increases aggressive phenotype of breast cancer cells and up-regulates H19/IGF2 expression through epigenetic modifications. Cancer Lett 2017; 385:198-206. [DOI: 10.1016/j.canlet.2016.10.023] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 10/13/2016] [Accepted: 10/14/2016] [Indexed: 11/22/2022]
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Franks SE, Jones RA, Briah R, Murray P, Moorehead RA. BMS-754807 is cytotoxic to non-small cell lung cancer cells and enhances the effects of platinum chemotherapeutics in the human lung cancer cell line A549. BMC Res Notes 2016; 9:134. [PMID: 26928578 PMCID: PMC4772483 DOI: 10.1186/s13104-016-1919-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Accepted: 02/08/2016] [Indexed: 12/11/2022] Open
Abstract
Background Despite advances in targeted therapy for lung cancer, survival for patients remains poor and lung cancer remains the leading cause of cancer-related deaths worldwide. The type I insulin-like growth factor receptor (IGF-IR) has emerged as a potential target for lung cancer treatment, however, clinical trials to date have provided disappointing results. Further research is needed to identify if certain patients would benefit from IGF-IR targeted therapies and the ideal approach to incorporate IGF-IR targeted agents with current therapies. Methods The dual IGF-IR/insulin receptor inhibitor, BMS-754807, was evaluated alone and in combination with platinum-based chemotherapeutics in two human non-small cell lung cancer (NSCLC) cell lines. Cell survival was determined using WST-1 assays and drug interaction was evaluated using Calcusyn software. Proliferation and apoptosis were determined using immunofluorescence for phospho-histone H3 and cleaved caspase 3, respectively. Results Treatment with BMS-754807 alone reduced cell survival and wound closure while enhancing apoptosis in both human lung cancer cell lines. These effects appear to be mediated through IGF-IR/IR signaling and, at least in part, through the PI3K/AKT pathway as administration of BMS-754807 to A549 or NCI-H358 cells significantly suppressed IGF-IR/IR and AKT phosphorylation. In addition of BMS-754807 enhanced the cytotoxic effects of carboplatin or cisplatin in a synergistic manner when given simultaneously to A549 cells. Conclusions BMS-754807 may be an effective therapeutic agent for the treatment of NSCLC, particularly in lung cancer cells expressing high levels of IGF-IR.
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Affiliation(s)
- S Elizabeth Franks
- Department of Biomedical Science, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada.
| | - Robert A Jones
- Department of Biomedical Science, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada.
| | - Ritesh Briah
- Department of Biomedical Science, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada.
| | - Payton Murray
- Department of Biomedical Science, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada.
| | - Roger A Moorehead
- Department of Biomedical Science, Ontario Veterinary College, University of Guelph, 50 Stone Road East, Guelph, ON, N1G2W1, Canada.
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16
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Ma Y, Jia Y, Chen L, Ezeogu L, Yu B, Xu N, Liao DJ. Weaknesses and Pitfalls of Using Mice and Rats in Cancer Chemoprevention Studies. J Cancer 2015; 6:1058-65. [PMID: 26366220 PMCID: PMC4565856 DOI: 10.7150/jca.12519] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2015] [Accepted: 07/19/2015] [Indexed: 12/31/2022] Open
Abstract
Many studies, using different chemical agents, have shown excellent cancer prevention efficacy in mice and rats. However, equivalent tests of cancer prevention in humans require decades of intake of the agents while the rodents' short lifespans cannot give us information of the long-term safety. Therefore, animals with a much longer lifespan should be used to bridge the lifespan gap between the rodents and humans. There are many transgenic mouse models of carcinogenesis available, in which DNA promoters are used to activate transgenes. One promoter may activate the transgene in multiple cell types while different promoters are activated at different ages of the mice. These spatial and temporal aspects of transgenes are often neglected and may be pitfalls or weaknesses in chemoprevention studies. The variation in the copy number of the transgene may widen data variation and requires use of more animals. Models of chemically-induced carcinogenesis do not have these transgene-related defects, but chemical carcinogens usually damage metabolic organs or tissues, thus affecting the metabolism of the chemopreventive agents. Moreover, many genetically edited and some chemically-induced carcinogenesis models produce tumors that exhibit cancerous histology but are not cancers because the tumor cells are still mortal, inducer-dependent, and unable to metastasize, and thus should be used with caution in chemoprevention studies. Lastly, since mice prefer an ambient temperature of 30-32°C, it should be debated whether future mouse studies should be performed at this temperature, but not at 21-23°C that cold-stresses the animals.
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Affiliation(s)
- Yukui Ma
- 1. Shandong Academy of Pharmaceutical Sciences, Ji'nan, Shandong 250101, P.R. China
| | - Yuping Jia
- 1. Shandong Academy of Pharmaceutical Sciences, Ji'nan, Shandong 250101, P.R. China
| | - Lichan Chen
- 2. Hormel Institute, University of Minnesota, Austin, MN 55912, USA
| | - Lewis Ezeogu
- 2. Hormel Institute, University of Minnesota, Austin, MN 55912, USA
| | - Baofa Yu
- 3. Beijing Baofa Cancer Hospital, Shahe Wangzhuang Gong Ye Yuan, Chang Pin Qu, Beijing 102206, P.R. China
| | - Ningzhi Xu
- 4. Laboratory of Cell and Molecular Biology, Cancer Institute, Chinese Academy of Medical Science, Beijing 100021, P.R. China
| | - D Joshua Liao
- 2. Hormel Institute, University of Minnesota, Austin, MN 55912, USA
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Hanna NH, Dahlberg SE, Kolesar JM, Aggarwal C, Hirsch FR, Ramalingam SS, Schiller JH. Three-arm, randomized, phase 2 study of carboplatin and paclitaxel in combination with cetuximab, cixutumumab, or both for advanced non-small cell lung cancer (NSCLC) patients who will not receive bevacizumab-based therapy: An Eastern Cooperative Oncology Group (ECOG) study (E4508). Cancer 2015; 121:2253-61. [PMID: 25740387 PMCID: PMC4560671 DOI: 10.1002/cncr.29308] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2014] [Revised: 01/08/2015] [Accepted: 01/26/2015] [Indexed: 11/06/2022]
Abstract
BACKGROUND Preclinical evidence supports the clinical investigation of inhibitors to the insulin-like growth factor receptor (IGFR) and the epidermal growth factor receptor (EGFR) either alone or in combination as treatment for patients with non-small cell lung cancer (NSCLC). METHODS Patients with chemotherapy-naïve, advanced NSCLC who had an Eastern Cooperative Oncology Group performance status of 0 or 1 were eligible. Patients were randomized to receive carboplatin intravenously at an area under the plasma drug concentration-time curve of 6.0 plus paclitaxel 200 mg/m(2) intravenously on day 1 every 3 weeks combined with either intravenous cetuximab weekly (arm A), intravenous cixutumumab every 2 weeks (arm B), or both (arm C). Patients who had nonprogessing disease after 12 weeks of therapy were permitted to continue on maintenance antibody therapy until they developed progressive disease. The primary endpoint was progression-free survival (PFS). The study design required 180 eligible patients and had 88% power to detect a 60% increase in median PFS for either comparison (arm A vs arm C or arm B vs arm C) using the log-rank test. RESULTS From September 2009 to December 2010, 140 patients were accrued. The study was closed to accrual early because of an excessive number of grade 5 events reported on arms A and C. Thirteen patients died during treatment (6 patients on arm A, 2 patients on arm B, and 5 patients on arm C), including 9 within approximately 1 month of starting therapy. The estimated median PFS for arms A, B, and C were similar at 3.4 months, 4.2 months, and 4 months, respectively. CONCLUSIONS On the basis of the apparent lack of efficacy and excessive premature deaths, the current results do not support the continued investigation of carboplatin, paclitaxel, and cixutumumab either alone or in combination with cetuximab for patients with advanced NSCLC.
