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Liu J, Miao X, Yao J, Wan Z, Yang X, Tian W. Investigating the clinical role and prognostic value of genes related to insulin-like growth factor signaling pathway in thyroid cancer. Aging (Albany NY) 2024; 16:2934-2952. [PMID: 38329437 PMCID: PMC10911384 DOI: 10.18632/aging.205524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Accepted: 12/27/2023] [Indexed: 02/09/2024]
Abstract
BACKGROUND Thyroid cancer (THCA) is the most common endocrine malignancy having a female predominance. The insulin-like growth factor (IGF) pathway contributed to the unregulated cell proliferation in multiple malignancies. We aimed to explore the IGF-related signature for THCA prognosis. METHOD The TCGA-THCA dataset was collected from the Cancer Genome Atlas (TCGA) for screening of key prognostic genes. The limma R package was applied for differentially expressed genes (DEGs) and the clusterProfiler R package was used for the Gene Ontology (GO) and KEGG analysis of DEGs. Then, the un/multivariate and least absolute shrinkage and selection operator (Lasso) Cox regression analysis was used for the establishment of RiskScore model. Receiver Operating Characteristic (ROC) analysis was used to verify the model's predictive performance. CIBERSORT and MCP-counter algorithms were applied for immune infiltration analysis. Finally, we analyzed the mutation features and the correlation between the RiskScore and cancer hallmark pathway by using the GSEA. RESULT We obtained 5 key RiskScore model genes for patient's risk stratification from the 721 DEGs. ROC analysis indicated that our model is an ideal classifier, the high-risk patients are associated with the poor prognosis, immune infiltration, high tumor mutation burden (TMB), stronger cancer stemness and stronger correlation with the typical cancer-activation pathways. A nomogram combined with multiple clinical features was developed and exhibited excellent performance upon long-term survival quantitative prediction. CONCLUSIONS We constructed an excellent prognostic model RiskScore based on IGF-related signature and concluded that the IGF signal pathway may become a reliable prognostic phenotype in THCA intervention.
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Affiliation(s)
- Junyan Liu
- Department of General Surgery, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing 100853, China
| | - Xin Miao
- Department of General Surgery, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing 100853, China
| | - Jing Yao
- Department of General Surgery, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing 100853, China
| | - Zheng Wan
- Department of General Surgery, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing 100853, China
| | - Xiaodong Yang
- Department of General Surgery, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing 100853, China
| | - Wen Tian
- Department of General Surgery, The First Medical Center, Chinese People’s Liberation Army (PLA) General Hospital, Beijing 100853, China
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Soni UK, Jenny L, Hegde RS. IGF-1R targeting in cancer - does sub-cellular localization matter? J Exp Clin Cancer Res 2023; 42:273. [PMID: 37858153 PMCID: PMC10588251 DOI: 10.1186/s13046-023-02850-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2023] [Accepted: 10/03/2023] [Indexed: 10/21/2023] Open
Abstract
The insulin-like growth factor receptor (IGF-1R) was among the most intensively pursued kinase targets in oncology. However, even after a slew of small-molecule and antibody therapeutics reached clinical trials for a range of solid tumors, the initial promise remains unfulfilled. Mechanisms of resistance to, and toxicities resulting from, IGF-1R-targeted drugs are well-catalogued, and there is general appreciation of the fact that a lack of biomarker-based patient stratification was a limitation of previous clinical trials. But no next-generation therapeutic strategies have yet successfully exploited this understanding in the clinic.Currently there is emerging interest in re-visiting IGF-1R targeted therapeutics in combination-treatment protocols with predictive biomarker-driven patient-stratification. One such biomarker that emerged from early clinical trials is the sub-cellular localization of IGF-1R. After providing some background on IGF-1R, its drugging history, and the trials that led to the termination of drug development for this target, we look more deeply into the correlation between sub-cellular localization of IGF-1R and susceptibility to various classes of IGF-1R - targeted agents.
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Affiliation(s)
- Upendra K Soni
- Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Liam Jenny
- Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Rashmi S Hegde
- Division of Developmental Biology, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA.
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Liu Y, Wang J, Hu X, Pan Z, Xu T, Xu J, Jiang L, Huang P, Zhang Y, Ge M. Radioiodine therapy in advanced differentiated thyroid cancer: Resistance and overcoming strategy. Drug Resist Updat 2023; 68:100939. [PMID: 36806005 DOI: 10.1016/j.drup.2023.100939] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 01/16/2023] [Accepted: 02/04/2023] [Indexed: 02/11/2023]
Abstract
Thyroid cancer is the most prevalent endocrine tumor and its incidence is fast-growing worldwide in recent years. Differentiated thyroid cancer (DTC) is the most common pathological subtype which is typically curable with surgery and Radioactive iodine (RAI) therapy (approximately 85%). Radioactive iodine is the first-line treatment for patients with metastatic Papillary Thyroid Cancer (PTC). However, 60% of patients with aggressive metastasis DTC developed resistance to RAI treatment and had a poor overall prognosis. The molecular mechanisms of RAI resistance include gene mutation and fusion, failure to transport RAI into the DTC cells, and interference with the tumor microenvironment (TME). However, it is unclear whether the above are the main drivers of the inability of patients with DTC to benefit from iodine therapy. With the development of new biological technologies, strategies that bolster RAI function include TKI-targeted therapy, DTC cell redifferentiation, and improved drug delivery via extracellular vesicles (EVs) have emerged. Despite some promising data and early success, overall survival was not prolonged in the majority of patients, and the disease continued to progress. It is still necessary to understand the genetic landscape and signaling pathways leading to iodine resistance and enhance the effectiveness and safety of the RAI sensitization approach. This review will summarize the mechanisms of RAI resistance, predictive biomarkers of RAI resistance, and the current RAI sensitization strategies.
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Affiliation(s)
- Yujia Liu
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jiafeng Wang
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, China
| | - Xiaoping Hu
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Zongfu Pan
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, China
| | - Tong Xu
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Jiajie Xu
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, China; Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Liehao Jiang
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, China; Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China
| | - Ping Huang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, China
| | - Yiwen Zhang
- Center for Clinical Pharmacy, Cancer Center, Department of Pharmacy, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China; Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, China.
| | - Minghua Ge
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, China; Otolaryngology & Head and Neck Center, Cancer Center, Department of Head and Neck Surgery, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
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Pidchenko N. Thyroid gland cancer and insulin resistance: a modern view of the problem. УКРАЇНСЬКИЙ РАДІОЛОГІЧНИЙ ТА ОНКОЛОГІЧНИЙ ЖУРНАЛ 2022. [DOI: 10.46879/ukroj.3.2022.79-92] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background. The impact of insulin resistance on the probability of increase in thyroid cancer risk has been drawing a lot of attention of researchers lately. This problem is far from being completely solved. Studying this interrelationship may influence the effectiveness of the treatment of the mentioned widespread pathology.
Purpose – to review present literature sources on research of interrelationship between insulin resistance and thyroid cancer, and also possible mechanisms of this relationship.
Materials and methods. Literature search was performed manually by the keywords (thyroid cancer, insulin resistance, IGF-1, IGF-2, abdominal obesity, increase in body mass index, metformin), and also literature sources from evidential data bases PubMed, Web of Science were reviewed. Metaanalyses, systematic reviews and cohort studies were also taken into account. 148 literature sources were studied in total. The sources, which had been published within the last 10 years, were preferably selected.
Results. Insulin resistance is viewed as an important independent factor of development of numerous malignancies. The carcinogenic activity of insulin resistance is caused by the resistance itself, as well as by the metabolic disorders related to it. It has been established that excessive weight and obesity are to a great extent attributed to more aggressive clinical pathological signs of thyroid cancer. Recent research showed a larger volume of thyroid and higher risk of knot forming in patients with insulin resistance. Thus, thyroid cancer is one of the main factors of thyroid transformation. Therapeutic methods of eliminating metabolic syndrome and associated hormonal diseases for prevention and therapy of oncologic diseases are drawing ever-greater scientific interest. The anti-tumor features of metformin and its capability of retarding carcinogenesis are shown in the studies.
Conclusions. The given literature analysis has proved that the problem of treating malignant thyroid tumors and their metastasis is caused not only by morphological, cellular and molecular-biological features of the tumor itself, but also by insufficient knowledge about the interrelationship between insulin resistance, abdominal obesity, increase in body mass index, high-calorie diet and reduction of consumption of polyunsaturated fats, harmful impact of environment with molecular changes, specific for thyroid cancer. It is confirmed by a significant increase in thyroid cancer rate, especially papillary histotype, alongside with an increase in obesity rate. The studying of possibilities of decreasing incidence and mortality rates of oncologic pathology when using medications, which stabilize insulin and contribute to a decrease in degree of hyperinsulinemia, one of which is metformin, generates profound interest
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Kushchayeva Y, Kushchayev S, Jensen K, Brown RJ. Impaired Glucose Metabolism, Anti-Diabetes Medications, and Risk of Thyroid Cancer. Cancers (Basel) 2022; 14:cancers14030555. [PMID: 35158824 PMCID: PMC8833385 DOI: 10.3390/cancers14030555] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Revised: 01/15/2022] [Accepted: 01/18/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary An epidemiologic link exists between obesity, insulin resistance, diabetes, and some cancers, such as breast cancer and colon cancer. The prevalence of obesity and diabetes is increasing, and additional epidemiologic data suggest that there may be a link between obesity and risk of thyroid abnormalities. Factors that may link obesity and diabetes with thyroid proliferative disorders include elevated circulating levels of insulin, increased body fat, high blood sugars, and exogenous insulin use. However, mechanisms underlying associations of obesity, diabetes, and thyroid proliferative disorders are not yet fully understood. The present manuscript reviews and summarizes current evidence of mechanisms and epidemiologic associations of obesity, insulin resistance, and use of anti-diabetes medications with benign and malignant proliferative disorders of the thyroid. Abstract The prevalence of obesity is progressively increasing along with the potential high risk for insulin resistance and development of type 2 diabetes mellitus. Obesity is associated with increased risk of many malignancies, and hyperinsulinemia has been proposed to be a link between obesity and cancer development. The incidence of thyroid cancer is also increasing, making this cancer the most common endocrine malignancy. There is some evidence of associations between obesity, insulin resistance and/or diabetes with thyroid proliferative disorders, including thyroid cancer. However, the etiology of such an association has not been fully elucidated. The goal of the present work is to review the current knowledge on crosstalk between thyroid and glucose metabolic pathways and the effects of obesity, insulin resistance, diabetes, and anti-hyperglycemic medications on the risk of thyroid cancer development.
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Affiliation(s)
- Yevgeniya Kushchayeva
- Diabetes and Endocrinology Center, University of South Florida, Tampa, FL 33612, USA
- Correspondence:
| | - Sergiy Kushchayev
- Department of Radiology, Moffitt Cancer Center, Tampa, FL 33612, USA;
| | - Kirk Jensen
- F. Edward Hébert School of Medicine, Uniformed Services University, Bethesda, MD 20814, USA;
| | - Rebecca J. Brown
- National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA;
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Franchini F, Palatucci G, Colao A, Ungaro P, Macchia PE, Nettore IC. Obesity and Thyroid Cancer Risk: An Update. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:ijerph19031116. [PMID: 35162142 PMCID: PMC8834607 DOI: 10.3390/ijerph19031116] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 02/07/2023]
Abstract
Thyroid cancer (TC) is the most common endocrine malignancy worldwide and its incidence has increased dramatically in recent years. In parallel, the prevalence of overweight and obesity has also increased, suggesting a possible link between these two diseases. Indeed, low-grade chronic inflammation, altered cytokine levels, insulin resistance, oxidative stress, and hormonal changes that occur in obese patients are all factors that contribute to the occurrence and growth of TC. In this review, the most recent evidence supporting the potential role of the mechanisms linking obesity to TC will be discussed.
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Affiliation(s)
- Fabiana Franchini
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (F.F.); (G.P.); (A.C.); (P.E.M.)
| | - Giuseppe Palatucci
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (F.F.); (G.P.); (A.C.); (P.E.M.)
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (F.F.); (G.P.); (A.C.); (P.E.M.)
| | - Paola Ungaro
- National Research Council–Institute for Experimental Endocrinology & Oncology ‘Gaetano Salvatore’, 80145 Napoli, Italy;
| | - Paolo Emidio Macchia
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (F.F.); (G.P.); (A.C.); (P.E.M.)
| | - Immacolata Cristina Nettore
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80131 Napoli, Italy; (F.F.); (G.P.); (A.C.); (P.E.M.)
