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Ferrer-Mayorga G, Muñoz A, González-Sancho JM. Vitamin D and colorectal cancer. FELDMAN AND PIKE'S VITAMIN D 2024:859-899. [DOI: 10.1016/b978-0-323-91338-6.00039-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Palui R, Sridharan K, Kamalanathan S, Sahoo J, Naik D. Growth hormone and gastrointestinal malignancy: An intriguing link. World J Gastrointest Pathophysiol 2023; 14:1-11. [PMID: 36743656 PMCID: PMC9896462 DOI: 10.4291/wjgp.v14.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 12/25/2022] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
Growth hormone (GH) excess is associated with several systemic complications, one of which is the increased risk of neoplastic processes particularly of the gastrointestinal (GI) tract. Among the GI neoplasms, the most reported association is with benign and malignant neoplasms of the colon. In the majority of published literature, an increased incidence of GI neoplasms, both colonic adenomas as well as colorectal carcinoma is reported. However, the studies on colon cancer-specific mortality rate are conflicting with recent studies reporting similar cancer-specific mortality rates in comparison to controls. Many studies have reported an association of colorectal neoplasms with GH levels. Pathogenic mechanisms put forward to explain this association of GH excess and GI neoplasms primarily involve the increased GH-insulin-like growth factor 1 (IGF-1) signaling. Both GH and IGF-1 have proliferative, anti-apoptotic, and angiogenic effects on the systemic tissues leading to cellular proliferation. Other contributing factors to the increased risk of GI neoplasms include slow intestinal transit with a redundant large bowel, altered bile acids, deranged local immune response, shared genetic susceptibility factors and hyperinsulinemia. In view of the increased risk association, most guidelines for the care of acromegaly patients recommend an initial screening colonoscopy. Recommendations for further follow-up colonoscopy differ but broadly, the guidelines agree that it depends on the findings at first colonoscopy and state of remission of GH excess. Regarding the concern about the risk of colorectal cancers in patients receiving recombinant GH therapy, most cohort studies do not show an increased risk.
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Affiliation(s)
- Rajan Palui
- Department of Endocrinology, The Mission Hospital, Durgapur 713212, West Bengal, India
| | - Kalyani Sridharan
- Department of Endocrinology, All India Institute of Medical Science, Rishikesh 249203, Uttarakhand, India
| | - Sadishkumar Kamalanathan
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Jayaprakash Sahoo
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
| | - Dukhabandhu Naik
- Department of Endocrinology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry 605006, India
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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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Yu GH, Jiang Z. Progress in understanding of relationship between diabetes and colorectal cancer. Shijie Huaren Xiaohua Zazhi 2021; 29:1323-1333. [DOI: 10.11569/wcjd.v29.i23.1323] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Several epidemiological studies have suggested that diabetes is closely associated with an increased risk of colorectal cancer and diabetes could be regarded as an independent risk factor for colorectal cancer. Potential pathophysiological mechanisms connecting diabetes and colorectal cancer include hyperglycemia, hyperinsulinemia, and insulin-like growth factor axis, chronic inflammation and oxidative stress, gastrointestinal motility disorder, and impaired immunological surveillance. Meanwhile, multiple studies have revealed that diabetes is negatively related to the prognosis of patients with colorectal cancer. This review mainly summarizes the current studies concerning the linkages between diabetes and colorectal cancer and the underlying pathophysiological mechanisms, so as to provide a theoretical basis for rational use of antidiabetic drugs and early diagnosis of diabetes-related colorectal cancer.