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Affiliation(s)
- Nasser H Hanna
- Indiana University Health Simon Cancer Center, Indianapolis, Indiana
| | - Suzanne E Dahlberg
- Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jill M Kolesar
- School of Pharmacy, University of Wisconsin, Madison, Wisconsin
| | - Charu Aggarwal
- Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Fred R Hirsch
- School of Medicine, Division of Medical Oncology, University of Colorado, Denver, Colorado
| | | | - Joan H Schiller
- Hematology/Oncology Division, University of Texas Southwestern Medical Center, Dallas, Texas
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18
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Dong Y, Li J, Han F, Chen H, Zhao X, Qin Q, Shi R, Liu J. High IGF2 expression is associated with poor clinical outcome in human ovarian cancer. Oncol Rep 2015; 34:936-42. [PMID: 26063585 DOI: 10.3892/or.2015.4048] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 05/06/2015] [Indexed: 11/06/2022] Open
Abstract
Ovarian cancer is one of the most common types of cancer in females and is the leading cause of death among gynaecological cancers in women worldwide. In the present study, we identified insulin-like growth factor 2 (IGF2) as a differentially expressed gene between cancerous and non-cancerous ovarian tissues. IGF2 was frequently increased in the human ovarian cancers when compared to the frequency in the non-cancerous ovarian tissues both at the mRNA (30/35) and protein level (61/72). The mean level of IGF2 in the tumor tissues was markedly higher than that in the non-cancerous tissues (nearly 3-fold change) (P=0.000). There was a significant correlation of IGF2 expression with histological grade (P=0.047). Kaplan-Meier analysis indicated that the ovarian cancer patients with high IGF2 expression showed a poorer prognosis both in regards to overall survival (OS) and progression-free survival (PFS) (n=1,648, P=0.000). Further analysis revealed that high expression of IGF2 was an unfavorable factor for the prognosis of the ovarian cancer patients at clinical stage I + II, stage III, histological grade 2, grade 3 or those treated with chemotherapy containing platin and Taxol. Our data provide evidence that IGF2 expression is frequently increased in ovarian cancer tissues, and high expression of IGF2 may be a significant prognostic factor for poor survival in ovarian cancer patients.
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Affiliation(s)
- Yan Dong
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, P.R. China
| | - Jianjun Li
- Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Fei Han
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, P.R. China
| | - Hongqiang Chen
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, P.R. China
| | - Xiaoxin Zhao
- Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Qin Qin
- Department of Oncology, Southwest Hospital, Third Military Medical University, Chongqing, P.R. China
| | - Ronghui Shi
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, P.R. China
| | - Jinyi Liu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University, Chongqing, P.R. China
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19
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Vidal SJ, Rodriguez-Bravo V, Quinn SA, Rodriguez-Barrueco R, Lujambio A, Williams E, Sun X, de la Iglesia-Vicente J, Lee A, Readhead B, Chen X, Galsky M, Esteve B, Petrylak DP, Dudley JT, Rabadan R, Silva JM, Hoshida Y, Lowe SW, Cordon-Cardo C, Domingo-Domenech J. A targetable GATA2-IGF2 axis confers aggressiveness in lethal prostate cancer. Cancer Cell 2015; 27:223-39. [PMID: 25670080 PMCID: PMC4356948 DOI: 10.1016/j.ccell.2014.11.013] [Citation(s) in RCA: 109] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 10/07/2014] [Accepted: 11/13/2014] [Indexed: 01/11/2023]
Abstract
Elucidating the determinants of aggressiveness in lethal prostate cancer may stimulate therapeutic strategies that improve clinical outcomes. We used experimental models and clinical databases to identify GATA2 as a regulator of chemotherapy resistance and tumorigenicity in this context. Mechanistically, direct upregulation of the growth hormone IGF2 emerged as a mediator of the aggressive properties regulated by GATA2. IGF2 in turn activated IGF1R and INSR as well as a downstream polykinase program. The characterization of this axis prompted a combination strategy whereby dual IGF1R/INSR inhibition restored the efficacy of chemotherapy and improved survival in preclinical models. These studies reveal a GATA2-IGF2 aggressiveness axis in lethal prostate cancer and identify a therapeutic opportunity in this challenging disease.
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Affiliation(s)
- Samuel J Vidal
- College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | | | - S Aidan Quinn
- Department of Pathology and Cell Biology, Columbia University, New York, NY, USA 10032, USA
| | | | - Amaia Lujambio
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Estrelania Williams
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Xiaochen Sun
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | | | - Albert Lee
- Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10031, USA
| | - Ben Readhead
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Xintong Chen
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Matthew Galsky
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Berta Esteve
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Daniel P Petrylak
- Yale Comprehensive Cancer Center, Yale School of Medicine, New Haven, CT 06510, USA
| | - Joel T Dudley
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Raul Rabadan
- Department of Biomedical Informatics, Center for Computational Biology and Bioinformatics, Columbia University, New York, NY 10031, USA
| | - Jose M Silva
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Yujin Hoshida
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Scott W Lowe
- Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Carlos Cordon-Cardo
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
| | - Josep Domingo-Domenech
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
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20
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MATYSZEWSKI ARTUR, CZARNECKA ANNAM, SOLAREK WOJCIECH, KORZEŃ PIOTR, SAFIR ILANJ, KUKWA WOJCIECH, SZCZYLIK CEZARY. Molecular basis of carcinogenesis in diabetic patients (Review). Int J Oncol 2015; 46:1435-43. [DOI: 10.3892/ijo.2015.2865] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2014] [Accepted: 12/10/2014] [Indexed: 11/05/2022] Open
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21
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Kuan PF. Propensity score method for partially matched omics studies. Cancer Inform 2014; 13:1-10. [PMID: 25535453 PMCID: PMC4267441 DOI: 10.4137/cin.s16352] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2014] [Revised: 09/21/2014] [Accepted: 09/23/2014] [Indexed: 01/15/2023] Open
Abstract
This paper focuses on the problem of partially matched samples in the presence of confounders. We propose using propensity score matching to adjust for confounding factors for the subset of data with incomplete pairs, followed by integrating the P-values computed from the complete and incomplete paired samples, respectively. Several simulations and a case study on DNA methylation are considered to evaluate the operating characteristics of the proposed method.
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Affiliation(s)
- Pei-Fen Kuan
- Departments of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, NY, USA
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22
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Park J, Morley TS, Kim M, Clegg DJ, Scherer PE. Obesity and cancer--mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol 2014; 10:455-465. [PMID: 24935119 PMCID: PMC4374431 DOI: 10.1038/nrendo.2014.94] [Citation(s) in RCA: 565] [Impact Index Per Article: 51.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Over the past several years, the field of cancer research has directed increased interest towards subsets of obesity-associated tumours, which include mammary, renal, oesophageal, gastrointestinal and reproductive cancers in both men and women. The increased risk of breast cancer that is associated with obesity has been widely reported; this has drawn much attention and as such, warrants investigation of the key mechanisms that link the obese state with cancer aetiology. For instance, the obese setting provides a unique adipose tissue microenvironment with concomitant systemic endocrine alterations that favour both tumour initiation and progression. Major metabolic differences exist within tumours that distinguish them from non-transformed healthy tissues. Importantly, considerable metabolic differences are induced by tumour cells in the stromal vascular fraction that surrounds them. The precise mechanisms that underlie the association of obesity with cancer and the accompanying metabolic changes that occur in the surrounding microenvironment remain elusive. Nonetheless, specific therapeutic agents designed for patients with obesity who develop tumours are clearly needed. This Review discusses recent advances in understanding the contributions of obesity to cancer and their implications for tumour treatment.