- Correspondence: ; Tel.: +39-081-7463848; Fax: +39-081-7462108
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Targeting the IGF-1R in prostate and colorectal cancer: reasons behind trial failure and future directions. Ther Deliv 2022; 13:167-186. [PMID: 35029130 DOI: 10.4155/tde-2021-0060] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
IGF-1Rs enact a significant part in cancer growth and its progress. IGF-1R inhibitors were encouraged in the early trials, but the patients did not benefit due to the unavailability of predictive biomarkers and IGF-1R system complexity. However, the linkage between IGF-1R and cancer was reported three decades ago. This review will shed light on the IGF-1R system, targeting IGF-1R through monoclonal antibodies, reasons behind IGF-1R trial failure and future directions. This study presented that targeting IGF-1R through monoclonal antibodies is still effective in cancer treatment, and there is a need to look for future directions. Cancer patients may benefit from using mAbs that target existing and new cancer targets, evidenced by promising results. It is also essential that the academician, trial experts and pharmaceutical companies play their role in finding a treatment for this deadly disease.
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Zhou Y, Yang Y, Zhou T, Li B, Wang Z. Adiponectin and Thyroid Cancer: Insight into the Association between Adiponectin and Obesity. Aging Dis 2021; 12:597-613. [PMID: 33815885 PMCID: PMC7990371 DOI: 10.14336/ad.2020.0919] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Accepted: 09/13/2020] [Indexed: 12/14/2022] Open
Abstract
In recent decades, the incidence and diagnosis of thyroid cancer have risen dramatically, and thyroid cancer has now become the most common endocrine cancer in the world. The onset of thyroid cancer is insidious, and its progression is slow and difficult to detect. Therefore, early prevention and treatment have important strategic significance. Moreover, an in-depth exploration of the pathogenesis of thyroid cancer is key to early prevention and treatment. Substantial evidence supports obesity as an independent risk factor for thyroid cancer. Adipose tissue dysfunction in the obese state is accompanied by dysregulation of a variety of adipocytokines. Adiponectin (APN) is one of the most pivotal adipocytokines, and its connection with obesity and obesity-related disease has gradually become a hot topic in research. Recently, the association between APN and thyroid cancer has received increasing attention. The purpose of this review is to systematically review previous studies, give prominence to APN, focus on the relationship between APN, obesity and thyroid cancer, and uncover the underlying pathogenic mechanisms.
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Affiliation(s)
- Yuanyuan Zhou
- 1Department of Endocrinology and Metabolism, The Second People's Hospital of Yunnan Province, Fourth Affiliated Hospital of Kunming Medical University, Kunming, China.,2Department of Endocrinology and Metabolism, Sixth Affiliated Hospital of Kunming Medical University, The People's Hospital of Yuxi City, Yuxi, China
| | - Ying Yang
- 1Department of Endocrinology and Metabolism, The Second People's Hospital of Yunnan Province, Fourth Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Taicheng Zhou
- 1Department of Endocrinology and Metabolism, The Second People's Hospital of Yunnan Province, Fourth Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Bai Li
- 3School of Medicine, Yunnan University, Kunming, China
| | - Zhanjian Wang
- 4Department of Endocrinology and Metabolism, The Third Hospital of Hebei Medical University, Shijiazhuang, China
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Zhao Y, Wang Y, Zhang X, Jia N, Ma Z, Fu J, Liu S. Papillary Thyroid Carcinoma in Patients with Acromegaly from a Single Center in China. World Neurosurg 2021; 149:e22-e28. [PMID: 33647496 DOI: 10.1016/j.wneu.2021.02.101] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/20/2021] [Accepted: 02/21/2021] [Indexed: 10/22/2022]
Abstract
OBJECTIVES An increased risk of thyroid cancers in patients with acromegaly has been addressed by numerous studies. However, the differences between patients with papillary thyroid cancer (PTC) with and without acromegaly remain to be clarified. We compared the clinical-pathologic data and genetic alterations of PTC between the 2 groups. PATIENTS AND METHODS Four patients with PTC and acromegaly and 32 age-matched patients with PTC without acromegaly were retrieved retrospectively from the hospital recordings. Mutational analysis was determined by direct sequencing. Insulin-like growth factor-1 receptor and insulin Rβ expression were analyzed by immunohistochemistry in acromegaly group. RESULTS The prevalence of multifocality involved in bilateral lobes in the acromegaly group was significantly increased (P = 0.017). The presence of bilateral lymph node metastasis showed the increasing trend even though without a significant difference because of the limited number of PTC patients in acromegaly group (P = 0.053). There was no significant difference in other factors, such as sex, tumor size in maximum diameter, lymph node metastasis, extrathyroidal extension, and TNM stage. Two (50%) PTCs in acromegalic group and 25 (78.12%) PTCs in the nonacromegalic group were detected to harbor BRAF600E mutation, and no patient was identified to have NRAS codon 61, KRAS codon 61/12/13 mutation. Insulin-like growth factor-1 receptor and insulin Rβ immunostaining showed low positive to positive in PTC cells and negative in adjacent normal tissues in patients with acromegaly. CONCLUSIONS Multifocality involved in 2 lobes is more common in patients with PTC and acromegaly, which shows more aggressive behaviors. BRAF mutation is not uncommon in patients with PTC and acromegaly.
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Affiliation(s)
- Yang Zhao
- Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, P. R. China
| | - Yuanyuan Wang
- Department of Pathology, the First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, P. R. China
| | - Xue Zhang
- Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, P. R. China
| | - Nan Jia
- Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, P. R. China
| | - Zhuoqun Ma
- Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, P. R. China
| | - Jiao Fu
- Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, P. R. China
| | - Shu Liu
- Department of Endocrinology, the First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, P. R. China.
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Vella V, De Francesco EM, Lappano R, Muoio MG, Manzella L, Maggiolini M, Belfiore A. Microenvironmental Determinants of Breast Cancer Metastasis: Focus on the Crucial Interplay Between Estrogen and Insulin/Insulin-Like Growth Factor Signaling. Front Cell Dev Biol 2020; 8:608412. [PMID: 33364239 PMCID: PMC7753049 DOI: 10.3389/fcell.2020.608412] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2020] [Accepted: 11/09/2020] [Indexed: 12/12/2022] Open
Abstract
The development and progression of the great majority of breast cancers (BCs) are mainly dependent on the biological action elicited by estrogens through the classical estrogen receptor (ER), as well as the alternate receptor named G-protein–coupled estrogen receptor (GPER). In addition to estrogens, other hormones and growth factors, including the insulin and insulin-like growth factor system (IIGFs), play a role in BC. IIGFs cooperates with estrogen signaling to generate a multilevel cross-communication that ultimately facilitates the transition toward aggressive and life-threatening BC phenotypes. In this regard, the majority of BC deaths are correlated with the formation of metastatic lesions at distant sites. A thorough scrutiny of the biological and biochemical events orchestrating metastasis formation and dissemination has shown that virtually all cell types within the tumor microenvironment work closely with BC cells to seed cancerous units at distant sites. By establishing an intricate scheme of paracrine interactions that lead to the expression of genes involved in metastasis initiation, progression, and virulence, the cross-talk between BC cells and the surrounding microenvironmental components does dictate tumor fate and patients’ prognosis. Following (i) a description of the main microenvironmental events prompting BC metastases and (ii) a concise overview of estrogen and the IIGFs signaling and their major regulatory functions in BC, here we provide a comprehensive analysis of the most recent findings on the role of these transduction pathways toward metastatic dissemination. In particular, we focused our attention on the main microenvironmental targets of the estrogen-IIGFs interplay, and we recapitulated relevant molecular nodes that orientate shared biological responses fostering the metastatic program. On the basis of available studies, we propose that a functional cross-talk between estrogens and IIGFs, by affecting the BC microenvironment, may contribute to the metastatic process and may be regarded as a novel target for combination therapies aimed at preventing the metastatic evolution.
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Affiliation(s)
- Veronica Vella
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Ernestina Marianna De Francesco
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
| | - Rosamaria Lappano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Maria Grazia Muoio
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy.,Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Livia Manzella
- Center of Experimental Oncology and Hematology, Azienda Ospedaliera Universitaria (A.O.U.) Policlinico Vittorio Emanuele, Catania, Italy.,Department of Clinical and Experimental Medicine, University of Catania, Catania, Italy
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania, Italy
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Karagiannis A, Kassi E, Chatzigeorgiou A, Koutsilieris M. IGF Bioregulation System in Benign and Malignant Thyroid Nodular Disease: A Systematic Review. In Vivo 2020; 34:3069-3091. [PMID: 33144411 PMCID: PMC7811675 DOI: 10.21873/invivo.12141] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Revised: 09/15/2020] [Accepted: 09/16/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND/AIM The insulin-like growth factor bioregulation system is implicated in cancer biology. Herein, we aim to review the evidence on the expression of the insulin-like growth factor 1 and 2 (IGF1 and IGF2), their receptors (IGF-Rs) and IGF-binding proteins (IGFBPs) in thyroid tissue and their possible association with benign and malignant thyroid nodular diseases. MATERIALS AND METHODS We systematically reviewed Pubmed and Scopus databases up to May 2020. A total of 375 articles were retrieved and analyzed. RESULTS Among 375 articles, 45 were included in this systematic review study. IGF1 was investigated in 31 studies, IGF2 in 1, IGF1 receptor in 15 and IGF-binding proteins in 13 articles. IGF1 expression in humans was dependent on the number and compound of benign nodules as well as the method of measurement. In differentiated thyroid carcinoma, a positive correlation between IGF1 and immunohistological stage was documented in some studies while in others only a positive trend was observed. IGF-1R and IGFBPs expression was higher in malignant rather than benign lesions. There was only a positive trend for increased IGF2 expression in malignancy, while IGFBPs were in most studies statistically increased in various cancer types compared to benign nodular disease. CONCLUSION The present data demonstrate that in most studies there is statistically positive expression of IGF-1 and less of IGF-2 in thyroid cancer compared to normal thyroid tissue.
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Affiliation(s)
- Apostolos Karagiannis
- Department of Physiology, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - Eva Kassi
- Department of Biological Chemistry, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National & Kapodistrian University of Athens, Athens, Greece
| | - Michael Koutsilieris
- Department of Physiology, Medical School, National & Kapodistrian University of Athens, Athens, Greece
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Vella V, Nicolosi ML, Giuliano M, Morrione A, Malaguarnera R, Belfiore A. Insulin Receptor Isoform A Modulates Metabolic Reprogramming of Breast Cancer Cells in Response to IGF2 and Insulin Stimulation. Cells 2019; 8:cells8091017. [PMID: 31480557 PMCID: PMC6770491 DOI: 10.3390/cells8091017] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2019] [Revised: 08/27/2019] [Accepted: 08/29/2019] [Indexed: 12/15/2022] Open
Abstract
Previously published work has demonstrated that overexpression of the insulin receptor isoform A (IR-A) might play a role in cancer progression and metastasis. The IR has a predominant metabolic role in physiology, but the potential role of IR-A in cancer metabolic reprogramming is unknown. We aimed to characterize the metabolic impact of IR-A and its ligand insulin like growth factor 2 (IGF2) in human breast cancer (BC) cells. To establish autocrine IGF2 action, we generated human BC cells MCF7 overexpressing the human IGF2, while we focused on the metabolic effect of IR-A by stably infecting IGF1R-ablated MCF7 (MCF7IGF1R-ve) cells with a human IR-A cDNA. We then evaluated the expression of key metabolism related molecules and measured real-time extracellular acidification rates and oxygen consumption rates using the Seahorse technology. MCF7/IGF2 cells showed increased proliferation and invasion associated with aerobic glycolysis and mitochondrial biogenesis and activity. In MCF7IGF1R-ve/IR-A cells insulin and IGF2 stimulated similar metabolic changes and were equipotent in eliciting proliferative responses, while IGF2 more potently induced invasion. The combined treatment with the glycolysis inhibitor 2-deoxyglucose (2DG) and the mitochondrial inhibitor metformin blocked cell invasion and colony formation with additive effects. Overall, these results indicate that IGF2 and IR-A overexpression may contribute to BC metabolic reprogramming.
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Affiliation(s)
- Veronica Vella
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania 95122, Italy
| | - Maria Luisa Nicolosi
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania 95122, Italy
| | - Marika Giuliano
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania 95122, Italy
| | - Andrea Morrione
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA
| | - Roberta Malaguarnera
- School of Human and Social Sciences, "Kore" University of Enna, Enna 94100, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Clinical and Experimental Medicine, University of Catania, Garibaldi-Nesima Hospital, Catania 95122, Italy.