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Affiliation(s)
- Guan-Hua Yu
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Zheng Jiang
- Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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5
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Battistone MF, Miragaya K, Rogozinski A, Agüero M, Alfieri A, Ballarino MC, Boero L, Danilowicz K, Diez S, Donoso M, Fainstein-Day P, Furioso A, Garcia-Basavilbaso N, Glerean M, Katz D, Loto M, Mallea-Gil S, Martinez M, Sabate MI, Servidio M, Slavinsky P, Stalldecker G, Sosa S, Szuman G, Tkatch J, Caldo I, Lubieniecki D, Guitelman M. Increased risk of preneoplastic colonic lesions and colorectal carcinoma in acromegaly: multicenter case-control study. Pituitary 2021; 24:96-103. [PMID: 33057946 DOI: 10.1007/s11102-020-01090-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/28/2020] [Indexed: 12/11/2022]
Abstract
PURPOSE Current international guidelines recommend colonoscopy in patients with acromegaly at the time of diagnosis, even though the risk of developing colorectal neoplasm is still controversial. The main objective of this Argentine multicenter study was to analyze through screening colonoscopy the presence of advanced neoplastic lesions considered as precancerous, in patients with acromegaly compared to a control group. METHODS This is a case-control retrospective study. Full length colonoscopy of 70 acromegalic patients and 128 control subjects were studied. Polyps were classified into non pre-cancerous lesions and advance neoplastic lesions which included advanced adenomas (preneoplastic) and colorectal carcinomas. RESULTS Thirty three out of 70 acromegalic patients and 32 out of 128 subjects controls presented polyps in the colonoscopy [47.1% vs 25%, p = 0.002, OR 2.68]. Non precancerous polyps were found in 11 (15.7%) and 23 (17.9%) (p = 0.690), while advanced neoplastic lesions were found in 22 (31.4%) and 9 (7.0%) (p = 0,0001 - OR: 6.06) patients and controls respectively. Advanced adenomas and colorectal carcinomas were found in 18 (27.3%) and 9 (7.0%) (p = 0,0006-OR: 4,57), and 4 (5.7%) and 0 (0.0%) p = 0.0063) of patients and controls respectively. The presence of insulin resistance was the only statistically significant associated factor among acromegalic patients with and without colonic polyps. CONCLUSIONS Our findings show an increased risk of preneoplastic colonic lesions and colorectal carcinoma in patients with chronic and sustained GH excess compared to a control group. This supports the recommendation to perform screening colonoscopy at diagnosis of acromegaly.
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Affiliation(s)
| | - Karina Miragaya
- Servicio de Endocrinología, Sanatorio Güemes, Buenos Aires, Argentina
| | - Amelia Rogozinski
- División Endocrinología, Hospital Ramos Mejía, Buenos Aires, Argentina
| | - Monica Agüero
- Grupo de trabajo Endocrinología, Hospital Tornú, Buenos Aires, Argentina
| | - Analia Alfieri
- Servicio de Endocrinología, Hospital Nacional Profesor A. Posadas, El Palomar, Buenos Aires, Argentina
| | | | - Laura Boero
- División Endocrinología, Hospital de Clínicas José de San Martin UBA, Buenos Aires, Argentina
| | - Karina Danilowicz
- División Endocrinología, Hospital de Clínicas José de San Martin UBA, Buenos Aires, Argentina
| | - Sabrina Diez
- Servicio de Endocrinología, Hospital General de Agudos Dr. Ignacio Pirovano,, Buenos Aires, Argentina
| | - Marina Donoso
- Servicio de Endocrinología, Hospital Nacional Profesor A. Posadas, El Palomar, Buenos Aires, Argentina
| | | | - Alejandra Furioso
- División Endocrinología, Hospital Ramos Mejía, Buenos Aires, Argentina
| | | | - Mariela Glerean
- Servicio de Endocrinología, Hospital Italiano, Buenos Aires, Argentina
| | - Debora Katz
- Sección Neuroendocrinología, FLENI, Buenos Aires, Argentina
| | - Monica Loto
- Servicio de Endocrinología, Hospital Británico, Buenos Aires, Argentina
| | - Susana Mallea-Gil
- Servicio de Endocrinología, Hospital Militar Central, Buenos Aires, Argentina
| | - Marcela Martinez
- Servicio de Endocrinología, Hospital C. Milstein, Buenos Aires, Argentina
| | - Maria Isabel Sabate
- Servicio de Endocrinología, Hospital Universitario Austral, Pilar, Buenos Aires, Argentina
| | - Marisa Servidio
- Unidad de Endocrinología, Hospital Teodoro Alvarez, Buenos Aires, Argentina
| | | | - Graciela Stalldecker
- Servicio de Endocrinología, Hospital General de Agudos Dr. Ignacio Pirovano,, Buenos Aires, Argentina
| | - Soledad Sosa
- División Endocrinología, Hospital de Clínicas José de San Martin UBA, Buenos Aires, Argentina
| | - Grabriela Szuman
- Servicio de Endocrinología, Sanatorio Municipal Dr. J. Mendez, Buenos Aires, Argentina
| | - Julieta Tkatch
- División Endocrinología, Hospital Carlos G. Durand, Buenos Aires, Argentina
| | - Ignacio Caldo
- Unidad de Gastroenterología, Hospital Carlos G. Durand, Buenos Aires, Argentina
| | - Daniela Lubieniecki