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Affiliation(s)
- Jiyoung Park
- Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, 50 UNIST Street, Ulsan 689-798, South Korea (J.P.). Touchstone Diabetes Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA (T.S.M., M.K., D.J.C., P.E.S.)
| | - Thomas S Morley
- Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, 50 UNIST Street, Ulsan 689-798, South Korea (J.P.). Touchstone Diabetes Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA (T.S.M., M.K., D.J.C., P.E.S.)
| | - Min Kim
- Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, 50 UNIST Street, Ulsan 689-798, South Korea (J.P.). Touchstone Diabetes Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA (T.S.M., M.K., D.J.C., P.E.S.)
| | - Deborah J Clegg
- Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, 50 UNIST Street, Ulsan 689-798, South Korea (J.P.). Touchstone Diabetes Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA (T.S.M., M.K., D.J.C., P.E.S.)
| | - Philipp E Scherer
- Department of Biological Sciences, School of Life Sciences, Ulsan National Institute of Science and Technology, 50 UNIST Street, Ulsan 689-798, South Korea (J.P.). Touchstone Diabetes Center, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA (T.S.M., M.K., D.J.C., P.E.S.)
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23
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Du X, Cui J, Wang C, Huo X, Lu J, Li Y, Chen Z. Detected microsatellite polymorphisms in genetically altered inbred mouse strains. Mol Genet Genomics 2013; 288:309-16. [PMID: 23700121 DOI: 10.1007/s00438-013-0751-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2012] [Accepted: 05/09/2013] [Indexed: 10/26/2022]
Abstract
Microsatellites are 50-200 repetitive DNA sequences composed of 1- to 6-base-pair-long reiterative motifs within the genome. They are vulnerable to DNA modifications, such as recombination and/or integration, and are recognized as "sentinel" DNA. Our previous report indicated that the genotypes of the microsatellite loci could change from mono- to poly-morphisms (CMP) in gene knockout (KO) mice, implying that genetic modification induces microsatellite mutation. However, it is still unclear whether the random insertion of DNA fragments into mice genomes produced via transgene (Tg) or N-ethyl-N-nitrosourea (ENU) would also result in microsatellite mutations or microsatellite loci genotypes changes. This study was designed to find possible clues to answer this question. In brief, 198 microsatellite loci that were distributed among almost all of the chromosomes (except for the Y) were examined through polymerase chain reaction to screen possible CMPs in six Tg strains. First, for each strain, the microsatellite sequences of all loci were compared between Tg and the corresponding background strain to exclude genetic interference. Simultaneously, to exclude spontaneous mutation-related CMPs that might exist in the examined six strains, mice from five spontaneously mutated inbred strains were used as the negative controls. Additionally, the sequences of all loci in these spontaneous mutated mice were compared to corresponding genetic background controls. The results showed that 40 of the 198 (20.2%) loci were identified as having CMPs in the examined Tg mice strains. The CMP genotypes were either homozygous or heterozygous compared to the background controls. Next, we applied the 40 CMP positive loci in ENU-mutated mice and their corresponding background controls. After that, a general comparison of CMPs that exist among Tg, ENU-treated and KO mouse strains was performed. The results indicated that four (D11mit258, D13mit3, D14mit102 and DXmit172) of the 40 (10%) CMP loci were shared by Tg and KO mice, two (D15mit5 and D14mit102) (5%) by Tg and ENU-treated mice, and one (D14mit102) (2.5%) by all three genetic modifications. Collectively, our study implies that genetic modifications by KO, Tg or chemical mutant can trigger microsatellite CMPs in inbred mouse strains. These shared microsatellite loci could be regarded as "hot spots" of microsatellite mutation for genetic monitoring in genetic modified mice.
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Affiliation(s)
- Xiaoyan Du
- Department of Laboratory Animal Science, School of Basic Medical Science, Capital Medical University, Beijing, 100069, China
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Louie SM, Roberts LS, Nomura DK. Mechanisms linking obesity and cancer. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1831:1499-508. [PMID: 23470257 DOI: 10.1016/j.bbalip.2013.02.008] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Revised: 02/20/2013] [Accepted: 02/23/2013] [Indexed: 12/31/2022]
Abstract
The incidence of obesity in US adults has been steadily increasing over the past few decades. Many comorbidities associated with obesity have been well-established such as type 2 diabetes and cardiovascular diseases. However, more recently an epidemiological relationship between obesity and the prevalence of a variety of cancers has also been uncovered. The shift of the paradigm surrounding white adipose tissue function from purely an energy storage tissue, to one that has both endocrine and metabolic relevance, has led to several mechanisms implicated in how obesity drives cancer prevalence and cancer deaths. Currently, there are four categories into which these mechanisms fall - increased lipids and lipid signaling, inflammatory responses, insulin resistance, and adipokines. In this review, we examine each of these categories and the mechanisms through which they drive cancer pathogenesis. Understanding the relationship(s) between obesity and cancer and especially the nodal points of control in these cascades will be essential in developing effective therapeutics or interventions for combating this deadly combination. This article is part of a Special Issue entitled Lipid Metabolism in Cancer.
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Affiliation(s)
- Sharon M Louie
- Program in Metabolic Biology, Department of Nutritional Sciences and Toxicology, 127 Morgan Hall, Berkeley, CA 94710, USA
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25
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Drelon C, Berthon A, Ragazzon B, Tissier F, Bandiera R, Sahut-Barnola I, de Joussineau C, Batisse-Lignier M, Lefrançois-Martinez AM, Bertherat J, Martinez A, Val P. Analysis of the role of Igf2 in adrenal tumour development in transgenic mouse models. PLoS One 2012; 7:e44171. [PMID: 22952916 PMCID: PMC3429465 DOI: 10.1371/journal.pone.0044171] [Citation(s) in RCA: 57] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2012] [Accepted: 07/30/2012] [Indexed: 01/12/2023] Open
Abstract
Adrenal cortical carcinomas (ACC) are rare but aggressive tumours associated with poor prognosis. The two most frequent alterations in ACC in patients are overexpression of the growth factor IGF2 and constitutive activation of Wnt/β-catenin signalling. Using a transgenic mouse model, we have previously shown that constitutive active β-catenin is a bona fide adrenal oncogene. However, although all these mice developed benign adrenal hyperplasia, malignant progression was infrequent, suggesting that secondary genetic events were required for aggressive tumour development. In the present paper, we have tested IGF2 oncogenic properties by developing two distinct transgenic mouse models of Igf2 overexpression in the adrenal cortex. Our analysis shows that despite overexpression levels ranging from 7 (basal) to 87 (ACTH-induced) fold, Igf2 has no tumour initiating potential in the adrenal cortex. However, it induces aberrant accumulation of Gli1 and Pod1-positive progenitor cells, in a hedgehog-independent manner. We have also tested the hypothesis that Igf2 may cooperate with Wnt signalling by mating Igf2 overexpressing lines with mice that express constitutive active β-catenin in the adrenal cortex. We show that the combination of both alterations has no effect on tumour phenotype at stages when β-catenin-induced tumours are benign. However, there is a mild promoting effect at later stages, characterised by increased Weiss score and proliferation. Formation of malignant tumours is nonetheless a rare event, even when Igf2 expression is further increased by ACTH treatment. Altogether these experiments suggest that the growth factor IGF2 is a mild contributor to malignant adrenocortical tumourigenesis.