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13
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Manzella L, Massimino M, Stella S, Tirrò E, Pennisi MS, Martorana F, Motta G, Vitale SR, Puma A, Romano C, Di Gregorio S, Russo M, Malandrino P, Vigneri P. Activation of the IGF Axis in Thyroid Cancer: Implications for Tumorigenesis and Treatment. Int J Mol Sci 2019; 20:E3258. [PMID: 31269742 PMCID: PMC6651760 DOI: 10.3390/ijms20133258] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 06/28/2019] [Accepted: 06/28/2019] [Indexed: 12/22/2022] Open
Abstract
The Insulin-like growth factor (IGF) axis is one of the best-established drivers of thyroid transformation, as thyroid cancer cells overexpress both IGF ligands and their receptors. Thyroid neoplasms encompass distinct clinical and biological entities as differentiated thyroid carcinomas (DTC)-comprising papillary (PTC) and follicular (FTC) tumors-respond to radioiodine therapy, while undifferentiated tumors-including poorly-differentiated (PDTC) or anaplastic thyroid carcinomas (ATCs)-are refractory to radioactive iodine and exhibit limited responses to chemotherapy. Thus, safe and effective treatments for the latter aggressive thyroid tumors are urgently needed. Despite a strong preclinical rationale for targeting the IGF axis in thyroid cancer, the results of the available clinical studies have been disappointing, possibly because of the crosstalk between IGF signaling and other pathways that may result in resistance to targeted agents aimed against individual components of these complex signaling networks. Based on these observations, the combinations between IGF-signaling inhibitors and other anti-tumor drugs, such as DNA damaging agents or kinase inhibitors, may represent a promising therapeutic strategy for undifferentiated thyroid carcinomas. In this review, we discuss the role of the IGF axis in thyroid tumorigenesis and also provide an update on the current knowledge of IGF-targeted combination therapies for thyroid cancer.
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Affiliation(s)
- Livia Manzella
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy.
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy.
| | - Michele Massimino
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
| | - Stefania Stella
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
| | - Elena Tirrò
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
| | - Maria Stella Pennisi
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
| | - Federica Martorana
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
- Department of Medical Oncology A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
| | - Gianmarco Motta
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
- Department of Medical Oncology A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
| | - Silvia Rita Vitale
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
| | - Adriana Puma
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
| | - Chiara Romano
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
| | - Sandra Di Gregorio
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
| | - Marco Russo
- Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, 95122, Italy
| | - Pasqualino Malandrino
- Endocrinology, Department of Clinical and Experimental Medicine, Garibaldi-Nesima Medical Center, University of Catania, 95122, Italy
| | - Paolo Vigneri
- Department of Clinical and Experimental Medicine, University of Catania, 95123 Catania, Italy
- Center of Experimental Oncology and Hematology, A.O.U. Policlinico-Vittorio Emanuele, 95123 Catania, Italy
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14
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Lawnicka H, Motylewska E, Borkowska M, Kuzdak K, Siejka A, Swietoslawski J, Stepien H, Stepien T. Elevated serum concentrations of IGF-1 and IGF-1R in patients with thyroid cancers. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2019; 164:77-83. [PMID: 31132076 DOI: 10.5507/bp.2019.018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2018] [Accepted: 04/12/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The rising incidence of thyroid cancer observed in the last few decades requires an improvement in diagnostic tools and management techniques for patients with thyroid nodules. AIMS The aim of this study was to assess serum concentrations of IGF-1 and IGF-1R in patients diagnosed with thyroid cancers. METHODS 36 patients diagnosed with papillary thyroid cancer (PTC), 11 subjects with follicular thyroid cancer (FTC), 9 patients with anaplastic thyroid cancer (ATC) and 19 subjects with multinodular nontoxic goiter (MNG) were enrolled to the study. The control group (CG) consisted of 20 healthy volunteers. Blood samples were collected one day before surgery. Serum IGF-1 and IGF-1R concentrations were measured using specific ELISA methods. RESULTS Significantly higher concentrations of IGF-1 were found in patients with PTC as compared with controls but not that obtained from subjects diagnosed with MNG. The concentration of IGF-1R was significantly elevated in subjects with PTC and ATC as compared with healthy volunteers. Similarly, patients diagnosed with PTC or ATC presented significantly higher serum concentration of IGF-1R in comparison to the MNG group. CONCLUSIONS Our results show that the IGF-1 - IGF-1R axis plays a significant role in the development of PTC and ATC and imply that serum concentrations of both cytokines may be considered as additional markers for the differentiation of malignancies during the preoperative diagnosis of patients with thyroid gland tumors. These results indicate that IGF-1R serum concentrations allow us to differentiate between MNG and PTC or ATC. Moreover IGF-1R serum values appear to be better predictor of PTC and ATC than IGF-1 concentrations.
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Affiliation(s)
- Hanna Lawnicka
- Department of Immunoendocrinology, Chair of Endocrinology, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
| | - Ewelina Motylewska
- Department of Immunoendocrinology, Chair of Endocrinology, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
| | - Magdalena Borkowska
- Clinic of Endocrinological and General Surgery, Chair of Endocrinology, Medical University of Lodz, Pabianicka 62, 93-513 Lodz, Poland
| | - Krzysztof Kuzdak
- Clinic of Endocrinological and General Surgery, Chair of Endocrinology, Medical University of Lodz, Pabianicka 62, 93-513 Lodz, Poland
| | - Agnieszka Siejka
- Clinic of Endocrinology, Chair of Endocrinology, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
| | - Jacek Swietoslawski
- Department of Neuroendocrinology, Interdepartmental Chair of Laboratory and Molecular Diagnostics, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
| | - Henryk Stepien
- Department of Immunoendocrinology, Chair of Endocrinology, Medical University of Lodz, Pomorska 251, 92-213, Lodz, Poland
| | - Tomasz Stepien
- Clinic of Endocrinological and General Surgery, Chair of Endocrinology, Medical University of Lodz, Pabianicka 62, 93-513 Lodz, Poland
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15
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Abstract
Receptor tyrosine kinases (RTKs) play important roles in cell growth, motility, differentiation, and survival. These single-pass membrane proteins are grouped into subfamilies based on the similarity of their extracellular domains. They are generally thought to be activated by ligand binding, which promotes homodimerization and then autophosphorylation in trans. However, RTK interactions are more complicated, as RTKs can interact in the absence of ligand and heterodimerize within and across subfamilies. Here, we review the known cross-subfamily RTK heterointeractions and their possible biological implications, as well as the methodologies which have been used to study them. Moreover, we demonstrate how thermodynamic models can be used to study RTKs and to explain many of the complicated biological effects which have been described in the literature. Finally, we discuss the concept of the RTK interactome: a putative, extensive network of interactions between the RTKs. This RTK interactome can produce unique signaling outputs; can amplify, inhibit, and modify signaling; and can allow for signaling backups. The existence of the RTK interactome could provide an explanation for the irreproducibility of experimental data from different studies and for the failure of some RTK inhibitors to produce the desired therapeutic effects. We argue that a deeper knowledge of RTK interactome thermodynamics can lead to a better understanding of fundamental RTK signaling processes in health and disease. We further argue that there is a need for quantitative, thermodynamic studies that probe the strengths of the interactions between RTKs and their ligands and between different RTKs.
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Affiliation(s)
- Michael D. Paul
- Department of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University, Baltimore MD 21218
| | - Kalina Hristova
- Department of Materials Science and Engineering, Institute for NanoBioTechnology, and Program in Molecular Biophysics, Johns Hopkins University, Baltimore MD 21218
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16
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Lima GEDCP, Fernandes VO, Montenegro APDR, Carvalho ABD, Karbage LBDAS, Aguiar LB, Macedo MSR, Ferreira LAA, Montenegro Júnior RM. Aggressive papillary thyroid carcinoma in a child with type 2 congenital generalized lipodystrophy. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2019; 63:79-83. [PMID: 30864635 PMCID: PMC10118842 DOI: 10.20945/2359-3997000000096] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 10/30/2018] [Indexed: 11/23/2022]
Abstract
Thyroid carcinoma (TC) is rare in children, particularly in those aged < 10 years. Several studies have demonstrated a correlation between neoplasms and hyperinsulinemia and insulin resistance, which are often associated with a higher risk for and/or aggressiveness of the neoplasm. Congenital generalized lipodystrophy (CGL) with autosomal recessive inheritance is a rare disease and is characterized by the lack of adipose tissue, severe insulin resistance, and early metabolic disturbances. Here, we reported a rare case of a type 2 CGL in a girl who presented with a papillary TC (PTC) at the age of 7 years. She had no family history of TC or previous exposure to ionizing radiation. She had a generalized lack of subcutaneous fat, including the palmar and plantar regions, muscle hypertrophy, intense acanthosis nigricans, hepatomegaly, hypertriglyceridemia, severe insulin resistance, and hypoleptinemia. A genetic analysis revealed a mutation in the BSCL2 gene (p.Thr109Asnfs* 5). Ultrasound revealed a hypoechoic solid nodule measuring 1.8 × 1.0 × 1.0 cm, and fine needle aspiration biopsy suggested malignancy. Total thyroidectomy was performed, and a histopathological examination confirmed PTC with vascular invasion and parathyroid lymph node metastasis (pT3N1Mx stage). This is the first report to describe a case of differentiated TC in a child with CGL. Severe insulin resistance that is generally observed in patients with CGL early in life, especially in those with type 2 CGL, may be associated with this uncommon presentation of aggressive PTC during childhood.
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Affiliation(s)
- Grayce Ellen da Cruz Paiva Lima
- Grupo Brasileiro para Estudos de Lipodistrofias Herdadas e Adquiridas (BRAZLIPO), Hospital Universitário Walter Cantídio, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
| | - Virgínia Oliveira Fernandes
- Grupo Brasileiro para Estudos de Lipodistrofias Herdadas e Adquiridas (BRAZLIPO), Hospital Universitário Walter Cantídio, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
| | - Ana Paula Dias Rangel Montenegro
- Grupo Brasileiro para Estudos de Lipodistrofias Herdadas e Adquiridas (BRAZLIPO), Hospital Universitário Walter Cantídio, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
| | - Annelise Barreto de Carvalho
- Grupo Brasileiro para Estudos de Lipodistrofias Herdadas e Adquiridas (BRAZLIPO), Hospital Universitário Walter Cantídio, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
| | - Lia Beatriz de Azevedo Sousa Karbage
- Grupo Brasileiro para Estudos de Lipodistrofias Herdadas e Adquiridas (BRAZLIPO), Hospital Universitário Walter Cantídio, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
| | - Lindenberg Barbosa Aguiar
- Grupo Brasileiro para Estudos de Lipodistrofias Herdadas e Adquiridas (BRAZLIPO), Hospital Universitário Walter Cantídio, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
| | - Mário Sérgio Rocha Macedo
- Grupo Brasileiro para Estudos de Lipodistrofias Herdadas e Adquiridas (BRAZLIPO), Hospital Universitário Walter Cantídio, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
| | - Luis Alberto Albano Ferreira
- Grupo Brasileiro para Estudos de Lipodistrofias Herdadas e Adquiridas (BRAZLIPO), Hospital Universitário Walter Cantídio, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
| | - Renan Magalhães Montenegro Júnior
- Grupo Brasileiro para Estudos de Lipodistrofias Herdadas e Adquiridas (BRAZLIPO), Hospital Universitário Walter Cantídio, Universidade Federal do Ceará (UFC), Fortaleza, CE, Brasil
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17
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The Emerging Role of Insulin Receptor Isoforms in Thyroid Cancer: Clinical Implications and New Perspectives. Int J Mol Sci 2018; 19:ijms19123814. [PMID: 30513575 PMCID: PMC6321330 DOI: 10.3390/ijms19123814] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 11/26/2018] [Accepted: 11/28/2018] [Indexed: 12/28/2022] Open
Abstract
Thyroid cancer (TC) is the most common endocrine tumor. Although the majority of TCs show good prognoses, a minor proportion are aggressive and refractory to conventional therapies. So far, the molecular mechanisms underlying TC pathogenesis are incompletely understood. Evidence suggests that TC cells and their precursors are responsive to insulin and insulin-like growth factors (IGFs), and often overexpress receptors for insulin (IR) and IGF-1 (IGF-1R). IR exists in two isoforms, namely IR-A and IR-B. The first binds insulin and IGF-2, unlike IR-B, which only binds insulin. IR-A is preferentially expressed in prenatal life and contributes to development through IGF-2 action. Aggressive TC overexpresses IR-A, IGF-2, and IGF-1R. The over-activation of IR-A/IGF-2 loop in TC is associated with stem-like features and refractoriness to some targeted therapies. Importantly, both IR isoforms crosstalk with IGF-1R, giving rise to the formation of hybrids receptors (HR-A or HR-B). Other interactions have been demonstrated with other molecules such as the non-integrin collagen receptor, discoidin domain receptor 1 (DDR1), and the receptor for the hepatocyte growth factor (HGF), Met. These functional networks provide mechanisms for IR signaling diversification, which may also exert a role in TC stem cell biology, thereby contributing to TC initiation and progression. This review focuses on the molecular mechanisms by which deregulated IR isoforms and their crosstalk with other molecules and signaling pathways in TC cells and their precursors may contribute to thyroid carcinogenesis, progression, and resistance to conventional treatments. We also highlight how targeting these alterations starting from TC progenitors cells may represent new therapeutic strategies to improve the clinical management of advanced TCs.