- Unidad de Gastroenterología, Hospital Carlos G. Durand, Buenos Aires, Argentina
| | - Mirtha Guitelman
- División Endocrinología, Hospital Carlos G. Durand, Buenos Aires, Argentina
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Ucan B, Kizilgul M, Karci AC, Duger H, Erkam Sencar M, Imga NN, Demirci T, Berker D, Erman Cakal. THE PREVALENCE OF CANCER AND ITS RELATION TO DISEASE ACTIVITY IN PATIENTS WITH ACROMEGALY: TWO CENTERS' EXPERIENCE. Endocr Pract 2021; 27:51-55. [PMID: 33475501 DOI: 10.4158/ep-2020-0398] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
OBJECTIVE Acromegaly is characterized by increased serum concentrations of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Although animal studies have demonstrated a relationship between these hormones and cancer risk, the results of human studies evaluating cancer prevalence in acromegaly are inconsistent. We aimed to investigate the prevalence of malignant neoplasms in patients with acromegaly. METHODS Cancer risk was evaluated in a cohort of 280 patients (male/female: 120/160; mean age: 50.93 ± 12.07 years) with acromegaly. Patients were categorized into 2 groups according to the presence or absence of cancer. Standard incidence ratios were calculated as compared to the general population. RESULTS From 280 patients, cancer was diagnosed in 19 (6.8%) patients; 9 (47%) of them had thyroid cancer, which was the most common cancer type. Standard incidence ratios of all cancers were 0.8 (95% CI, 0.5-1.1) and 1.0 (95% CI, 0.8-1.3) in men and women, respectively. Compared to patients without cancer, the current age was higher in patients with cancer (59 [49-65] to 51 [42-59], P = .027). In contrast, the age at diagnosis was similar in both groups. Not only was the time to diagnosis and disease duration similar in both groups but also the basal and current GH and IGF-1 levels. The prevalence of active disease was also similar between the groups (32% to 23%, P = .394). CONCLUSION Our findings were not consistent with the studies suggesting that patients with acromegaly encounter an increased cancer risk. Furthermore, there were similar basal and current GH and IGF-1 levels in patients with acromegaly, both with and without cancer.
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Affiliation(s)
- Bekir Ucan
- Department of Endocrinology and Metabolism, University of Health Sciences, Dıskapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
| | - Muhammed Kizilgul
- Department of Endocrinology and Metabolism, University of Health Sciences, Dıskapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey.
| | - Alper Cagri Karci
- Department of Endocrinology and Metabolism, University of Health Sciences, Numune Training and Research Hospital, Ankara, Turkey
| | - Hakan Duger
- Department of Endocrinology and Metabolism, University of Health Sciences, Dıskapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
| | - Muhammed Erkam Sencar
- Department of Endocrinology and Metabolism, University of Health Sciences, Dıskapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
| | - Narin Nasiroglu Imga
- Department of Endocrinology and Metabolism, University of Health Sciences, Numune Training and Research Hospital, Ankara, Turkey
| | - Taner Demirci
- Department of Endocrinology and Metabolism, University of Health Sciences, Dıskapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
| | - Dilek Berker
- Department of Endocrinology and Metabolism, University of Health Sciences, Numune Training and Research Hospital, Ankara, Turkey
| | - Erman Cakal
- Department of Endocrinology and Metabolism, University of Health Sciences, Dıskapı Yıldırım Beyazıt Training and Research Hospital, Ankara, Turkey
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Massaro C, Safadeh E, Sgueglia G, Stunnenberg HG, Altucci L, Dell’Aversana C. MicroRNA-Assisted Hormone Cell Signaling in Colorectal Cancer Resistance. Cells 2020; 10:cells10010039. [PMID: 33396628 PMCID: PMC7823834 DOI: 10.3390/cells10010039] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 12/26/2020] [Accepted: 12/28/2020] [Indexed: 12/17/2022] Open
Abstract
Despite substantial progress in cancer therapy, colorectal cancer (CRC) is still the third leading cause of cancer death worldwide, mainly due to the acquisition of resistance and disease recurrence in patients. Growing evidence indicates that deregulation of hormone signaling pathways and their cross-talk with other signaling cascades inside CRC cells may have an impact on therapy resistance. MicroRNAs (miRNAs) are small conserved non-coding RNAs thatfunction as negative regulators in many gene expression processes. Key studies have identified miRNA alterations in cancer progression and drug resistance. In this review, we provide a comprehensive overview and assessment of miRNAs role in hormone signaling pathways in CRC drug resistance and their potential as future targets for overcoming resistance to treatment.