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Affiliation(s)
- Coralie Drelon
- Clermont Université, Université Blaise Pascal, GReD, Clermont-Ferrand, France
- CNRS UMR 6293, GReD, Aubière, France
- Inserm U1103, GReD, Aubière, France
| | - Annabel Berthon
- Clermont Université, Université Blaise Pascal, GReD, Clermont-Ferrand, France
- CNRS UMR 6293, GReD, Aubière, France
- Inserm U1103, GReD, Aubière, France
| | - Bruno Ragazzon
- Institut Cochin, Université Paris Descartes, CNRS UMR 8104, Paris, France
- Inserm U1016, Paris, France
- Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Department of Endocrinology, Reference Center for Rare Adrenal Diseases, Paris, France
| | - Frédérique Tissier
- Institut Cochin, Université Paris Descartes, CNRS UMR 8104, Paris, France
- Inserm U1016, Paris, France
- Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Department of Endocrinology, Reference Center for Rare Adrenal Diseases, Paris, France
| | | | - Isabelle Sahut-Barnola
- Clermont Université, Université Blaise Pascal, GReD, Clermont-Ferrand, France
- CNRS UMR 6293, GReD, Aubière, France
- Inserm U1103, GReD, Aubière, France
| | - Cyrille de Joussineau
- Clermont Université, Université Blaise Pascal, GReD, Clermont-Ferrand, France
- CNRS UMR 6293, GReD, Aubière, France
- Inserm U1103, GReD, Aubière, France
| | - Marie Batisse-Lignier
- Clermont Université, Université Blaise Pascal, GReD, Clermont-Ferrand, France
- CNRS UMR 6293, GReD, Aubière, France
- Inserm U1103, GReD, Aubière, France
- Centre Hospitalier Universitaire, Service d'Endocrinologie, Faculté de Médecine, Clermont-Ferrand, France
| | - Anne-Marie Lefrançois-Martinez
- Clermont Université, Université Blaise Pascal, GReD, Clermont-Ferrand, France
- CNRS UMR 6293, GReD, Aubière, France
- Inserm U1103, GReD, Aubière, France
| | - Jérôme Bertherat
- Institut Cochin, Université Paris Descartes, CNRS UMR 8104, Paris, France
- Inserm U1016, Paris, France
- Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Department of Endocrinology, Reference Center for Rare Adrenal Diseases, Paris, France
| | - Antoine Martinez
- Clermont Université, Université Blaise Pascal, GReD, Clermont-Ferrand, France
- CNRS UMR 6293, GReD, Aubière, France
- Inserm U1103, GReD, Aubière, France
| | - Pierre Val
- Clermont Université, Université Blaise Pascal, GReD, Clermont-Ferrand, France
- CNRS UMR 6293, GReD, Aubière, France
- Inserm U1103, GReD, Aubière, France
- * E-mail:
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Duerfeldt AS, Peterson LB, Maynard JC, Ng CL, Eletto D, Ostrovsky O, Shinogle HE, Moore DS, Argon Y, Nicchitta CV, Blagg BSJ. Development of a Grp94 inhibitor. J Am Chem Soc 2012; 134:9796-804. [PMID: 22642269 DOI: 10.1021/ja303477g] [Citation(s) in RCA: 91] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Heat shock protein 90 (Hsp90) represents a promising therapeutic target for the treatment of cancer and other diseases. Unfortunately, results from clinical trials have been disappointing as off-target effects and toxicities have been observed. These detriments may be a consequence of pan-Hsp90 inhibition, as all clinically evaluated Hsp90 inhibitors simultaneously disrupt all four human Hsp90 isoforms. Using a structure-based approach, we designed an inhibitor of Grp94, the ER-resident Hsp90. The effect manifested by compound 2 on several Grp94 and Hsp90α/β (cytosolic isoforms) clients were investigated. Compound 2 prevented intracellular trafficking of the Toll receptor, inhibited the secretion of IGF-II, affected the conformation of Grp94, and suppressed Drosophila larval growth, all Grp94-dependent processes. In contrast, compound 2 had no effect on cell viability or cytosolic Hsp90α/β client proteins at similar concentrations. The design, synthesis, and evaluation of 2 are described herein.
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Affiliation(s)
- Adam S Duerfeldt
- Department of Medicinal Chemistry, The University of Kansas, Lawrence, Kansas 66047, USA
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Lin JC, Wu YY, Wu JY, Lin TC, Wu CT, Chang YL, Jou YS, Hong TM, Yang PC. TROP2 is epigenetically inactivated and modulates IGF-1R signalling in lung adenocarcinoma. EMBO Mol Med 2012; 4:472-85. [PMID: 22419550 PMCID: PMC3443948 DOI: 10.1002/emmm.201200222] [Citation(s) in RCA: 76] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2011] [Revised: 01/13/2012] [Accepted: 01/25/2012] [Indexed: 12/25/2022] Open
Abstract
Trop-2, a cell surface glycoprotein, contains both extracellular epidermal growth factor-like and thyroglobulin type-1 repeat domains. Low TROP2 expression was observed in lung adenocarcinoma tissues as compared with their normal counterparts. The lack of expression could be due to either the loss of heterozygosity (LOH) or hypermethylation of the CpG island DNA of TROP2 upstream promoter region as confirmed by bisulphite sequencing and methylation-specific (MS) polymerase chain reaction (PCR). 5-Aza-2′-deoxycytidine treatment on lung cancer cell (CL) lines, CL1-5 and A549, reversed the hypermethylation status and elevated both TROP2 mRNA and protein expression levels. Enforced expression of TROP2 in the lung CL line H1299 reduced AKT as well as ERK activation and suppressed cell proliferation and colony formation. Conversely, silencing TROP2 with shRNA transfection in the less efficiently tumour-forming cell line H322M enhanced AKT activation and increased tumour growth. Trop-2 could attenuate IGF-1R signalling-mediated AKT/β-catenin and ERK activation through a direct binding of IGF1. In conclusion, inactivation of TROP2 due to LOH or by DNA methylation may play an important role in lung cancer tumourigenicity through losing its suppressive effect on IGF-1R signalling and tumour growth.
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Affiliation(s)
- Jau-Chen Lin
- Department of Respiratory Therapy, Fu-Jen Catholic University, New Taipei, Taiwan
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28
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Abstract
The increasing incidence of obesity and its co-morbid conditions poses a great challenge to global health. In addition to cardiovascular disease and diabetes, epidemiological data demonstrate a link between obesity and multiple types of cancer. The molecular mechanisms underlying how obesity causes an increased risk of cancer are poorly understood. Obesity disrupts the dynamic role of the adipocyte in energy homeostasis, resulting in inflammation and alteration of adipokine (for example, leptin and adiponectin) signalling. Additionally, obesity causes secondary changes that are related to insulin signalling and lipid deregulation that may also foster cancer development. Understanding these molecular links may provide an avenue for preventive and therapeutic strategies to reduce cancer risk and mortality in an increasingly obese population.
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Affiliation(s)
- Melin J Khandekar
- Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA
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29
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Scagliotti GV, Novello S. The role of the insulin-like growth factor signaling pathway in non-small cell lung cancer and other solid tumors. Cancer Treat Rev 2011; 38:292-302. [PMID: 21907495 DOI: 10.1016/j.ctrv.2011.07.008] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2011] [Revised: 07/15/2011] [Accepted: 07/25/2011] [Indexed: 01/25/2023]
Abstract
The type 1 insulin-like growth factor receptor (IGF-1R) and its downstream signaling components have become increasingly recognized as having a driving role in the development of malignancy, and consequently IGF-1R has become a potential target for cancer therapy. Several inhibitors of IGF-1R are in clinical development for the treatment of solid tumors, including non-small cell lung cancer (NSCLC). These IGF-1R-targeted agents include monoclonal antibodies such as cixutumumab (IMC-A12), AMG-479, AVE1642, BIIB022, dalotuzumab (MK-0646), and robatumumab (Sch717454), the ligand neutralizing antibody Medi-573, and the small molecule inhibitors BMS-754807, linsitinib (OSI-906), XL228, and AXL1717. Two phase III trials of the anti-IGF-1R monoclonal antibody, figitumumab (CP-751,871), were discontinued in 2010 as it was considered unlikely either trial would meet their primary endpoints. In light of disappointing clinical data with figitumumab and other targeted agents, it is likely that the use of molecular markers will become important in predicting response to treatment. This review outlines the role of IGF-1R signaling in solid tumors with a particular focus on NSCLC, and provides an overview of clinical data.
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Affiliation(s)
- Giorgio V Scagliotti
- Department of Clinical and Biological Sciences, Thoracic Oncology Unit, University of Turin, S. Luigi Hospital, Orbassano, Italy.