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18
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Cheng W, Huang PC, Chao HM, Jeng YM, Hsu HC, Pan HW, Hwu WL, Lee YM. Glypican-3 induces oncogenicity by preventing IGF-1R degradation, a process that can be blocked by Grb10. Oncotarget 2017; 8:80429-80442. [PMID: 29113314 PMCID: PMC5655209 DOI: 10.18632/oncotarget.19035] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Accepted: 06/18/2017] [Indexed: 02/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and is a major cause of cancer-related death worldwide. Previously, we demonstrated that glypican-3 (GPC3) is highly expressed in HCC, and that GPC3 induces oncogenicity and promotes the growth of cancer cells through IGF-1 receptor (IGF-1R). In the present study, we investigated the mechanisms of GPC3-mediated enhancement of IGF-1R signaling. We demonstrated that GPC3 decreased IGF-1-induced IGF-1R ubiquitination and degradation and increased c-Myc protein levels. GPC3 bound to Grb10, a mediator of ligand-induced receptor ubiquitination, and the overexpression of Grb10 blocked GPC3-enhanced IGF-1-induced ERK phosphorylation. GPC3 promoted the growth of NIH3T3 and PLC-PRF-5 cells in serum-free medium but did not promote the growth of IGF-1R negative R- cells. Grb10 overexpression decreased GPC3-promoted cell growth. Therefore, the present study elucidates the mechanisms of GPC3-induced oncogenicity, which may highlight new strategies for the treatment of HCC.
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Affiliation(s)
- Wei Cheng
- Department of Pathology, Kee-Lung Hospital, Ministry of Health and Welfare, Kee-Lung, Taiwan.,Ching Kuo Institute of Management and Health, Kee-Lung, Taiwan.,National Taipei University of Nursing and Health Sciences, Taipei, Taiwan
| | - Po-Chun Huang
- Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.,Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan
| | - Hsiao-Mei Chao
- Department of Pathology, Wang Fang Hospital, Taipei Medical University, Taipei, Taiwan
| | - Yung-Ming Jeng
- Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hey-Chi Hsu
- Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Hung-Wei Pan
- Department of Medical Education and Research, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan
| | - Wuh-Liang Hwu
- Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
| | - Yu-May Lee
- Institute of Biochemical Sciences, National Taiwan University, Taipei, Taiwan.,Institute of Biological Chemistry, Academia Sinica, Taipei, Taiwan.,Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
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19
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Woll SC, Podrabsky JE. Insulin-like growth factor signaling regulates developmental trajectory associated with diapause in embryos of the annual killifish Austrofundulus limnaeus. ACTA ACUST UNITED AC 2017; 220:2777-2786. [PMID: 28515235 DOI: 10.1242/jeb.151373] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2016] [Accepted: 05/10/2017] [Indexed: 01/12/2023]
Abstract
Annual killifishes exhibit a number of unique life history characters including the occurrence of embryonic diapause, unique cell movements associated with dispersion and subsequent reaggregation of the embryonic blastomeres, and a short post-embryonic life span. Insulin-like growth factor (IGF) signaling is known to play a role in the regulation of metabolic dormancy in a number of animals but has not been explored in annual killifishes. The abundance of IGF proteins during development and the developmental effects of blocking IGF signaling by pharmacological inhibition of the insulin-like growth factor I receptor (IGF1R) were explored in embryos of the annual killifish Austrofundulus limnaeus Blocking of IGF signaling in embryos that would normally escape entrance into diapause resulted in a phenotype that was remarkably similar to that of embryos entering diapause. IGF-I protein abundance spikes during early development in embryos that will not enter diapause. In contrast, IGF-I levels remain low during early development in embryos that will enter diapause II. IGF-II protein is packaged at higher levels in escape-bound embryos compared with diapause-bound embryos. However, IGF-II levels quickly decrease and remain low during early development and only increase substantially during late development in both developmental trajectories. Developmental patterns of IGF-I and IGF-II protein abundance under conditions that would either induce or bypass entrance into diapause are consistent with a role for IGF signaling in the regulation of developmental trajectory and entrance into diapause in this species. We propose that IGF signaling may be a unifying regulatory pathway that explains the larger suite of characters that are associated with the complex life history of annual killifishes.
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Affiliation(s)
- S Cody Woll
- Department of Biology, Portland State University, PO Box 751, Portland, OR 97207, USA
| | - Jason E Podrabsky
- Department of Biology, Portland State University, PO Box 751, Portland, OR 97207, USA
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20
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Silva APS, Coelho PV, Anazetti M, Simioni PU. Targeted therapies for the treatment of non-small-cell lung cancer: Monoclonal antibodies and biological inhibitors. Hum Vaccin Immunother 2016; 13:843-853. [PMID: 27831000 PMCID: PMC5404364 DOI: 10.1080/21645515.2016.1249551] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
The usual treatments for patients with non-small-cell lung cancer (NSCLC), such as advanced lung adenocarcinoma, are unspecific and aggressive, and include lung resection, radiotherapy and chemotherapy. Recently, treatment with monoclonal antibodies and biological inhibitors has emerged as an effective alternative, generating effective results with few side effects. In recent years, several clinical trials using monoclonal antibodies presented potential benefits to NSCLC, and 4 of them are already approved for the treatment of NSCLC, such as cetuximab, bevacizumab, nivolumab and pembrolizumab. Also, biological inhibitors are attractive tolls for biological applications. Among the approved inhibitors are crizotinib, erlotinib, afatinib and gefitinib, and side effects are usually mild to intense. Nevertheless, biological molecule treatments are under development, and several new monoclonal antibodies and biological inhibitors are in trial to treat NSCLC. Also under trial study are as follows: anti-epidermal growth factor receptor (EGFR) antibodies (nimotuzumab and ficlatuzumab), anti-IGF 1 receptor (IGF-1R) monoclonal antibody (figitumumab), anti-NR-LU-10 monoclonal antibody (nofetumomab) as well as antibodies directly affecting the cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) molecule (ipilimumab and tremelimumab), to receptor activator of nuclear factor-kappa B ligand (RANKL) (denosumab) or to polymerase enzyme (veliparib and olaparib). Among new inhibitors under investigation are poly-ADP ribose polymerase (PARP) inhibitors (veliparib and olaparib) and phosphatidylinositol 3-kinase (PI3K) inhibitor (buparlisib). However, the success of immunotherapies still requires extensive research and additional controlled trials to evaluate the long-term benefits and side effects.
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Affiliation(s)
- Ana P S Silva
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil
| | - Priscila V Coelho
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil
| | - Maristella Anazetti
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil.,b Department of Health Science , Faculty DeVry Metrocamp , Campinas , SP , Brazil
| | - Patricia U Simioni
- a Department of Biomedical Science , Faculty of Americana , Americana , SP , Brazil.,c Department of Genetics , Evolution and Bioagents, Institute of Biology, University of Campinas (UNICAMP) , Campinas , SP , Brazil.,d Department of Biochemistry and Microbiology , Institute of Biosciences, Universidade Estadual Paulista, UNESP , Rio Claro , SP , Brazil
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21
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Altieri B, Tirabassi G, Della Casa S, Ronchi CL, Balercia G, Orio F, Pontecorvi A, Colao A, Muscogiuri G. Adrenocortical tumors and insulin resistance: What is the first step? Int J Cancer 2015; 138:2785-94. [PMID: 26637955 DOI: 10.1002/ijc.29950] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2015] [Revised: 11/05/2015] [Accepted: 11/23/2015] [Indexed: 01/15/2023]
Abstract
The pathogenetic mechanisms underlying the onset of adrenocortical tumors (ACTs) are still largely unknown. Recently, more attention has been paid to the role of insulin and insulin-like growth factor (IGF) system on general tumor development and progression. Increased levels of insulin, IGF-1 and IGF-2 are associated with tumor cell growth and increased risk of cancer promotion and progression in patients with type 2 diabetes. Insulin resistance and compensatory hyperinsulinemia may play a role in adrenal tumor growth through the activation of insulin and IGF-1 receptors. Interestingly, apparently non-functioning ACTs are often associated with a high prevalence of insulin resistance and metabolic syndrome. However, it is unclear if ACT develops from a primary insulin resistance and compensatory hyperinsulinemia or if insulin resistance is only secondary to the slight cortisol hypersecretion by ACT. The aim of this review is to summarize the current evidence regarding the relationship between hyperinsulinemia and adrenocortical tumors.
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Affiliation(s)
- Barbara Altieri
- Institute of Medical Pathology, Division of Endocrinology and Metabolic Diseases, Catholic University, Rome, Italy
| | - Giacomo Tirabassi
- Division of Endocrinology, Department of Clinical and Molecular Sciences, Umberto I Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Silvia Della Casa
- Institute of Medical Pathology, Division of Endocrinology and Metabolic Diseases, Catholic University, Rome, Italy
| | - Cristina L Ronchi
- Endocrine and Diabetes Unit, Department of Internal Medicine I, University Hospital, University of Wuerzburg, Wuerzburg, Germany
| | - Giancarlo Balercia
- Division of Endocrinology, Department of Clinical and Molecular Sciences, Umberto I Hospital, Polytechnic University of Marche, Ancona, Italy
| | - Francesco Orio
- Department of Sports Science and Wellness, Parthenope University, Naples, Italy.,Department of Endocrinology and Diabetology, Fertility Techniques Structure, University Hospital S. Giovanni Di Dio E Ruggi D'aragona, Salerno, Italy
| | - Alfredo Pontecorvi
- Institute of Medical Pathology, Division of Endocrinology and Metabolic Diseases, Catholic University, Rome, Italy
| | - Annamaria Colao
- Department of Clinical Medicine and Surgery, Section of Endocrinology, Federico II University, Naples, Italy
| | - Giovanna Muscogiuri
- Department of Clinical Medicine and Surgery, Section of Endocrinology, Federico II University, Naples, Italy
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22
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Pitoia F, Abelleira E, Bueno F, Urciuoli C, Schmidt A, Niepomniszcze H. Insulin resistance is another factor that increases the risk of recurrence in patients with thyroid cancer. Endocrine 2015; 48:894-901. [PMID: 25209891 DOI: 10.1007/s12020-014-0416-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2014] [Accepted: 09/01/2014] [Indexed: 12/15/2022]
Abstract
The objective of this study was to evaluate the initial response to treatment and the long-term outcome of patients with papillary thyroid cancer (PTC), according to the modified 2014 risk of recurrence classification of the American Thyroid Association and the presence or absence of insulin resistance (IR). We retrospectively reviewed our database of 636 records and selected 171 patients in whom we had previously validated the ATA risk of recurrence (RR) classification. From these patients, 38 non-diabetic subjects were included for analysis according to the following criteria: age older than 18 years, classic papillary thyroid carcinoma, stable body mass index 5 years previous to PTC diagnosis and during the entire time of follow-up, low and intermediate RR, follow-up after initial treatment at least for 3 years, and absence of any drug treatment for the metabolic syndrome. The IR was evaluated through the homeostasis model assessment (HOMA) index. When equal or higher than 2.5, patients were considered as harboring IR. The initial response to treatment was classified as remission or persistent disease (biochemical and/or structural). The clinical status at final follow-up was defined as no evidence of disease, biochemical persistent disease, structural persistent disease, or recurrence (biochemical or structural disease identified after a period of no evidence of disease). RR was as follows: low: n=15, intermediate: n=23. The median follow-up of this patient cohort was 5.5 years (range 3-22 years). We found no statistically significant differences when the response to initial treatment was considered in low-risk patients with or without IR. However, remission was more frequently found in those patients without IR when the intermediate RR was considered (36 vs. 11%, p=0.01). When considering the status at final follow-up, we found more frequency of structural persistent disease in both, low and intermediate RR patients with IR (10 vs. 0%, p=0.02 and 45 vs.7%, p=0.01, respectively). In this series of patients with PTC, the state of IR was associated with increased frequency of structural persistent disease at final follow-up. The IR could have a deleterious effect on the outcome of patients with PTC.
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Affiliation(s)
- Fabián Pitoia
- División Endocrinología, Hospital de Clínicas, University of Buenos Aires, Córdoba 2351, 5th Floor, Buenos Aires, Argentina,
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23
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Crudden C, Girnita A, Girnita L. Targeting the IGF-1R: The Tale of the Tortoise and the Hare. Front Endocrinol (Lausanne) 2015; 6:64. [PMID: 25964779 PMCID: PMC4410616 DOI: 10.3389/fendo.2015.00064] [Citation(s) in RCA: 62] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2015] [Accepted: 04/11/2015] [Indexed: 11/13/2022] Open
Abstract
The insulin-like growth factor type 1 receptor (IGF-1R) plays a key role in the development and maintenance of cancer. Since the first links between growth factor receptors and oncogenes were noted over three decades ago, targeting the IGF-1R has been of great interest. This review follows the progress from inception through intense pharmaceutical development, disappointing clinical trials and recent updates to the signaling paradigm. In light of major developments in signaling understanding and activation complexities, we examine reasons for failure of first line targeting approaches. Recent findings include the fact that the IGF-1R can signal in the absence of the ligand, in the absence of kinase activity, and utilizes components of the GPCR system. With recognition of the unappreciated complexities that this first wave of targeting approaches encountered, we advocate re-recognition of IGF-1R as a valid target for cancer treatment and look to future directions, where both research and pharmaceutical strengths can lend themselves to finally unearthing anti-IGF-1R potential.