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Affiliation(s)
- Crescenzo Massaro
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
| | - Elham Safadeh
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
| | - Giulia Sgueglia
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
| | | | - Lucia Altucci
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
- Correspondence: (L.A.); (C.D.); Tel.: +39-081-566-7564 (L.A.); +39-081-566-7566 (C.D.)
| | - Carmela Dell’Aversana
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, Via De Crecchio, 7, 80138 Naples, Italy; (C.M.); (E.S.); (G.S.)
- Institute of Experimental Endocrinology and Oncology “Gaetano Salvatore” (IEOS)-National Research Council (CNR), Via Sergio Pansini 5, 80131 Naples, Italy
- Correspondence: (L.A.); (C.D.); Tel.: +39-081-566-7564 (L.A.); +39-081-566-7566 (C.D.)
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8
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Crudden C, Shibano T, Song D, Dragomir MP, Cismas S, Serly J, Nedelcu D, Fuentes-Mattei E, Tica A, Calin GA, Girnita A, Girnita L. Inhibition of G Protein-Coupled Receptor Kinase 2 Promotes Unbiased Downregulation of IGF1 Receptor and Restrains Malignant Cell Growth. Cancer Res 2020; 81:501-514. [PMID: 33158816 DOI: 10.1158/0008-5472.can-20-1662] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Revised: 10/03/2020] [Accepted: 10/30/2020] [Indexed: 11/16/2022]
Abstract
The ability of a receptor to preferentially activate only a subset of available downstream signal cascades is termed biased signaling. Although comprehensively recognized for the G protein-coupled receptors (GPCR), this process is scarcely explored downstream of receptor tyrosine kinases (RTK), including the cancer-relevant insulin-like growth factor-1 receptor (IGF1R). Successful IGF1R targeting requires receptor downregulation, yet therapy-mediated removal from the cell surface activates cancer-protective β-arrestin-biased signaling (β-arr-BS). As these overlapping processes are initiated by the β-arr/IGF1R interaction and controlled by GPCR-kinases (GRK), we explored GRKs as potential anticancer therapeutic targets to disconnect IGF1R downregulation and β-arr-BS. Transgenic modulation demonstrated that GRK2 inhibition or GRK6 overexpression enhanced degradation of IGF1R, but both scenarios sustained IGF1-induced β-arr-BS. Pharmacologic inhibition of GRK2 by the clinically approved antidepressant, serotonin reuptake inhibitor paroxetine (PX), recapitulated the effects of GRK2 silencing with dose- and time-dependent IGF1R downregulation without associated β-arr-BS. In vivo, PX treatment caused substantial downregulation of IGF1R, suppressing the growth of Ewing's sarcoma xenografts. Functional studies reveal that PX exploits the antagonism between β-arrestin isoforms; in low ligand conditions, PX favored β-arrestin1/Mdm2-mediated ubiquitination/degradation of IGF1R, a scenario usually exclusive to ligand abundancy, making PX more effective than antibody-mediated IGF1R downregulation. This study provides the rationale, molecular mechanism, and validation of a clinically feasible concept for "system bias" targeting of the IGF1R to uncouple downregulation from signaling. Demonstrating system bias as an effective anticancer approach, our study reveals a novel strategy for the rational design or repurposing of therapeutics to selectively cross-target the IGF1R or other RTK. SIGNIFICANCE: This work provides insight into the molecular and biological roles of biased signaling downstream RTK and provides a novel "system bias" strategy to increase the efficacy of anti-IGF1R-targeted therapy in cancer.