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30
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McLaughlin M, Vandenbroeck K. The endoplasmic reticulum protein folding factory and its chaperones: new targets for drug discovery? Br J Pharmacol 2011; 162:328-45. [PMID: 20942857 DOI: 10.1111/j.1476-5381.2010.01064.x] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
Cytosolic heat shock proteins have received significant attention as emerging therapeutic targets. Much of this excitement has been triggered by the discovery that HSP90 plays a central role in the maintenance and stability of multifarious oncogenic membrane receptors and their resultant tyrosine kinase activity. Numerous studies have dealt with the effects of small molecules on chaperone- and stress-related pathways of the endoplasmic reticulum (ER). However, unlike cytosolic chaperones, relatively little emphasis has been placed upon translational avenues towards targeting of the ER for inhibition of folding/secretion of disease-promoting proteins. Here, we summarise existing small molecule inhibitors and potential future targets of ER chaperone-mediated inhibition. Client proteins of translational relevance in disease treatment are outlined, alongside putative future disease treatment modalities based on ER-centric targeted therapies. Particular attention is paid to cancer and autoimmune disorders via the effects of the GRP94 inhibitor geldanamycin and its population of client proteins, overloading of the unfolded protein response, and inhibition of members of the IL-12 family of cytokines by celecoxib and non-coxib analogues.
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31
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Boldt HB, Conover CA. Overexpression of pregnancy-associated plasma protein-A in ovarian cancer cells promotes tumor growth in vivo. Endocrinology 2011; 152:1470-8. [PMID: 21303951 DOI: 10.1210/en.2010-1095] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
Pregnancy-associated plasma protein-A (PAPP-A) is an important regulatory component of the IGF system. Through proteolysis of inhibitory IGF binding proteins (IGFBPs), PAPP-A acts as a positive modulator of local IGF signaling in a variety of biological systems. A role of IGF in the progression of several common forms of human cancer is now emerging, and therapeutic intervention of IGF receptor signaling is currently being explored. However, little is known about the activities of other components of the IGF system in relation to cancer. We hypothesized that PAPP-A acts to enhance tumor growth in vivo. To test this hypothesis, we overexpressed wild-type PAPP-A or a mutant PAPP-A with markedly reduced IGFBP protease activity in SKOV3 cells, a human ovarian carcinoma cell line with low tumorigenic potential. In vitro, SKOV3 clones with elevated PAPP-A expression (PAPP-A-1, PAPP-A-28) showed accelerated anchorage-independent growth in soft agar assays compared to clones overexpressing mutant PAPP-A (E483Q-1, E483Q-5) and vector controls. PAPP-A-28, with the highest PAPP-A expression and IGFBP proteolytic activity, also had markedly increased cell invasion through Matrigel. In vivo, we found significantly accelerated tumor growth rates of PAPP-A-overexpressing SKOV3 clones compared with mutant PAPP-A and controls. Investigation of angiogenesis indicated that overexpression of PAPP-A favored development of mature tumor vasculature and that tumor precursors of PAPP-A-28 in particular had a significantly higher degree of vascularization months before obvious tumor development. In conclusion, our data show that PAPP-A proteolytic activity enhances the tumorigenic potential of ovarian cancer cells and establish a novel tumor growth-promoting role of PAPP-A.
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Affiliation(s)
- Henning B Boldt
- Division of Endocrinology, Metabolism, and Nutrition, Endocrine Research Unit, Mayo Clinic, Rochester, Minnesota 55905, USA
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32
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Leroith D, Scheinman EJ, Bitton-Worms K. The Role of Insulin and Insulin-like Growth Factors in the Increased Risk of Cancer in Diabetes. Rambam Maimonides Med J 2011; 2:e0043. [PMID: 23908801 PMCID: PMC3678929 DOI: 10.5041/rmmj.10043] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Patients with type 2 diabetes (T2D) are at increased risk of developing cancer. This evidence arises from numerous epidemiologic studies that relate a positive association between T2D and cancer. In-vitro and several in-vivo experiments have attempted to discern the potential mechanistic factors involved in this relationship. Candidates include hyperinsulinemia, insulin-like growth factor-1 (IGF-1), and insulin-like growth factor-2 (IGF-2) signaling. These studies demonstrated that increased insulin, IGF-1, and IGF-2 signaling through the insulin receptor and IGF-1 receptor can induce cancer development and progression.
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Affiliation(s)
- Derek Leroith
- "Diabetes and Metabolism Clinical Research Center of Excellence", Legacy Heritage Clinical Research Institute at Rambam (LHCRIR), Haifa, Israel
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33
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Piątkiewicz P, Czech A. Glucose metabolism disorders and the risk of cancer. Arch Immunol Ther Exp (Warsz) 2011; 59:215-30. [PMID: 21448680 DOI: 10.1007/s00005-011-0119-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2010] [Accepted: 11/29/2010] [Indexed: 12/13/2022]
Abstract
Diabetes and cancer are diseases which take the size of an epidemic spread across the globe. Those diseases are influenced by many factors, both genetic and environmental. Precise knowledge of the complex relationships and interactions between these two conditions is of great importance for their prevention and treatment. Many epidemiological studies have shown that certain types of cancer, especially gastrointestinal cancers (pancreas, liver, colon) and also the urinary and reproductive system cancers in women are more common in patients with diabetes or related metabolic disorders. There are also studies showing the inverse relationship between diabetes and cancer, or the lack of it, but they are less numerous and relate mainly to prostate cancer or squamous cell carcinoma of the esophagus. Epidemiological studies, however, do not say anything about the mechanisms of these dependencies. For this purpose, molecular research is needed on the metabolism of cells (including tumor cells) and on metabolic dysfunctions that arise due to changes in the cell environment taking place in the sick, as well as in the intensely treated human organism.
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Affiliation(s)
- Paweł Piątkiewicz
- Chair and Department of Internal Medicine and Diabetology, Medical University of Warsaw, Brodnowski Hospital, Kondratowicza 8, 03-242 Warsaw, Poland.
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34
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Clayton PE, Banerjee I, Murray PG, Renehan AG. Growth hormone, the insulin-like growth factor axis, insulin and cancer risk. Nat Rev Endocrinol 2011; 7:11-24. [PMID: 20956999 DOI: 10.1038/nrendo.2010.171] [Citation(s) in RCA: 255] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Growth hormone (GH), insulin-like growth factor (IGF)-I and insulin have potent growth-promoting and anabolic actions. Their potential involvement in tumor promotion and progression has been of concern for several decades. The evidence that GH, IGF-I and insulin can promote and contribute to cancer progression comes from various sources, including transgenic and knockout mouse models and animal and human cell lines derived from cancers. Assessments of the GH-IGF axis in healthy individuals followed up to assess cancer incidence provide direct evidence of this risk; raised IGF-I levels in blood are associated with a slightly increased risk of some cancers. Studies of human diseases characterized by excess growth factor secretion or treated with growth factors have produced reassuring data, with no notable increases in de novo cancers in children treated with GH. Although follow-up for the vast majority of these children does not yet extend beyond young adulthood, a slight increase in cancers in those with long-standing excess GH secretion (as seen in patients with acromegaly) and no overall increase in cancer with insulin treatment, have been observed. Nevertheless, long-term surveillance for cancer incidence in all populations exposed to increased levels of GH is vitally important.
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Affiliation(s)
- Peter E Clayton
- Manchester Academic Health Sciences Centre, University of Manchester, Paediatric Endocrinology, Royal Manchester Children's Hospital, Oxford Road, Manchester, UK.