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Affiliation(s)
- Caitrin Crudden
- Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Ada Girnita
- Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- Department of Dermatology, Karolinska University Hospital, Stockholm, Sweden
| | - Leonard Girnita
- Department of Oncology and Pathology, Cancer Centre Karolinska, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
- *Correspondence: Leonard Girnita, Cancer Centre Karolinska, Karolinska Institutet, Karolinska University Hospital, CCK R8:04, Stockholm S-17176, Sweden,
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24
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De Marco P, Cirillo F, Vivacqua A, Malaguarnera R, Belfiore A, Maggiolini M. Novel Aspects Concerning the Functional Cross-Talk between the Insulin/IGF-I System and Estrogen Signaling in Cancer Cells. Front Endocrinol (Lausanne) 2015; 6:30. [PMID: 25798130 PMCID: PMC4351617 DOI: 10.3389/fendo.2015.00030] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2015] [Accepted: 02/19/2015] [Indexed: 12/13/2022] Open
Abstract
The insulin/IGF system plays an important role in cancer progression. Accordingly, elevated levels of circulating insulin have been associated with an increased cancer risk as well as with aggressive and metastatic cancer phenotypes. Numerous studies have documented that estrogens cooperate with the insulin/IGF system in multiple pathophysiological conditions. The biological responses to estrogens are mainly mediated by the estrogen receptors (ER)α and ERβ, which act as transcription factors; however, several studies have recently demonstrated that a member of the G protein-coupled receptors, named GPR30/G-protein estrogen receptor (GPER), is also involved in the estrogen signaling in normal and malignant cells as well as in cancer-associated fibroblasts (CAFs). In this regard, novel mechanisms linking the action of estrogens through GPER with the insulin/IGF system have been recently demonstrated. This review recapitulates the relevant aspects of this functional cross-talk between the insulin/IGF and the estrogenic GPER transduction pathways, which occurs in various cell types and may account for cancer progression.
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Affiliation(s)
- Paola De Marco
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Francesca Cirillo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Adele Vivacqua
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
| | - Roberta Malaguarnera
- Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Antonino Belfiore
- Endocrinology, Department of Health, University Magna Graecia of Catanzaro, Catanzaro, Italy
- *Correspondence: Antonino Belfiore, Università degli Studi Magna Graecia di Catanzaro, Viale Europa, Loc. Germaneto, Catanzaro 88100, Italy e-mail: ; Marcello Maggiolini, Università della Calabria, via P. Bucci, Rende 87036, Italy e-mail:
| | - Marcello Maggiolini
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, Italy
- *Correspondence: Antonino Belfiore, Università degli Studi Magna Graecia di Catanzaro, Viale Europa, Loc. Germaneto, Catanzaro 88100, Italy e-mail: ; Marcello Maggiolini, Università della Calabria, via P. Bucci, Rende 87036, Italy e-mail:
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25
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Pazaitou-Panayiotou K, Polyzos SA, Mantzoros CS. Obesity and thyroid cancer: epidemiologic associations and underlying mechanisms. Obes Rev 2013; 14:1006-22. [PMID: 24034423 DOI: 10.1111/obr.12070] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2013] [Revised: 07/16/2013] [Accepted: 07/16/2013] [Indexed: 12/26/2022]
Abstract
The incidence of thyroid cancer has been rising over the past few decades along with a parallel increase in obesity. Observational studies have provided evidence for a potential association between the two. By contrast, clinical data for a link between type 2 diabetes mellitus, a condition strongly associated with obesity, and thyroid cancer are limited and largely not supportive of such an association. Obesity leads to hypoadiponectinemia, a pro-inflammatory state, and insulin resistance, which, in turn, leads to high circulating insulin and insulin-like growth factor-1 levels, thereby possibly increasing the risk for thyroid cancer. Thus, insulin resistance possibly plays a pivotal role in underlying the observed association between obesity and thyroid cancer, potentially leading to the development and/or progression of thyroid cancer, through its interconnections with other factors including insulin-like growth factor-1, adipocytokines/cytokines and thyroid-stimulating hormone. In this review, epidemiological and clinical evidence and potential mechanisms underlying the proposed association between obesity and thyroid cancer risk are reviewed. If the association between obesity and thyroid cancer demonstrated in observational studies proves to be causal, targeting obesity (and/or downstream mediators of risk) could be of importance in the prevention and management of thyroid cancer.
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26
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Wang T, Ning G, Bloomgarden Z. Diabetes and cancer relationships. J Diabetes 2013; 5:378-90. [PMID: 23574745 DOI: 10.1111/1753-0407.12057] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2012] [Revised: 03/10/2013] [Accepted: 03/24/2013] [Indexed: 12/29/2022] Open
Abstract
Diabetes and cancer are both heterogeneous and multifactorial diseases with tremendous impact on health worldwide. Epidemiologic evidence suggests that certain malignancies may be associated with diabetes, as well as with diabetes risk factors and, perhaps, with certain diabetes treatments. Numerous biological mechanisms could account for these relationships. Insulin-like growth factor (IGF)-1, IGF-2, IGF-1 receptors, insulin, and the insulin receptor play roles in the development and progression of cancers. Although evidence from randomized controlled trials does not support or refute associations of diabetes and its treatments with either increased or reduced risk of cancer incidence or prognosis, consideration of malignancy incidence rates and the magnitude of the trials that would be required to address these issues explains why such studies may not be readily undertaken.
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Affiliation(s)
- Tiange Wang
- Key Laboratory for Endocrine and Metabolic Diseases of Ministry of Health, Shanghai, China; Shanghai Clinical Center for Endocrine and Metabolic Diseases, Rui-Jin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China; E-Institute of Shanghai Universities, Shanghai, China
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27
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Something old, something new and something borrowed: emerging paradigm of insulin-like growth factor type 1 receptor (IGF-1R) signaling regulation. Cell Mol Life Sci 2013; 71:2403-27. [PMID: 24276851 PMCID: PMC4055838 DOI: 10.1007/s00018-013-1514-y] [Citation(s) in RCA: 143] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2013] [Revised: 10/17/2013] [Accepted: 11/07/2013] [Indexed: 12/14/2022]
Abstract
The insulin-like growth factor type 1 receptor (IGF-1R) plays a key role in the development and progression of cancer; however, therapeutics targeting it have had disappointing results in the clinic. As a receptor tyrosine kinase (RTK), IGF-1R is traditionally described as an ON/OFF system, with ligand stabilizing the ON state and exclusive kinase-dependent signaling activation. Newly added to the traditional model, ubiquitin-mediated receptor downregulation and degradation was originally described as a response to ligand/receptor interaction and thus inseparable from kinase signaling activation. Yet, the classical model has proven over-simplified and insufficient to explain experimental evidence accumulated over the last decade, including kinase-independent signaling, unbalanced signaling, or dissociation between signaling and receptor downregulation. Based on the recent findings that IGF-1R “borrows” components of G-protein coupled receptor (GPCR) signaling, including β-arrestins and G-protein-related kinases, we discuss the emerging paradigm for the IGF-1R as a functional RTK/GPCR hybrid, which integrates the kinase signaling with the IGF-1R canonical GPCR characteristics. The contradictions to the classical IGF-1R signaling concept as well as the design of anti-IGF-1R therapeutics treatment are considered in the light of this paradigm shift and we advocate recognition of IGF-1R as a valid target for cancer treatment.
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28
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Zu K, Martin NE, Fiorentino M, Flavin R, Lis RT, Sinnott JA, Finn S, Penney KL, Ma J, Fazli L, Gleave ME, Bismar TA, Stampfer MJ, Pollak MN, Loda M, Mucci LA, Giovannucci E. Protein expression of PTEN, insulin-like growth factor I receptor (IGF-IR), and lethal prostate cancer: a prospective study. Cancer Epidemiol Biomarkers Prev 2013; 22:1984-93. [PMID: 23983239 DOI: 10.1158/1055-9965.epi-13-0349] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Loss of PTEN has been shown to be associated with aggressive behavior of prostate cancer. It is less clear that loss of PTEN also increases the risk of cancer mortality. We investigated the association between PTEN expression and prostate cancer mortality and the potential effect modification by IGF-IR, a direct activator of the phosphoinositide-3-kinase (PI3K) pathway. METHODS Protein expression in tumor was evaluated using tumor tissues obtained from 805 participants of the Physicians' Health and the Health Professionals Follow-up studies who were diagnosed with prostate cancer and underwent radical prostatectomy. Proportional hazard models were used to assess PTEN expression and its interaction with IGF-IR, in relation to lethal prostate cancer (cancer-specific death or distant metastases). RESULTS Low PTEN expression was associated with an increased risk of lethal prostate cancer [HR, 1.7; 95% confidence interval (CI), 0.98-3.2; Ptrend = 0.04]. The association was attenuated after adjustment for Gleason grade, tumor stage, and prostate-specific antigen (PSA) at diagnosis. A significant negative interaction between PTEN and IGF-IR was found (Pinteraction = 0.03). Either reduction in PTEN or increase in IGF-IR expression was sufficient to worsen prognosis. Models including PTEN and IGF-IR expression offer additional predicting power to prostate cancer survival, compared to those only including demographic and clinical factors. CONCLUSIONS Low PTEN protein expression significantly increases the risk of lethal prostate cancer, particularly when the IGF-IR expression remains at normal level. IMPACT PTEN and IGF-IR expression in tumor are promising candidates for independent prognostic factors to predict lethal prostate cancer.
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Affiliation(s)
- Ke Zu
- Authors' Affiliations: Departments of Nutrition, Epidemiology, and Biostatistics, Harvard School of Public Health; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School; Department of Radiation Oncology, Dana-Farber Cancer Institute/Brigham and Women's Hospital; Departments of Pathology and Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts; Molecular and Transplantation Pathology Laboratory, F. Addarii Institute of Oncology, University of Bologna, Bologna, Italy; Center of Public Health Sciences, University of Iceland, Reykjavik, Iceland; The Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia; Department of Pathology & Laboratory Medicine and Oncology, University of Calgary, Calgary, Alberta; and Departments of Medicine and Oncology, McGill University, Jewish General Hospital, Montreal, Quebec, Canada
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29
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Ock S, Ahn J, Lee SH, Kang H, Offermanns S, Ahn HY, Jo YS, Shong M, Cho BY, Jo D, Abel ED, Lee TJ, Park WJ, Lee IK, Kim J. IGF-1 receptor deficiency in thyrocytes impairs thyroid hormone secretion and completely inhibits TSH-stimulated goiter. FASEB J 2013; 27:4899-908. [PMID: 23982142 DOI: 10.1096/fj.13-231381] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Although thyroid-stimulating hormone (TSH) is known to be a major regulator of thyroid hormone biosynthesis and thyroid growth, insulin-like growth factor 1 (IGF-1) is required for mediating thyrocyte growth in concert with TSH in vitro. We generated mice with thyrocyte-selective ablation of IGF-1 receptor (TIGF1RKO) to explore the role of IGF-1 receptor signaling on thyroid function and growth. In 5-wk-old TIGF1RKO mice, serum thyroxine (T4) concentrations were decreased by 30% in concert with a 43% down-regulation of the monocarboxylate transporter 8 (MCT8), which is involved in T4 secretion. Despite a 3.5-fold increase in circulating concentrations of TSH, thyroid architecture and size were normal. Furthermore, thyrocyte area was increased by 40% in WT thyroids after 10 d TSH injection, but this effect was absent in TSH-injected TIGF1RKO mice. WT mice treated with methimazole and sodium perchlorate for 2 or 6 wk exhibited pronounced goiter development (2.0 and 5.4-fold, respectively), but in TIGF1RKO mice, goiter development was completely abrogated. These data reveal an essential role for IGF-1 receptor signaling in the regulation of thyroid function and TSH-stimulated goitrogenesis.
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Affiliation(s)
- Sangmi Ock
- 2Division of Endocrinology and Metabolism, Department of Internal Medicine, Chung-Ang University, 224-1 Heuk Seok-dong, Dongjak-ku Seoul 156-755, Korea.
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30
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Ramalingam L, Oh E, Thurmond DC. Novel roles for insulin receptor (IR) in adipocytes and skeletal muscle cells via new and unexpected substrates. Cell Mol Life Sci 2013; 70:2815-34. [PMID: 23052216 PMCID: PMC3556358 DOI: 10.1007/s00018-012-1176-1] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2012] [Revised: 08/21/2012] [Accepted: 09/18/2012] [Indexed: 01/30/2023]
Abstract
The insulin signaling pathway regulates whole-body glucose homeostasis by transducing extracellular signals from the insulin receptor (IR) to downstream intracellular targets, thus coordinating a multitude of biological functions. Dysregulation of IR or its signal transduction is associated with insulin resistance, which may culminate in type 2 diabetes. Following initial stimulation of IR, insulin signaling diverges into different pathways, activating multiple substrates that have roles in various metabolic and cellular processes. The integration of multiple pathways arising from IR activation continues to expand as new IR substrates are identified and characterized. Accordingly, our review will focus on roles for IR substrates as they pertain to three primary areas: metabolism/glucose uptake, mitogenesis/growth, and aging/longevity. While IR functions in a seemingly pleiotropic manner in many cell types, through these three main roles in fat and skeletal muscle cells, IR multi-tasks to regulate whole-body glucose homeostasis to impact healthspan and lifespan.