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Affiliation(s)
- Caitrin Crudden
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.,Department of Pathology, Cancer Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Takashi Shibano
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Dawei Song
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Mihnea P Dragomir
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Sonia Cismas
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Julianna Serly
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Daniela Nedelcu
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden
| | - Enrique Fuentes-Mattei
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Andrei Tica
- Department of Pharmacology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
| | - George A Calin
- Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, Texas
| | - Ada Girnita
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.,Dermatology Department, Karolinska University Hospital, Stockholm, Sweden
| | - Leonard Girnita
- Department of Oncology and Pathology, BioClinicum, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
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Murphy N, Carreras-Torres R, Song M, Chan AT, Martin RM, Papadimitriou N, Dimou N, Tsilidis KK, Banbury B, Bradbury KE, Besevic J, Rinaldi S, Riboli E, Cross AJ, Travis RC, Agnoli C, Albanes D, Berndt SI, Bézieau S, Bishop DT, Brenner H, Buchanan DD, Onland-Moret NC, Burnett-Hartman A, Campbell PT, Casey G, Castellví-Bel S, Chang-Claude J, Chirlaque MD, de la Chapelle A, English D, Figueiredo JC, Gallinger SJ, Giles GG, Gruber SB, Gsur A, Hampe J, Hampel H, Harrison TA, Hoffmeister M, Hsu L, Huang WY, Huyghe JR, Jenkins MA, Keku TO, Kühn T, Kweon SS, Le Marchand L, Li CI, Li L, Lindblom A, Martín V, Milne RL, Moreno V, Newcomb PA, Offit K, Ogino S, Ose J, Perduca V, Phipps AI, Platz EA, Potter JD, Qu C, Rennert G, Sakoda LC, Schafmayer C, Schoen RE, Slattery ML, Tangen CM, Ulrich CM, van Duijnhoven FJB, Van Guelpen B, Visvanathan K, Vodicka P, Vodickova L, Vymetalkova V, Wang H, White E, Wolk A, Woods MO, Wu AH, Zheng W, Peters U, Gunter MJ. Circulating Levels of Insulin-like Growth Factor 1 and Insulin-like Growth Factor Binding Protein 3 Associate With Risk of Colorectal Cancer Based on Serologic and Mendelian Randomization Analyses. Gastroenterology 2020; 158:1300-1312.e20. [PMID: 31884074 PMCID: PMC7152801 DOI: 10.1053/j.gastro.2019.12.020] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 12/13/2019] [Accepted: 12/19/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND & AIMS Human studies examining associations between circulating levels of insulin-like growth factor 1 (IGF1) and insulin-like growth factor binding protein 3 (IGFBP3) and colorectal cancer risk have reported inconsistent results. We conducted complementary serologic and Mendelian randomization (MR) analyses to determine whether alterations in circulating levels of IGF1 or IGFBP3 are associated with colorectal cancer development. METHODS Serum levels of IGF1 were measured in blood samples collected from 397,380 participants from the UK Biobank, from 2006 through 2010. Incident cancer cases and cancer cases recorded first in death certificates were identified through linkage to national cancer and death registries. Complete follow-up was available through March 31, 2016. For the MR analyses, we identified genetic variants associated with circulating levels of IGF1 and IGFBP3. The association of these genetic variants with colorectal cancer was examined with 2-sample MR methods using genome-wide association study consortia data (52,865 cases with colorectal cancer and 46,287 individuals without [controls]) RESULTS: After a median follow-up period of 7.1 years, 2665 cases of colorectal cancer were recorded. In a multivariable-adjusted model, circulating level of IGF1 associated with colorectal cancer risk (hazard ratio per 1 standard deviation increment of IGF1, 1.11; 95% confidence interval [CI] 1.05-1.17). Similar associations were found by sex, follow-up time, and tumor subsite. In the MR analyses, a 1 standard deviation increment in IGF1 level, predicted based on genetic factors, was associated with a higher risk of colorectal cancer risk (odds ratio 1.08; 95% CI 1.03-1.12; P = 3.3 × 10-4). Level of IGFBP3, predicted based on genetic factors, was associated with colorectal cancer risk (odds ratio per 1 standard deviation increment, 1.12; 95% CI 1.06-1.18; P = 4.2 × 10-5). Colorectal cancer risk was associated with only 1 variant in the IGFBP3 gene region (rs11977526), which also associated with anthropometric traits and circulating level of IGF2. CONCLUSIONS In an analysis of blood samples from almost 400,000 participants in the UK Biobank, we found an association between circulating level of IGF1 and colorectal cancer. Using genetic data from 52,865 cases with colorectal cancer and 46,287 controls, a higher level of IGF1, determined by genetic factors, was associated with colorectal cancer. Further studies are needed to determine how this signaling pathway might contribute to colorectal carcinogenesis.