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35
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Jones RA, Petrik JJ, Moorehead RA. Preneoplastic changes persist after IGF-IR downregulation and tumor regression. Oncogene 2010; 29:4779-86. [DOI: 10.1038/onc.2010.231] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
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36
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Gualberto A, Karp DD. Development of the monoclonal antibody figitumumab, targeting the insulin-like growth factor-1 receptor, for the treatment of patients with non-small-cell lung cancer. Clin Lung Cancer 2010; 10:273-80. [PMID: 19632947 DOI: 10.3816/clc.2009.n.038] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Figitumumab (CP-751,871) is a fully human immunoglobulin G2 monoclonal antibody highly potent and specific against the insulin-like growth factor-1 receptor. Figitumumab has an effective half-life of approximately 20 days, and it has been well tolerated in clinical studies when given alone or in combination with chemotherapy and targeted agents. Mild to moderate asymptomatic hyperglycemia is observed with figitumumab therapy, but it is generally manageable and well tolerated. Because of its extended half-life and absence of dose-limiting toxicity and hypersensitivity, figitumumab compares well to other compounds in its class. Furthermore, recent data suggest that figitumumab might be active in combination with platinum doublets for the treatment of chemotherapy-naive non-small-cell lung cancer (NSCLC). This article discusses the results to date of the figitumumab development program and the rationale for further testing of this agent as a therapeutic option for the treatment of patients with NSCLC.
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37
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Camidge DR, Dziadziuszko R, Hirsch FR. The rationale and development of therapeutic insulin-like growth factor axis inhibition for lung and other cancers. Clin Lung Cancer 2010; 10:262-72. [PMID: 19632946 DOI: 10.3816/clc.2009.n.037] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The insulin-like growth factor (IGF) axis involves elements of endocrine, paracrine, and autocrine control. It is centrally involved in normal development and growth. Core signaling is driven through the IGF-1 receptor (IGF-1R) in either homo-multimeric complexes or hetero-multimeric complexes with the insulin receptor (IR). Signaling is affected by a large number of upstream and downstream factors, including the differential expression of various intracellular IR substrates, a range of stimulatory ligands (insulin, IGF-1, and IGF-2), the expression of specific clearance receptors (eg, IGF-2R), and different IGF-binding proteins. Considerable evidence exists to implicate aspects of the IGF axis in the development and maintenance of many different nonneoplastic and neoplastic diseases, including both small-cell lung cancer and non-small-cell lung cancer (NSCLC). A large number of different anticancer strategies directed against the IGF axis are being developed. Monoclonal antibodies directed against the IGF-1R are the furthest advanced clinically. Hyperglycemia appears to be a class effect. To date, the major difference among the antibodies used in clinical trials seems to be their plasma half-lives, leading to a number of different administration regimens being taken forward. Early signals of monotherapy activity have been notably reported in patients with Ewing sarcoma and in several other cancers. Encouraging increases in the NSCLC response rate have already been reported after the addition of an anti-IGF-1R antibody to first-line carboplatin and paclitaxel. Explorations of aspects of ligands, binding proteins, receptors, and receptor substrates are all ongoing to identify potential biomarkers predictive of benefit from IGF axis intervention.
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Affiliation(s)
- D Ross Camidge
- Developmental Therapeutics Program, University of Colorado Cancer Center, Denver Thoracic Oncology Program, University of Colorado Cancer Center, Denver, Colorado 80045, USA.
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38
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Kim WY, Jin Q, Oh SH, Kim ES, Yang YJ, Lee DH, Feng L, Behrens C, Prudkin L, Miller YE, Lee JJ, Lippman SM, Hong WK, Wistuba II, Lee HY. Elevated epithelial insulin-like growth factor expression is a risk factor for lung cancer development. Cancer Res 2009; 69:7439-48. [PMID: 19738076 PMCID: PMC2745504 DOI: 10.1158/0008-5472.can-08-3792] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling has been implicated in several human neoplasms. However, the role of serum levels of IGFs in lung cancer risk is controversial. We assessed the role of tissue-derived IGFs in lung carcinogenesis. We found that IGF-I and IGF-II levels in bronchial tissue specimens containing high-grade dysplasia were significantly higher than in those containing normal epithelium, hyperplasia, and squamous metaplasia. Derivatives of human bronchial epithelial cell lines with activation mutation in KRAS(V12) or loss of p53 overexpressed IGF-I and IGF-II. The transformed characteristics of these cells were significantly suppressed by inactivation of IGF-IR or inhibition of IGF-I or IGF-II expression but enhanced by overexpression of IGF-IR or exposure to the tobacco carcinogens (TC) 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone and benzo(a)pyrene. We further determined the role of IGF-IR signaling in lung tumorigenesis by determining the antitumor activities of the selective IGF-IR tyrosine kinase inhibitor cis-3-[3-(4-methyl-piperazin-l-yl)-cyclobutyl]-1-(2-phenyl-quinolin-7-yl)-imidazo [1,5-a]pyrazin-8-ylamine using an in vitro progressive cell system and an in vivo mouse model with a lung-specific IGF-I transgene after exposure to TCs, including 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone plus benzo(a)pyrene. Our results show that airway epithelial cells produce IGFs in an autocrine or paracrine manner, and these IGFs act jointly with TCs to enhance lung carcinogenesis. Furthermore, the use of selective IGF-IR inhibitors may be a rational approach to controlling lung cancer.
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Affiliation(s)
- Woo-Young Kim
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Quanri Jin
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Seung-Hyun Oh
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Edward S. Kim
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Youn Joo Yang
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Dong Hoon Lee
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Lei Feng
- Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Carmen Behrens
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
- Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Ludmila Prudkin
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - York E. Miller
- Department of Medicine, Denver Veterans Affairs Medical Center, University of Colorado Denver, Denver, Colorado
| | - J. Jack Lee
- Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
- The University of Texas Graduate School of Biomedical Sciences, Houston, Texas
| | - Scott M. Lippman
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Waun Ki Hong
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Ignacio I. Wistuba
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
- Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Ho-Young Lee
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
- The University of Texas Graduate School of Biomedical Sciences, Houston, Texas
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39
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Linnerth NM, Siwicky MD, Campbell CI, Watson KLM, Petrik JJ, Whitsett JA, Moorehead RA. Type I insulin-like growth factor receptor induces pulmonary tumorigenesis. Neoplasia 2009; 11:672-82. [PMID: 19568412 PMCID: PMC2697353 DOI: 10.1593/neo.09310] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2009] [Revised: 04/13/2009] [Accepted: 04/13/2009] [Indexed: 11/18/2022]
Abstract
Despite the type I insulin-like growth factor receptor (IGF-IR) being highly expressed in more than 80% of human lung tumors, a transgenic model of IGF-IR overexpression in the lung has not been created. We produced two novel transgenic mouse models in which IGF-IR is overexpressed in either lung type II alveolar cells (surfactant protein C [SPC]-IGFIR) or Clara cells (CCSP-IGFIR) in a doxycycline-inducible manner. Overexpression of IGF-IR in either cell type caused multifocal adenomatous alveolar hyperplasia with papillary and solid adenomas. These tumors expressed thyroid transcription factor 1 and Kruppel-like factor 5 in most tumor cells. Similar to our previous work with lung tumors that developed in the mouse mammary tumor virus-IGF-II transgenic mice, the lung tumors that develop in the SPC-IGFIR and CCSP-IGFIR transgenic mice expressed high levels of the cyclic adenosine monophosphate response element binding protein that was localized primarily to the nucleus. Although elevated IGF-IR expression can initiate lung tumor development, tumors can become independent of IGF-IR signaling as IGF-IR down-regulation in established tumors produced tumor regression in some, but not all, of the tumors. These findings implicate IGF-IR as an important initiator of lung tumorigenesis and suggest that the SPC-IGFIR and CCSP-IGFIR transgenic mice can be used to further our understanding of human lung cancer and the role IGF-IR plays in this disease.