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Affiliation(s)
- Latha Ramalingam
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN USA
| | - Eunjin Oh
- Department of Pediatrics, Herman B Wells Center, Indiana University School of Medicine, Indianapolis, IN USA
| | - Debbie C. Thurmond
- Departments of Pediatrics, Biochemistry and Molecular Biology, and Cellular and Integrative Physiology, Herman B Wells Center, Indiana University School of Medicine, 635 Barnhill Drive MS 2031, Indianapolis, IN 46202 USA
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31
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Xie L, Wang W. Weight control and cancer preventive mechanisms: role of insulin growth factor-1-mediated signaling pathways. Exp Biol Med (Maywood) 2013; 238:127-32. [PMID: 23576795 DOI: 10.1177/1535370213477602] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Overweight and obese not only increase the risk of cardiovascular disease and type-2 diabetes mellitus, but are also now known risk factors for a variety of cancers. Weight control, via dietary calorie restriction and/or exercise, has been demonstrated to be beneficial for cancer prevention in various experimental models, but the underlying mechanisms are still not well defined. Recent studies conducted in a mouse skin carcinogenesis model show that weight loss induced a significant reduction of the circulating levels of insulin growth factor (IGF)-1 and other hormones, including insulin and leptin, resulting in reduced IGF-1-dependent signaling pathways, i.e. Ras-MAPK proliferation and protein kinase B-phosphoinositide 3-kinase (Akt-PI3K) antiapoptosis. Selective targeting IGF-1 to Akt/mammalian target of rapamycin and AMP-activated protein kinase pathways, via negative energy balance, might inactivate cell cycle progression and ultimately suppress tumor development. This review highlights the current studies focused on the major role of reducing IGF-1-activated signaling via weight control as a potential cancer preventive mechanism.
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Affiliation(s)
- Linglin Xie
- Department of Biochemistry and Molecular Biology, University of North Dakota, Grand Forks, ND 58202, USA.
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32
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Nakabayashi H, Kawahara M, Tanaka K, Nagamune T. Construction of antibody/insulin receptor chimera for growth induction of mammalian cells. Cytotechnology 2013; 65:945-53. [PMID: 23615961 DOI: 10.1007/s10616-013-9571-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 04/16/2013] [Indexed: 12/12/2022] Open
Abstract
The insulin receptor (IR) is expressed ubiquitously in various tissues, where insulin exerts various biological effects on the target cells, such as cellular metabolic changes, cell proliferation and differentiation. Therefore, mimicry of insulin signaling would be a promising strategy to realize artificial control of such cellular fates. In this study, we constructed an antibody/insulin receptor chimera that enables to utilize any antigen as the ligand in principle. We constructed chimeric receptors consisting of anti-fluorescein single chain Fv (scFv), the extracellular D2 domain of erythropoietin receptor and the transmembrane/intracellular domains of IR (scFv-IR; S-IR). The function of S-IR was evaluated in terms of growth signal transduction in murine pro-B Ba/F3 cells and murine fibroblast NIH/3T3 cells. S-IR exerted IL-3-independent cell growth in Ba/F3 cells, while NIH/3T3 cells expressing S-IR acquired growth advantage over parental NIH/3T3 cells in a low-serum condition. S-IR induced phosphorylation of S-IR itself and key signaling molecules downstream of IR. Although antigen-independent activation was significantly observed, S-IR enabled specific amplification of the gene-transduced cells.
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Affiliation(s)
- Hideto Nakabayashi
- Department of Chemistry and Biotechnology, School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, 113-8656, Tokyo, Japan
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Salvadori M. Antineoplastic effects of mammalian target of rapamycine inhibitors. World J Transplant 2012; 2:74-83. [PMID: 24175199 PMCID: PMC3782237 DOI: 10.5500/wjt.v2.i5.74] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/14/2011] [Revised: 08/08/2012] [Accepted: 10/20/2012] [Indexed: 02/05/2023] Open
Abstract
Cancer after transplantation is the third cause of death and one of the more relevant comorbidities. Aim of this review is to verify the role of different pathogenetic mechanisms in cancer development in transplant patients and in general population as well. In particular has been outlined the different role exerted by two different families of drug as calcineurin inhibitor and mammalian target of rapamycin (mTOR) inhibitor. The role of mTOR pathways in cell homeostasis is complex but enough clear. As a consequence the mTOR pathway deregulation is involved in the genesis of several cancers. Hence the relevant role of mTOR inhibitors. The authors review the complex mechanism of action of mTOR inhibitors, not only for what concerns the immune system but also other cells as endothelial, smooth muscle and epithelial cells. The mechanism of action is still now not completely defined and understood. It implies the inhibition of mTOR pathway at different levels, but mainly at level of the phosphorylation of several intracellular kinases that contribute to activate mTOR complex. Many prospective and retrospective studies in transplant patients document the antineoplastic role of mTOR inhibition. More recently mTOR inhibitors proven to be effective in the treatment of some cancers also in general population. Kidney cancers, neuroendocrine tumors and liver cancers seem to be the most sensitive to these drugs. Best results are obtained with a combination treatment, targeting the mTOR pathway at different levels.
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Affiliation(s)
- Maurizio Salvadori
- Maurizio Salvadori, Renal Unit, Careggi University Hospital, Viale Pieraccini 18, Florence 50139, Italy
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34
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The insulin and igf-I pathway in endocrine glands carcinogenesis. JOURNAL OF ONCOLOGY 2012; 2012:635614. [PMID: 22927847 PMCID: PMC3423951 DOI: 10.1155/2012/635614] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 06/20/2012] [Indexed: 12/26/2022]
Abstract
Endocrine cancers are a heterogeneous group of diseases that may arise from endocrine cells in any gland of the endocrine system. These malignancies may show an aggressive behavior and resistance to the common anticancer therapies. The etiopathogenesis of these tumors remains mostly unknown. The normal embryological development and differentiation of several endocrine glands are regulated by specific pituitary tropins, which, in adult life, control the function and trophism of the endocrine gland. Pituitary tropins act in concert with peptide growth factors, including the insulin-like growth factors (IGFs), which are considered key regulators of cell growth, proliferation, and apoptosis. While pituitary TSH is regarded as tumor-promoting factor for metastatic thyroid cancer, the role of other pituitary hormones in endocrine cancers is uncertain. However, multiple molecular abnormalities of the IGF system frequently occur in endocrine cancers and may have a role in tumorigenesis as well as in tumor progression and resistance to therapies. Herein, we will review studies indicating a role of IGF system dysregulation in endocrine cancers and will discuss the possible implications of these findings for tumor prevention and treatment, with a major focus on cancers from the thyroid, adrenal, and ovary, which are the most extensively studied.
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35
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Pierre-Eugene C, Pagesy P, Nguyen TT, Neuillé M, Tschank G, Tennagels N, Hampe C, Issad T. Effect of insulin analogues on insulin/IGF1 hybrid receptors: increased activation by glargine but not by its metabolites M1 and M2. PLoS One 2012; 7:e41992. [PMID: 22848683 PMCID: PMC3406060 DOI: 10.1371/journal.pone.0041992] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 06/28/2012] [Indexed: 12/28/2022] Open
Abstract
Background In diabetic patients, the pharmacokinetics of injected human insulin does not permit optimal control of glycemia. Fast and slow acting insulin analogues have been developed, but they may have adverse properties, such as increased mitogenic or anti-apoptotic signaling. Insulin/IGF1 hybrid receptors (IR/IGF1R), present in most tissues, have been proposed to transmit biological effects close to those of IGF1R. However, the study of hybrid receptors is difficult because of the presence of IR and IGF1R homodimers. Our objective was to perform the first study on the pharmacological properties of the five marketed insulin analogues towards IR/IGF1R hybrids. Methodology To study the effect of insulin analogues on IR/IGF1R hybrids, we used our previously developed Bioluminescence Resonance Energy Transfer (BRET) assay that permits specific analysis of the pharmacological properties of hybrid receptors. Moreover, we have developed a new, highly sensitive BRET-based assay to monitor phophatidylinositol-3 phosphate (PIP3) production in living cells. Using this assay, we performed a detailed pharmacological analysis of PIP3 production induced by IGF1, insulin and insulin analogues in living breast cancer-derived MCF-7 and MDA-MB231 cells. Results Among the five insulin analogues tested, only glargine stimulated IR/IGF1R hybrids with an EC50 that was significantly lower than insulin and close to that of IGF1. Glargine more efficiently stimulated PIP3 production in MCF-7 cells but not in MDA-MB231 cells as compared to insulin. In contrast, glargine metabolites M1 and M2 showed lower potency for hybrid receptors stimulation, PIP3 production, Akt and Erk1/2 phosphorylation and DNA synthesis in MCF-7 cells, compared to insulin. Conclusion Glargine, possibly acting through IR/IGF1R hybrids, displays higher potency, whereas its metabolites M1 and M2 display lower potency than insulin for the stimulation of proliferative/anti-apoptotic pathways in MCF-7 cells.
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Affiliation(s)
- Cécile Pierre-Eugene
- Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France
- INSERM, U1016, Paris, France
| | - Patrick Pagesy
- Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France
- INSERM, U1016, Paris, France
| | - Tuyet Thu Nguyen
- Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France
- INSERM, U1016, Paris, France
| | - Marion Neuillé
- Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France
- INSERM, U1016, Paris, France
| | | | | | - Cornelia Hampe
- Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France
- INSERM, U1016, Paris, France
| | - Tarik Issad
- Institut Cochin, Université Paris Descartes, CNRS (UMR8104), Paris, France
- INSERM, U1016, Paris, France
- * E-mail:
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Abstract
Insulin-like growth factor (IGF) plays an important role in tissue growth and development. Several studies have demonstrated the association between circulating levels of IGF-1 and -2 and cancer risk, and the IGF system has been implicated in the oncogenesis of essentially all solid and hematologic malignancies. The optimal strategy for targeting IGF signaling in patients with cancer is not clear. The modest benefits reported thus far underscore the need for a better understanding of IGF signaling, which would enable clinicians to identify the subset of patients with the greatest likelihood of attaining benefit from this targeted approach.
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Affiliation(s)
- S John Weroha
- Department of Oncology, Mayo Clinic College of Medicine, 200 First Street Southwest, Rochester, MN 55905, USA
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37
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Abstract
The IGF axis is a tightly controlled endocrine system that regulates cell growth and development, known to have an important function in cancer biology. IGF1 and IGF2 can promote cancer growth in a GH-independent manner both through paracrine and autocrine secretion and can also confer resistance to chemotherapy and radiation. Many alterations of this system have been found in neoplasias, including increased expression of ligands and receptors, loss of heterozygosity of the IGF2 locus and increased IGF1R gene copy number. The IGF1 network is an attractive candidate for targeted therapy, including receptor blockade with monoclonal antibodies and small molecule inhibitors of receptor downstream signaling. This article reviews the role of the IGF axis in the initiation and progression of cancer, and describes the recent advances in IGF inhibition as a therapeutic tool.
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Affiliation(s)
- Fernanda I Arnaldez
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10 CRC Room 1-3816, Bethesda, MD 20892, USA.
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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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39
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Kim JG, Kang MJ, Yoon YK, Kim HP, Park J, Song SH, Han SW, Park JW, Kang GH, Kang KW, Oh DY, Im SA, Bang YJ, Yi EC, Kim TY. Heterodimerization of glycosylated insulin-like growth factor-1 receptors and insulin receptors in cancer cells sensitive to anti-IGF1R antibody. PLoS One 2012; 7:e33322. [PMID: 22438913 PMCID: PMC3306383 DOI: 10.1371/journal.pone.0033322] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2011] [Accepted: 02/07/2012] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Identification of predictive biomarkers is essential for the successful development of targeted therapy. Insulin-like growth factor 1 receptor (IGF1R) has been examined as a potential therapeutic target for various cancers. However, recent clinical trials showed that anti-IGF1R antibody and chemotherapy are not effective for treating lung cancer. METHODOLOGY/PRINCIPAL FINDINGS In order to define biomarkers for predicting successful IGF1R targeted therapy, we evaluated the anti-proliferation effect of figitumumab (CP-751,871), a humanized anti-IGF1R antibody, against nine gastric and eight hepatocellular cancer cell lines. Out of 17 cancer cell lines, figitumumab effectively inhibited the growth of three cell lines (SNU719, HepG2, and SNU368), decreased p-AKT and p-STAT3 levels, and induced G 1 arrest in a dose-dependent manner. Interestingly, these cells showed co-overexpression and altered mobility of the IGF1R and insulin receptor (IR). Immunoprecipitaion (IP) assays and ELISA confirmed the presence of IGF1R/IR heterodimeric receptors in figitumumab-sensitive cells. Treatment with figitumumab led to the dissociation of IGF1-dependent heterodimeric receptors and inhibited tumor growth with decreased levels of heterodimeric receptors in a mouse xenograft model. We next found that both IGF1R and IR were N-linked glyosylated in figitumumab-sensitive cells. In particular, mass spectrometry showed that IGF1R had N-linked glycans at N913 in three figitumumab-sensitive cell lines. We observed that an absence of N-linked glycosylation at N913 led to a lack of membranous localization of IGF1R and figitumumab insensitivity. CONCLUSION AND SIGNIFICANCE The data suggest that the level of N-linked glycosylated IGF1R/IR heterodimeric receptor is highly associated with sensitivity to anti-IGF1R antibody in cancer cells.