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Affiliation(s)
- Neil Murphy
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
| | - Robert Carreras-Torres
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain
| | - Mingyang Song
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Andrew T Chan
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
| | - Richard M Martin
- MRC Integrative Epidemiology Unit (IEU), Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Bristol Medical School, Department of Population Health Sciences, University of Bristol, Bristol, UK; National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and the University of Bristol, Bristol, UK
| | - Nikos Papadimitriou
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Niki Dimou
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Konstantinos K Tsilidis
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece; Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Barbara Banbury
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Kathryn E Bradbury
- National Institute for Health Innovation, School of Population Health, The University of Auckland, Auckland, New Zealand
| | - Jelena Besevic
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Sabina Rinaldi
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Elio Riboli
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Amanda J Cross
- Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK
| | - Ruth C Travis
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Claudia Agnoli
- Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Demetrius Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Sonja I Berndt
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stéphane Bézieau
- Service de Génétique Médicale, Centre Hospitalier Universitaire (CHU) Nantes, Nantes, France
| | - D Timothy Bishop
- Institute of Medical Research at St. James's, University of Leeds, Leeds, UK
| | - Hermann Brenner
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Daniel D Buchanan
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria 3010, Australia; University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Parkville, Victoria 3010, Australia; Genetic Medicine and Family Cancer Clinic, The Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - N Charlotte Onland-Moret
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
| | | | - Peter T Campbell
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia
| | - Graham Casey
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia
| | - Sergi Castellví-Bel
- Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), University of Barcelona, Barcelona, Spain
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - María-Dolores Chirlaque
- Department of Epidemiology, Regional Health Council, IMIB-Arrixaca, Murcia University, Murcia, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain
| | - Albert de la Chapelle
- Department of Cancer Biology and Genetics and the Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio
| | - Dallas English
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles California
| | - Steven J Gallinger
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Graham G Giles
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Stephen B Gruber
- Department of Preventive Medicine & USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California
| | - Andrea Gsur
- Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria
| | - Jochen Hampe
- Department of Medicine I, University Hospital Dresden, Technische Universität Dresden (TU Dresden), Dresden, Germany
| | - Heather Hampel
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio
| | - Tabitha A Harrison
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Li Hsu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Biostatistics, University of Washington, Seattle, Washington
| | - Wen-Yi Huang
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Jeroen R Huyghe
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Mark A Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia
| | - Temitope O Keku
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina
| | - Tilman Kühn
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sun-Seog Kweon
- Department of Preventive Medicine, Chonnam National University Medical School, Gwangju, Korea; Jeonnam Regional Cancer Center, Chonnam National University Hwasun Hospital, Hwasun, Korea
| | | | - Christopher I Li
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Li Li
- Department of Family Medicine, University of Virginia, Charlottesville, Virginia
| | - Annika Lindblom
- Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden; Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden
| | - Vicente Martín
- CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Biomedicine Institute (IBIOMED), University of León, León, Spain
| | - Roger L Milne
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Victor Moreno
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain; CIBER in Epidemiology and Public Health (CIBERESP), Madrid, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Polly A Newcomb
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; School of Public Health, University of Washington, Seattle, Washington
| | - Kenneth Offit
- Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York
| | - Shuji Ogino
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts; Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Cancer Immunology and Cancer Epidemiology Programs, Dana-Farber Harvard Cancer Center, Boston, Massachusetts; Broad Institute of MIT and Harvard, Cambridge, Massachusetts
| | - Jennifer Ose
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | - Vittorio Perduca
- CESP (Inserm U1018), Fac. de médecine - Université Paris-Saclay, Fac. de médecine - UVSQ, 94805, Villejuif, France; Gustave Roussy, F-94805, Villejuif, France; Laboratoire de Mathématiques Appliquées MAP5 (UMR CNRS 8145), Université Paris Descartes, France
| | - Amanda I Phipps
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington
| | - Elizabeth A Platz
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - John D Potter