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Affiliation(s)
- Nicolle M Linnerth
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Ontario, Canada
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40
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Gallagher EM, O'Shea DM, Fitzpatrick P, Harrison M, Gilmartin B, Watson JA, Clarke T, Leonard MO, McGoldrick A, Meehan M, Watson C, Furlong F, O'Kelly P, Fitzpatrick JM, Dervan PA, O'Grady A, Kay EW, McCann A. Recurrence of urothelial carcinoma of the bladder: a role for insulin-like growth factor-II loss of imprinting and cytoplasmic E-cadherin immunolocalization. Clin Cancer Res 2008; 14:6829-38. [PMID: 18980977 DOI: 10.1158/1078-0432.ccr-08-0577] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE This study documents the frequency of insulin-like growth factor-II (IGF-II) loss of imprinting (LOI) in a series of 87 bladder tissues. E-cadherin (CDH1) immunolocalization was also investigated due to the known redistribution of this adherence protein to the cytoplasm following exogenous exposure to IGF-II. EXPERIMENTAL DESIGN Informative IGF-II cases were identified following DNA-PCR amplification and subsequent sequencing of the transcribable ApaI RFLP in exon 9 of IGF-II. Similar approaches using primer-specific cDNA templates identified the imprinting status of IGF-II in these informative cases. CDH1 cellular localization was assessed on a tissue microarray platform of 114 urothelial carcinoma of the bladder (UCB) cases (70 pT(a) noninvasive and 44 pT(1) lamina propria invasive) using the commercially available Novocastra antibody. RESULTS IGF-II LOI was evident in 7 of 17 (41%) UCB tumors and 4 of 11 (36%) tumor-associated normal urothelial samples. Two of four pT(1) grade 3 tumors, the subject of much debate concerning their suitability for radical cystectomy, showed LOI at the IGF-II locus. In those tumors showing IGF-II LOI, 4 of 7 (57%) displayed concomitant CDH1 cytoplasmic staining. In contrast, only 3 of 10 (30%) IGF-II maintenance of imprinting tumors had concomitant CDH1 cytoplasmic localization. UCB cell lines displaying cytoplasmic CDH1 immunolocalization expressed significantly higher levels of IGF-II (CAL29, HT1376, and RT112) compared with RT4, a cell line displaying crisp membranous CDH1 staining. Finally, cytoplasmic CDH1 staining was an independent predictor of a shorter time to recurrence independent of tumor grade and stage. CONCLUSIONS We suggest that CDH1 cytoplasmic immunolocalization as a result of increased IGF-II levels identifies those nonmuscle invasive presentations most likely to recur and therefore might benefit from more radical nonconserving bladder surgery.
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Affiliation(s)
- Emma M Gallagher
- UCD School of Medicine and Medical Science, University College Dublin, Belfield, Dublin, Ireland
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Abstract
The insulin-like growth factor (IGF) pathway is involved in the normal control of fetal development, tissue growth, and metabolism. Two distinct ligands (insulin-like growth factor-1 [IGF-1] and IGF-2) plus insulin, and two receptors (insulin-like growth factor receptor-1 [IGF-1R] and the insulin receptor) capable of both homo- and heteropolymerization mediate the actions of this pathway. Cellular functions of IGF-regulated signaling are influenced by the expression of a variety of receptor docking proteins, including four different insulin receptor substrate proteins. Downstream signaling is primarily through the phosphatidylinositol-3 kinase-Akt pathway and the mitogen-activated protein kinase pathway, resulting in increased cell proliferation and apoptosis inhibition. Ligand-driven activation is influenced by upstream endocrine factors (particularly for IGF-1), imprinting (for IGF-2), by multiple circulating and tissue-based IGF-binding proteins/proteases, and by the expression of the IGF-2 clearance receptor (IGF-2R). Deregulation of IGF signaling has been described in several cancer types, including both small cell and non-small cell lung cancer. A number of IGF receptor inhibitors, including monoclonal antibodies and small molecule inhibitors are currently undergoing testing in clinical trials as both monotherapy, and in combination with chemotherapy, or with other targeted agents. Preliminary results from a randomized phase II trial of an anti-IGF-1R monoclonal antibody in combination with carboplatin/paclitaxel already suggest a potential efficacy benefit from targeting this pathway in the first line advanced non-small cell lung cancer setting.
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Seo HS, Liu DD, Bekele BN, Kim MK, Pisters K, Lippman SM, Wistuba II, Koo JS. Cyclic AMP response element-binding protein overexpression: a feature associated with negative prognosis in never smokers with non-small cell lung cancer. Cancer Res 2008; 68:6065-73. [PMID: 18676828 PMCID: PMC3058903 DOI: 10.1158/0008-5472.can-07-5376] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Lung cancer is the leading cause of cancer deaths worldwide. Recent advances in targeted therapies hold promise for the development of new treatments for certain subsets of cancer patients by targeting specific signaling molecule. Based on the identification of the transcription factor cyclic AMP response element-binding protein (CREB) as an important regulator of growth of several types of cancers and our recent findings of its importance in normal differentiation of bronchial epithelial cells, we hypothesized that CREB plays an important pathobiologic role in lung carcinogenesis. We conducted this initial study to determine whether the expression and activation status of CREB are altered in non-small cell lung cancer (NSCLC) and of any prognostic importance in NSCLC patients. We found that the expression levels of mRNA and protein of CREB and phosphorylated CREB (p-CREB) were significantly higher in most of the NSCLC cell lines and tumor specimens than in the normal human tracheobronchial epithelial cells and adjacent normal lung tissue, respectively. Analysis of CREB mRNA expression and the CREB gene copy number showed that CREB overexpression occurred mainly at the transcriptional level. Immunohistochemical analysis of tissue microarray slides containing sections of NSCLC specimens obtained from 310 patients showed that a decreased survival duration was significantly associated with overexpression of CREB or p-CREB in never smokers but not in current or former smokers with NSCLC. These are the first reported results illustrating the potential of CREB as a molecular target for the prevention and treatment of NSCLC, especially in never smokers.
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Affiliation(s)
- Hye-Sook Seo
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Diane D. Liu
- Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - B. Nebiyou Bekele
- Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Mi-Kyoung Kim
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Katherine Pisters
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Scott M. Lippman
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Ignacio I. Wistuba
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
- Department of Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Ja Seok Koo
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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43
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Kittaka N, Takemasa I, Takeda Y, Marubashi S, Nagano H, Umeshita K, Dono K, Matsubara K, Matsuura N, Monden M. Molecular mapping of human hepatocellular carcinoma provides deeper biological insight from genomic data. Eur J Cancer 2008; 44:885-97. [PMID: 18337085 DOI: 10.1016/j.ejca.2008.02.019] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2007] [Revised: 02/05/2008] [Accepted: 02/12/2008] [Indexed: 01/21/2023]
Abstract
DNA microarray analysis of human cancer has resulted in considerable accumulation of global gene profiles. However, extraction and understanding the underlying biology of cancer progression remains a significant challenge. This study applied a novel integrative computational and analytical approach to this challenge in human hepatocellular carcinoma (HCC) with the aim of identifying potential molecular markers or novel therapeutic targets. We analysed 100 HCC tissue samples by human 30K DNA microarray. The gene expression data were uploaded into the network analysis tool, and the biological networks were displayed graphically. We identified several activated 'hotspot' regions harbouring a concentration of upregulated genes. Several 'hotspot' regions revealed integrin and Akt/NF-kappaB signalling. We identified key members linked to these signalling pathways including osteopontin (SPP1), glypican-3 (GPC3), annexin 2 (ANXA2), S100A10 and vimentin (VIM). Our integrative approach should significantly enhance the power of microarray data in identifying novel potential targets in human cancer.