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MESH Headings
- Animals
- Antibodies, Monoclonal/pharmacology
- Base Sequence
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/therapy
- Cell Division
- Cell Line, Tumor
- Dimerization
- Female
- G1 Phase Cell Cycle Checkpoints
- Gene Knockdown Techniques
- Glycosylation
- Hep G2 Cells
- Humans
- Immunoglobulins, Intravenous
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms/therapy
- Mice
- Mice, Inbred BALB C
- Protein Structure, Quaternary
- Proto-Oncogene Proteins c-akt/metabolism
- RNA, Small Interfering/genetics
- Receptor, IGF Type 1/antagonists & inhibitors
- Receptor, IGF Type 1/chemistry
- Receptor, IGF Type 1/genetics
- Receptor, IGF Type 1/metabolism
- Receptor, Insulin/chemistry
- Receptor, Insulin/metabolism
- STAT3 Transcription Factor/metabolism
- Signal Transduction
- Stomach Neoplasms/metabolism
- Stomach Neoplasms/pathology
- Stomach Neoplasms/therapy
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Jun Gyu Kim
- Cancer Research Institute, Seoul National University, Seoul, South Korea
| | - Min Jueng Kang
- WCU Department of Molecular Medicine and Biopharmaceutical Science, Graduated School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
| | - Young-Kwang Yoon
- Cancer Research Institute, Seoul National University, Seoul, South Korea
| | - Hwang-Phill Kim
- Cancer Research Institute, Seoul National University, Seoul, South Korea
| | - Jinah Park
- Cancer Research Institute, Seoul National University, Seoul, South Korea
| | - Sang-Hyun Song
- Cancer Research Institute, Seoul National University, Seoul, South Korea
| | - Sae-Won Han
- Department of Internal Medicine, Seoul National University, Seoul, South Korea
| | - Jong-Wan Park
- Department of Pharmacology, Seoul National University, Seoul, South Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University, Seoul, South Korea
| | - Keon Wook Kang
- Department of Nuclear Medicine, College of Medicine, Seoul National University, Seoul, South Korea
| | - Do Youn Oh
- Cancer Research Institute, Seoul National University, Seoul, South Korea
- Department of Internal Medicine, Seoul National University, Seoul, South Korea
| | - Seock-Ah Im
- Cancer Research Institute, Seoul National University, Seoul, South Korea
- Department of Internal Medicine, Seoul National University, Seoul, South Korea
| | - Yung-Jue Bang
- Cancer Research Institute, Seoul National University, Seoul, South Korea
- Department of Internal Medicine, Seoul National University, Seoul, South Korea
- WCU Department of Molecular Medicine and Biopharmaceutical Science, Graduated School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
| | - Eugene C. Yi
- WCU Department of Molecular Medicine and Biopharmaceutical Science, Graduated School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
| | - Tae-You Kim
- Cancer Research Institute, Seoul National University, Seoul, South Korea
- Department of Internal Medicine, Seoul National University, Seoul, South Korea
- WCU Department of Molecular Medicine and Biopharmaceutical Science, Graduated School of Convergence Science and Technology, Seoul National University, Seoul, South Korea
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Feng X, Aleem E, Lin Y, Axelson M, Larsson O, Strömberg T. Multiple antitumor effects of picropodophyllin in colon carcinoma cell lines: clinical implications. Int J Oncol 2011; 40:1251-8. [PMID: 22159423 PMCID: PMC3584617 DOI: 10.3892/ijo.2011.1281] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2011] [Accepted: 11/17/2011] [Indexed: 12/20/2022] Open
Abstract
Although colorectal cancer can be successfully treated by conventional strategies such as chemo/radiotherapy and surgery, a substantial number of cases, in particular those with liver metastases, remain incurable. Therefore, novel treatment approaches are warranted. The IGF-1R and its ligands, mainly IGF-1 and IGF-2, have been suggested to play pivotal roles in proliferation, survival and migration of adenocarcinoma cells of the colon/rectum. Therefore, interference with IGF-1R-mediated signaling may represent a therapeutic option for this malignancy. In this study, semi-quantitative RT-PCR analyses of 48 paired, colorectal cancer patient samples showed significant overexpression of tumor IGF-1R and IGF-2 mRNA. There was also an overexpression of MMP-7, which was significantly correlated with histopathological parameters. Based on these findings, the effect of the IGF-1R-inhibitory cyclolignan picropodophyllin (PPP) was assessed in the four colon carcinoma cell lines HT-29, HCT-116, DLD-1 and CaCO-2. PPP strongly and dose-dependently inhibited proliferation and migration in all cell lines. However, when exposed to 0.5 μM PPP, only HT-29 showed a net decrease of viable cells as compared with the cell number at the beginning of the experiment, a finding that coincided with decreased expression/phosphorylation of IGF-1R, AKT and ERK. This cell line also exhibited PPP-induced downregulation of MMP-7 and MMP-9. Similar to the DLD-1 and HCT-116 cell lines, HT-29 also showed substantial cell detachment in response to PPP. Although a net reduction of cells by PPP seems to require a synchronized downregulation of IGF-1R, AKT and ERK1/2, part of the antitumor effect may be explained by other, possibly IGF-1R-unrelated mechanism(s). Such a multitude of inhibitory effects of PPP in colon cancer cells together with its low toxicity in vivo makes it a promising drug candidate in the treatment of this disease.
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Affiliation(s)
- Xiaoying Feng
- Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska, 17176 Stockholm, Sweden
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41
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Altered expression of insulin receptor isoforms in breast cancer. PLoS One 2011; 6:e26177. [PMID: 22046260 PMCID: PMC3202518 DOI: 10.1371/journal.pone.0026177] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Accepted: 09/21/2011] [Indexed: 12/21/2022] Open
Abstract
Purpose Insulin-like growth factor (IGF) signaling through human insulin receptor isoform A (IR-A) contributes to tumorigenesis and intrinsic resistance to anti-IGF1R therapy. In the present study, we (a) developed quantitative TaqMan real time-PCR-based assays (qRT-PCR) to measure human insulin receptor isoforms with high specificity, (b) evaluated isoform expression levels in molecularly-defined breast cancer subtypes, and (c) identified the IR-A:IR-B mRNA ratio as a potential biomarker guiding patient stratification for anti-IGF therapies. Experimental Design mRNA expression levels of IR-A and IR-B were measured in 42 primary breast cancers and 19 matched adjacent normal tissues with TaqMan qRT-PCR assays. The results were further confirmed in 165 breast cancers. The tumor samples were profiled using whole genome microarrays and subsequently subtyped using the PAM50 breast cancer gene signature. The relationship between the IR-A:IR-B ratio and cancer subtype, as well as markers of proliferation were characterized. Results The mRNA expression levels of IR-A in the breast tumors were similar to those observed in the adjacent normal tissues, while the mRNA levels of IR-B were significantly decreased in tumors. The IR-A:IR-B ratio was significantly higher in luminal B breast cancer than in luminal A. Strong concordance between the IR-A:IR-B ratio and the composite Oncotype DX proliferation score was observed for stratifying the latter two breast cancer subtypes. Conclusions The reduction in IR-B expression is the key to the altered IR-A:IR-B ratio observed in breast cancer. The IR-A:IR-B ratio may have biomarker utility in guiding a patient stratification strategy for an anti-IGF therapeutic.
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42
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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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43
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Cannata D, Fierz Y, Vijayakumar A, LeRoith D. Type 2 diabetes and cancer: what is the connection? ACTA ACUST UNITED AC 2011; 77:197-213. [PMID: 20309918 DOI: 10.1002/msj.20167] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Epidemiological studies have demonstrated an association between type 2 diabetes and cancer. Type 2 diabetes is characterized by insulin resistance and hyperinsulinemia. Hyperinsulinemia may lead to cancer through insulin's effect on its cognate receptor and the insulin-like growth factor system. The effects of insulin and insulin-like growth factor I on cancer development and progression have been demonstrated in animal and human studies. Type 2 diabetes has been positively associated with cancers of the breast, colon, and pancreas. An inverse relationship has been observed between type 2 diabetes and prostate cancer, and this may be due to lower testosterone levels in men with type 2 diabetes. Medications used to treat type 2 diabetes may affect cancer cells directly or indirectly by affecting serum insulin levels. Hyperinsulinemia may be an important risk factor for cancer as well as a target for cancer therapy.
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Affiliation(s)
- Dara Cannata
- Mount Sinai School of Medicine, New York, NY, USA
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44
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Spallone G, Botti E, Costanzo A. Targeted therapy in nonmelanoma skin cancers. Cancers (Basel) 2011; 3:2255-73. [PMID: 24212808 PMCID: PMC3757416 DOI: 10.3390/cancers3022255] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2011] [Revised: 04/11/2011] [Accepted: 04/26/2011] [Indexed: 12/13/2022] Open
Abstract
Nonmelanoma skin cancer (NMSC) is the most prevalent cancer in light-skinned populations, and includes mainly Basal Cell Carcinomas (BCC), representing around 75% of NMSC and Squamous Cell Carcinomas (SCC). The incidence of these tumors is continuously growing. It was found that the overall number of procedures for NMSC in US rose by 76%, from 1,158,298 in 1992 to 2,048,517 in 2006. Although mortality from NMSC tends to be very low, clearly the morbidity related to these skin cancers is very high. Treatment options for NMSC include both surgical and nonsurgical interventions. Surgery was considered the gold standard therapy, however, advancements in the knowledge of pathogenic mechanisms of NMSCs led to the identification of key targets for drug intervention and to the consequent development of several targeted therapies. These represent the future in treatment of these common forms of cancer ensuring a high cure rate, preservation of the maximal amount of normal surrounding tissue and optimal cosmetic outcome. Here, we will review recent advancements in NMSC targeted therapies focusing on BCC and SCC.
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Affiliation(s)
- Giulia Spallone
- Department of Dermatology, University of Rome "Tor Vergata", Via Montpellier 1, 00199, Rome, Italy.
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45
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Malaguarnera R, Frasca F, Garozzo A, Gianì F, Pandini G, Vella V, Vigneri R, Belfiore A. Insulin receptor isoforms and insulin-like growth factor receptor in human follicular cell precursors from papillary thyroid cancer and normal thyroid. J Clin Endocrinol Metab 2011; 96:766-74. [PMID: 21123448 DOI: 10.1210/jc.2010-1255] [Citation(s) in RCA: 122] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
CONTEXT Factors involved in the biology of normal and cancer stem/precursor cells from the thyroid are unknown. Thyroid cancer cells are responsive to insulin and IGF-I and IGF-II and often overexpress the insulin receptor (IR) and the IGF-I receptor (IGF-IR). OBJECTIVE We investigated the role of IR isoforms (IR-A and IR-B), IGF-IR, and their ligands in thyroid follicular cell precursors both normal and malignant. DESIGN We established cultures of follicular cell precursors as thyrospheres from three papillary thyroid cancers and the corresponding nonaffected tissues. The expression of IR, IGF-IR, and their ligands was evaluated by quantitative RT-PCR and, in one case, also by Western blot. The effects of insulin and IGFs on thyrosphere growth and self-renewal were evaluated. RESULTS Thyrospheres were characterized by the expression of stem cell markers and low/absent thyroid specific markers. Thyrospheres from normal tissue, but not from cancer tissue, could be induced to differentiate. Both IR isoforms, IGF-IR, IGF-I and IGF-II, were expressed at high levels in thyrospheres and markedly decreased in differentiating cells. IR-A was the predominant isoform in thyrospheres, especially from cancer, while IR-B was predominant in differentiating cells. Cancer thyrosphere growth was stimulated by insulin and IGFs. CONCLUSIONS Our data suggest that IR isoforms and IGF-IR play a role in the biology of follicular thyroid precursors. Cell differentiation is associated with marked changes in the expression of these receptors and cognate ligands. These data may provide insight for future differentiation therapies in thyroid cancer.