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Affiliation(s)
- Nobuyoshi Kittaka
- Department of Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
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Aggarwal S, Kim SW, Ryu SH, Chung WC, Koo JS. Growth suppression of lung cancer cells by targeting cyclic AMP response element-binding protein. Cancer Res 2008; 68:981-8. [PMID: 18281471 PMCID: PMC2921320 DOI: 10.1158/0008-5472.can-06-0249] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Genes regulated by cyclic AMP-response element-binding protein (CREB) have been reported to suppress apoptosis, induce cell proliferation, and mediate inflammation and tumor metastasis. However, it is not clear whether CREB is critically involved in lung carcinogenesis. We found that non-small cell lung cancer (NSCLC) cell lines exhibited elevated constitutive activity in CREB, in its immediate upstream kinases (ribosomal s6 kinase and extracellular signal kinase), and in the CREB-regulated cell survival proteins Bcl-2 and Bcl-xL. We hypothesized that constitutively active CREB is important to lung cancer cell growth and survival and therefore could be a potential therapeutic target for NSCLC. Ectopic expression of dominant repressor CREB and transfection with small interfering RNA against CREB suppressed the growth and survival of NSCLC cells and induced apoptotic cell death. Furthermore, treating H1734 NSCLC cells with an inhibitor of the CREB signaling pathway Ro-31-8220 inhibited CREB activation by blocking the activity of extracellular signal kinase and ribosomal s6 kinase, arrested the cell cycle at the G(2)-M phase, and subsequently induced apoptosis with the suppression of Bcl-2 and Bcl-xL expression. Ro-31-8220 suppressed both the anchorage-dependent and independent growth of NSCLC cells, but its cytotoxic effect was much less prominent in normal bronchial epithelial cells. Our results indicate that active CREB plays an important role in NSCLC cell growth and survival. Thus, agents that suppress CREB activation could have potential therapeutic value for NSCLC treatment.
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Affiliation(s)
- Sita Aggarwal
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Seung-Wook Kim
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Seung-Hee Ryu
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Wen-Cheng Chung
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
| | - Ja Seok Koo
- Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
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Xu H, Bourne PA, Spaulding BO, Wang HL. High-grade neuroendocrine carcinomas of the lung express K homology domain containing protein overexpressed in cancer but carcinoid tumors do not. Hum Pathol 2007; 38:555-63. [PMID: 17316760 DOI: 10.1016/j.humpath.2006.11.011] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2006] [Revised: 11/10/2006] [Accepted: 11/13/2006] [Indexed: 11/30/2022]
Abstract
K homology domain containing protein overexpressed in cancer (KOC) is a member of the insulin-like growth factor (IGF) messenger RNA-binding protein family and is expressed during embryogenesis and in certain malignancies. KOC, known as L523S and IGF messenger RNA-binding protein 3, was shown to be frequently expressed in high-grade neuroendocrine carcinomas of the lung in our immunohistochemical studies using a monoclonal antibody against human KOC. Specifically, all 10 small cell lung carcinomas (SCLCs) exhibited strong cytoplasmic staining, 9 with diffuse positivity and 1 with focal positivity. Among 14 large cell neuroendocrine carcinomas (LCNECs), 9 exhibited strong and diffuse cytoplasmic staining, and 5 cases showed focal immunoreactivity. In contrast, no KOC was detected in 21 typical and atypical carcinoids, except for one atypical carcinoid with oncocytic cells showing weak cytoplasmic staining. Although SCLCs exhibited a strong and diffuse staining pattern more frequently (90%) than LCNECs (64%), the difference did not reach statistical significance (P = .3408). Interestingly, our immunohistochemical studies demonstrated that IGF-II, reportedly regulated by KOC, was comparably expressed in SCLC, LCNEC, and typical and atypical carcinoids, irrespective of KOC expression status of the tumors. These results support the formulation that KOC may play an important role in the regulation of biologic behavior of high-grade neuroendocrine carcinomas. In addition, detection of KOC expression may be diagnostically useful in distinguishing high-grade neuroendocrine carcinomas from carcinoid tumors. Our findings of equivalent IGF-II expression in KOC-positive SCLC and LCNEC and KOC-negative carcinoid tumors suggest different regulatory mechanisms involved in the control of IGF-II expression in these tumors.
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Affiliation(s)
- Haodong Xu
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
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Soroceanu L, Kharbanda S, Chen R, Soriano RH, Aldape K, Misra A, Zha J, Forrest WF, Nigro JM, Modrusan Z, Feuerstein BG, Phillips HS. Identification of IGF2 signaling through phosphoinositide-3-kinase regulatory subunit 3 as a growth-promoting axis in glioblastoma. Proc Natl Acad Sci U S A 2007; 104:3466-71. [PMID: 17360667 PMCID: PMC1802005 DOI: 10.1073/pnas.0611271104] [Citation(s) in RCA: 92] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2006] [Indexed: 01/19/2023] Open
Abstract
Amplification or overexpression of growth factor receptors is a frequent occurrence in malignant gliomas. Using both expression profiling and in situ hybridization, we identified insulin-like growth factor 2 (IGF2) as a marker for a subset of glioblastomas (GBMs) that lack amplification or overexpression of EGF receptor. Among 165 primary high-grade astrocytomas, 13% of grade IV tumors and 2% of grade III tumors expressed IGF2 mRNA levels >50-fold the sample population median. IGF2-overexpressing tumors frequently displayed PTEN loss, were highly proliferative, exhibited strong staining for phospho-Akt, and belonged to a subclass of GBMs characterized by poor survival. Using a serum-free culture system, we discovered that IGF2 can substitute for EGF to support the growth of GBM-derived neurospheres. The growth-promoting effects of IGF2 were mediated by the insulin-like growth factor receptor 1 and phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3), a regulatory subunit of phosphoinositide 3-kinase that shows genomic gains in some highly proliferative GBM cases. PIK3R3 knockdown inhibited IGF2-induced growth of GBM-derived neurospheres. The current results provide evidence that the IGF2-PIK3R3 signaling axis is involved in promoting the growth of a subclass of highly aggressive human GBMs that lack EGF receptor amplification. Our data underscore the importance of the phosphoinositide 3-kinase/Akt pathway for growth of high-grade gliomas and suggest that multiple molecular alterations that activate this signaling cascade may promote tumorigenesis. Further, these findings highlight the parallels between growth factors or receptors that are overexpressed in GBMs and those that support in vitro growth of tumor-derived stem-like cells.
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Affiliation(s)
| | | | | | | | - Ken Aldape
- Department of Pathology, M. D. Anderson Cancer Center, Houston, TX 77030; and
| | - Anjan Misra
- Brain Tumor Research Center, University of California, San Francisco, CA 94143
| | - Jiping Zha
- Pathology, Genentech, Inc., South San Francisco, CA 94080
| | | | - Janice M. Nigro
- Brain Tumor Research Center, University of California, San Francisco, CA 94143
| | | | - Burt G. Feuerstein
- Brain Tumor Research Center, University of California, San Francisco, CA 94143
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Linnerth NM, Baldwin M, Campbell C, Brown M, McGowan H, Moorehead RA. IGF-II induces CREB phosphorylation and cell survival in human lung cancer cells. Oncogene 2005; 24:7310-9. [PMID: 16158061 DOI: 10.1038/sj.onc.1208882] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
We have previously shown that lung tumors arising in MMTV-IGF-II transgenic mice displayed elevated levels of phosphorylated cAMP response element binding protein (CREB). To investigate the role that insulin-like growth factor II (IGF-II) and CREB play in human lung tumorigenesis, A549 and NCI-H358 cells were examined. In these cell lines, IGF-II administration enhances human tumor cell survival and CREB phosphorylation. Further, the effects of IGF-II on cell survival and CREB phosphorylation appeared to be mediated, at least in part, by activation of the Erk pathways, as inhibition of these signaling pathways reduced tumor cell survival and CREB phosphorylation. Specifically, Erk5 appeared as the predominant mediator of CREB phosporylation. To further verify the importance of CREB in human lung tumorigenesis, A549 and NCI-H358 cells were stably transfected with a vector containing a dominant negative CREB construct (KCREB). KCREB transfection significantly inhibited the soft agar growth of both human tumor cell lines. In contrast, overexpression of wild-type CREB in the normal human bronchial epithelial cell line, HBE135, enhanced soft agar growth. Therefore, our results indicate that CREB and its associated proteins play a significant role in lung adenocarcinoma and IGF-II induces CREB phosphorylation, at least in part, via the Erk5 signaling pathway.
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Affiliation(s)
- Nicolle M Linnerth
- Department of Biomedical Sciences, Ontario Veterinary College, University of Guelph, Guelph, ON, Canada N1G2W1
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