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MESH Headings
- Blotting, Western
- Carcinoma, Papillary/genetics
- Carcinoma, Papillary/metabolism
- Cell Adhesion
- Cell Line, Tumor
- Cells, Cultured
- DNA Primers
- Gene Expression Regulation, Neoplastic/physiology
- Humans
- Ligands
- Neoplastic Stem Cells/metabolism
- Receptor, IGF Type 1/genetics
- Receptor, IGF Type 1/metabolism
- Receptor, IGF Type 2/genetics
- Receptor, IGF Type 2/metabolism
- Receptor, Insulin/genetics
- Receptor, Insulin/metabolism
- Receptors, Somatomedin/genetics
- Receptors, Somatomedin/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Thyroid Gland/cytology
- Thyroid Gland/metabolism
- Thyroid Neoplasms/genetics
- Thyroid Neoplasms/metabolism
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Affiliation(s)
- Roberta Malaguarnera
- Department of Clinical and Experimental Medicine, University Magna Graecia of Catanzaro, 88100 Catanzaro, Italy
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46
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Galer CE, Corey CL, Wang Z, Younes MN, Gomez-Rivera F, Jasser SA, Ludwig DL, El-Naggar AK, Weber RS, Myers JN. Dual inhibition of epidermal growth factor receptor and insulin-like growth factor receptor I: reduction of angiogenesis and tumor growth in cutaneous squamous cell carcinoma. Head Neck 2011; 33:189-98. [PMID: 20848439 PMCID: PMC3010504 DOI: 10.1002/hed.21419] [Citation(s) in RCA: 45] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Cutaneous squamous cell carcinoma (CSCC) is the second most common nonmelanoma skin cancer. Most of the approximately 250,000 cases occurring annually in the United States are small, nonaggressive, and cured by excision alone. However, a subset of these tumors which are defined by poorly differentiated histology, large tumor size, invasion of adjacent structures, and/or regional metastases can prove resistant to treatment despite adjuvant radiotherapy and can have an increased risk of recurrence and nodal metastasis. Novel therapeutic approaches are necessary to improve the outcomes for patients with aggressive CSCC. METHODS We analyzed the effect of targeted therapy on the growth and survival of CSCC cell lines using an anti-insulin-like growth factor-I receptor (IGF-IR) antibody, A12, alone or in combination with an anti-epidermal growth factor receptor (EGFR) antibody, cetuximab, both in vitro and in vivo in an athymic nude mouse model of CSCC. RESULTS Treatment with A12 and cetuximab inhibited the signaling pathways of IGF-IR and EGFR and inhibited proliferation and induced apoptosis of squamous cell carcinoma (SCC) cell lines in vitro. Immunohistochemical staining revealed decreased proliferating cell nuclear antigen (PCNA), microvessel density, and increased apoptosis within the treated tumor xenografts. In addition, the administration of A12, alone or in combination with cetuximab inhibited the growth of tumors by 51% and 92%, respectively, and significantly enhanced survival in the nude mouse model of CSCC (p = .044 and p < .001, respectively). CONCLUSION These data suggest that dual treatment with monoclonal antibodies to the EGFR and IGF-IR may be therapeutically useful in the treatment of CSCC.
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MESH Headings
- Angiogenesis Inhibitors/pharmacology
- Angiogenesis Inhibitors/therapeutic use
- Animals
- Anthracenes/pharmacology
- Antibodies, Monoclonal/pharmacology
- Antibodies, Monoclonal/therapeutic use
- Antibodies, Monoclonal, Humanized
- Carcinoma, Squamous Cell/drug therapy
- Carcinoma, Squamous Cell/pathology
- Cetuximab
- ErbB Receptors/antagonists & inhibitors
- Humans
- In Vitro Techniques
- Mice
- Mice, Nude
- Neovascularization, Pathologic/prevention & control
- Receptor, IGF Type 1/antagonists & inhibitors
- Skin Neoplasms/drug therapy
- Skin Neoplasms/pathology
- Treatment Outcome
- Tumor Cells, Cultured/drug effects
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Affiliation(s)
- Chad E. Galer
- Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Christina L. Corey
- Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Zhuoying Wang
- Department of Pathology, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Maher N. Younes
- Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Fernando Gomez-Rivera
- Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Samar A. Jasser
- Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | | | - Adel K. El-Naggar
- Department of Head and Neck Surgery, Cancer Hospital of Fudan University, Shanghai, China
| | - Randal S. Weber
- Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
| | - Jeffrey N. Myers
- Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
- Bobby R. Alford Department of Otolaryngology-Head and Neck Surgery, Baylor College of Medicine, Houston, TX, USA
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Ock S, Lee SH, Ahn J, Lee TJ, Cho CH, Abel ED, Kimura S, Kim J. Conditional deletion of insulin receptor in thyrocytes does not affect thyroid structure and function. Endocr J 2011; 58:1013-9. [PMID: 21908931 PMCID: PMC3471790 DOI: 10.1507/endocrj.ej11-0007] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Thyroid-stimulating hormone (TSH) is the primary regulator of thyroid growth and function acting via cyclic AMP signaling cascades. In cultured thyrocytes, insulin and/or insulin-like growth factor-1 (IGF-1) are required for mediating thyrocyte proliferation in concert with TSH. To determine the role of insulin signaling in thyroid, growth in vivo, mice with thyrocyte-selective ablation of the insulin receptor (IR) were generated by crossing mice homozygous for a floxed IR allele with transgenic mice in which thyrocyte-specific expression of Cre recombinase was driven by the human thyroid peroxidase (TPO) gene promoter. Immunohistochemistry and Western blot analysis confirmed near complete loss of IR expression in the thyroid of thyrocyte IR knockout mice. These mice are viable and have no obvious thyroid dysfunction and macro- and microscopic thyroid morphology was normal. Thus, insulin signaling in thyrocytes does not play an essential role in the architecture and function of the thyroid in vivo.
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Affiliation(s)
- Sangmi Ock
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Seok Hong Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Jihyun Ahn
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Tae Jin Lee
- Department of Pathology, College of Medicine, Chung-Ang University, Seoul, Korea
| | - Chung-Hyun Cho
- Department of Pharmacology, College of Medicine, Seoul National University, Seoul, Korea
| | - E. Dale Abel
- Division of Endocrinology, Metabolism and Diabetes, Program in Molecular Medicine, University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Shioko Kimura
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jaetaek Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Korea
- Corresponding author: Jaetaek Kim, M.D., Ph.D., Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, 156-755, Korea, Phone: 82-2-6299-1397, Fax: 82-2-6299-1390,
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Dinchuk JE, Cao C, Huang F, Reeves KA, Wang J, Myers F, Cantor GH, Zhou X, Attar RM, Gottardis M, Carboni JM. Insulin receptor (IR) pathway hyperactivity in IGF-IR null cells and suppression of downstream growth signaling using the dual IGF-IR/IR inhibitor, BMS-754807. Endocrinology 2010; 151:4123-32. [PMID: 20610571 DOI: 10.1210/en.2010-0032] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
The biology of IGF-IR/IR signaling was studied in normal mouse embryonic fibroblasts (MEFs) that were either wild type (wt), heterozygous (het), or null for the IGF-IR. The ability of IGF-I, IGF-II, or insulin to stimulate serum-starved MEFs was characterized by gene expression profiling and biochemical analyses for activation of downstream signals. Each genotypic group of MEFs exhibited distinct patterns of expression both while resting and in response to stimulation. The insulin receptor (IR) pathway in IGF-IR null MEFs was hypersensitive to insulin ligand stimulation resulting in greater AKT phosphorylation than in wt or het MEFs stimulated with the same ligand. Interestingly, the IR pathway hypersensitivity in IGF-IR null MEFs occurred with no observed changes in the levels of IR isoforms A or B. A new small molecule IGF-IR inhibitor (BMS-754807), having equipotent activity against both IGF-IR and IR, proved effective in suppressing both AKT and ERK phosphorylation from both the IGF-IR and IR pathways by all three ligands tested in wt, het, and null MEFs. The use of a dual IGF-IR/IR inhibitor addresses concerns about the use of growth inhibiting therapies directed against the IGF-IR receptor in certain cancers. Lastly, comparison of the antiproliferative effects (IC(50)s) of various compounds in wt vs. null MEFs demonstrates that genetically characterized MEFs provide a simple and inexpensive tool with which to define compounds as having mostly on-target or off-target IGF-IR activities because off-target compounds affect both wt and null MEFs equally.
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MESH Headings
- Animals
- Blotting, Western
- Cell Proliferation/drug effects
- Cells, Cultured
- Cluster Analysis
- Embryo, Mammalian/cytology
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Female
- Fibroblasts/cytology
- Fibroblasts/drug effects
- Fibroblasts/metabolism
- Gene Expression Profiling
- Insulin/pharmacology
- Insulin-Like Growth Factor I/pharmacology
- Insulin-Like Growth Factor II/pharmacology
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Inbred Strains
- Mice, Knockout
- Phosphorylation/drug effects
- Proto-Oncogene Proteins c-akt/metabolism
- Pyrazoles/pharmacology
- Receptor, IGF Type 1/antagonists & inhibitors
- Receptor, IGF Type 1/genetics
- Receptor, IGF Type 1/metabolism
- Receptor, Insulin/antagonists & inhibitors
- Receptor, Insulin/genetics
- Receptor, Insulin/metabolism
- Reverse Transcriptase Polymerase Chain Reaction
- Signal Transduction/drug effects
- Triazines/pharmacology
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Affiliation(s)
- Joseph E Dinchuk
- Bristol-Myers Squibb Research and Development, K23-02, Princeton, New Jersey 08543-4000, USA.
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Zhang G, Li X, Zhang L, Zhao L, Jiang J, Wang J, Wei L. The expression and role of hybrid insulin/insulin-like growth factor receptor type 1 in endometrial carcinoma cells. CANCER GENETICS AND CYTOGENETICS 2010; 200:140-148. [PMID: 20620597 DOI: 10.1016/j.cancergencyto.2010.04.007] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2010] [Revised: 03/22/2010] [Accepted: 04/07/2010] [Indexed: 01/06/2023]
Abstract
Insulin receptor (IR) and type 1 insulin-like growth factor receptor (IGF-IR) can assemble heteromerically as a hybrid insulin/IGF-I receptor (hybrid-R) in tissues that express both molecules. There is little information about hybrid-R in endometrial carcinoma, in which both IR and IGF-IR are frequently overexpressed. We used immunoprecipitation to detect hybrid-R expression in two endometrial carcinoma cell lines: HEC-1a, which has low estrogen receptor (ER) expression, and Ishikawa, which is positive for ER expression. To explore the role of hybrid-R in endometrial carcinoma cells, we examined phosphorylation of extracellular signal-regulated kinase (ERK1/2), which is a key molecule in the mitogen-activated protein kinase (MAPK) pathway. The effect of inhibiting IGF-I, IGF-II, and insulin on cell cycle progression and apoptosis was assessed by flow cytometry. Both cell lines expressed hybrid-R, and HEC-1a cells had higher expression levels than did Ishikawa cells. IGF-I induced ERK1/2 phosphorylation in HEC-1a cells mainly through hybrid-R; in Ishikawa cells, this effect was mediated only in part by hybrid-R. Insulin stimulated ERK1/2 phosphorylation partly through hybrid-R in HEC-1a cells, but not in Ishikawa cells. Both IGFs and insulin increased cellular DNA content in the S phase of the cell cycle in HEC-1a through hybrid-R. In contrast, in Ishikawa cells, only insulin enhanced DNA content in S phase through hybrid-R. Both IGFs and insulin significantly decreased apoptosis in HEC-1a cells through hybrid-R, and a similar but moderate effect was observed in Ishikawa cells. Hybrid-R, which is present in endometrial carcinoma cells, may have an important role in mediating IGF- and insulin-induced cell growth and in preventing apoptosis.
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Affiliation(s)
- Guo Zhang
- Department of Gynecology, Peking University People's Hospital, No. 11 Xi-Zhi-Men South Street, Xi Cheng District, Beijing, China
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50
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Runnels HA, Arbuckle JA, Bailey KS, Nicastro PJ, Sun D, Pegg JA, Meyer DM, Evans M, Bono CP, Lie WR, Moffat MA, Casperson GF, Lennard S, Elvin J, Vaughan T, Smith CE, Morton PA. Human monoclonal antibodies to the insulin-like growth factor 1 receptor inhibit receptor activation and tumor growth in preclinical studies. Adv Ther 2010; 27:458-75. [PMID: 20574692 DOI: 10.1007/s12325-010-0026-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2010] [Indexed: 11/28/2022]
Abstract
INTRODUCTION The insulin-like growth factor type 1 (IGF-1) receptor contributes importantly to transformation and survival of tumor cells both in vitro and in vivo, and selective antagonists of the IGF-1 receptor (IGF-1R) activity represent an attractive experimental approach for human cancer therapy. METHODS Using a phage display library, we identified several high-affinity fully human monoclonal antibodies with inhibitory activity against both human and rodent IGF.1Rs. RESULTS These candidate therapeutic antibodies recognized several distinct epitopes and effectively blocked ligand-mediated receptor signal transduction and cellular proliferation in vitro. They also induced IGF-1R downregulation and catabolism following antibody-mediated endocytosis. These antibodies exhibited activity against human, primate, and rodent IGF-1Rs, and dose-dependently inhibited the growth of established human tumors in nude mice. CONCLUSION These fully human antibodies therefore have the potential to provide an effective anti-tumor biological therapy in the human clinical setting.
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