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Centre for Public Health Research, Massey University, Wellington, New Zealand
| | - Conghui Qu
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Gad Rennert
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel; Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel
| | - Lori C Sakoda
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Division of Research, Kaiser Permanente Northern California, Oakland, California
| | - Clemens Schafmayer
- Department of General and Thoracic Surgery, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Robert E Schoen
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Martha L Slattery
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah
| | - Catherine M Tangen
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Cornelia M Ulrich
- Huntsman Cancer Institute and Department of Population Health Sciences, University of Utah, Salt Lake City, Utah
| | | | - Bethany Van Guelpen
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden; Wallenberg Centre for Molecular Medicine, Umeå University, Umeå, Sweden
| | - Kala Visvanathan
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Pavel Vodicka
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Ludmila Vodickova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Veronika Vymetalkova
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University, Prague, Czech Republic; Faculty of Medicine and Biomedical Center in Pilsen, Charles University, Pilsen, Czech Republic
| | - Hansong Wang
- University of Hawaii Cancer Center, Honolulu, Hawaii
| | - Emily White
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington
| | - Alicja Wolk
- Institute of Environmental Medicine, Karolinska Institute, Stockholm, Sweden
| | - Michael O Woods
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada
| | - Anna H Wu
- University of Southern California, Preventive Medicine, Los Angeles, California
| | - Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt Epidemiology Center, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Ulrike Peters
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Epidemiology, University of Washington, Seattle, Washington
| | - Marc J Gunter
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
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10
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Kasprzak A, Adamek A. Insulin-Like Growth Factor 2 (IGF2) Signaling in Colorectal Cancer-From Basic Research to Potential Clinical Applications. Int J Mol Sci 2019; 20:ijms20194915. [PMID: 31623387 PMCID: PMC6801528 DOI: 10.3390/ijms20194915] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 09/27/2019] [Accepted: 09/30/2019] [Indexed: 02/07/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common cancers in men and women worldwide as well as is the leading cause of death in the western world. Almost a third of the patients has or will develop liver metastases. While genetic as well as epigenetic mechanisms are important in CRC pathogenesis, the basis of the most cases of cancer is unknown. High spatial and inter-patient variability of the molecular alterations qualifies this cancer in the group of highly heterogeneous tumors, which makes it harder to elucidate the mechanisms underlying CRC progression. Determination of highly sensitive and specific early diagnosis markers and understanding the cellular and molecular mechanism(s) of cancer progression are still a challenge of the current era in oncology of solid tumors. One of the accepted risk factors for CRC development is overexpression of insulin-like growth factor 2 (IGF2), a 7.5-kDa peptide produced by liver and many other tissues. IGF2 is the first gene discovered to be parentally imprinted. Loss of imprinting (LOI) or aberrant imprinting of IGF2 could lead to IGF2 overexpression, increased cell proliferation, and CRC development. IGF2 as a mitogen is associated with increased risk of developing colorectal neoplasia. Higher serum IGF2 concentration as well as its tissue overexpression in CRC compared to control are associated with metastasis. IGF2 protein was one of the three candidates for a selective marker of CRC progression and staging. Recent research indicates dysregulation of different micro- and long non-coding RNAs (miRNAs and lncRNAs, respectively) embedded within the IGF2 gene in CRC carcinogenesis, with some of them indicated as potential diagnostic and prognostic CRC biomarkers. This review systematises the knowledge on the role of genetic and epigenetic instabilities of IGF2 gene, free (active form of IGF2) and IGF-binding protein (IGFBP) bound (inactive form), paracrine/autocrine secretion of IGF2, as well as mechanisms of inducing dysplasia in vitro and tumorigenicity in vivo. We have tried to answer which molecular changes of the IGF2 gene and its regulatory mechanisms have the most significance in initiation, progression (including liver metastasis), prognosis, and potential anti-IGF2 therapy in CRC patients.
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Affiliation(s)
- Aldona Kasprzak
- Department of Histology and Embryology, University of Medical Sciences, Swiecicki Street 6, 60-781 Poznan, Poland.
| | - Agnieszka Adamek
- Department of Infectious Diseases, Hepatology and Acquired Immunodeficiencies, University of Medical Sciences, Szwajcarska Street 3, 61-285 Poznan, Poland.
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11
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Abstract
Acromegaly results in a significantly increased morbidity and mortality due to cardiovascular and respiratory complications, as well as malignancies arising mainly from the colon. Furthermore, an increased lifetime risk of malignant transformation of pre-malignant colonic lesions relates to a worse overall prognosis from colorectal cancer, which is currently considered a major disease-related complication. In this review we provide some insight into colonic changes in this condition, summarize current knowledge and evidence on the use of colonoscopic screening in patients with acromegaly, and suggest a recommended screening protocol.
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Affiliation(s)
- Dorota Dworakowska
- Department of Hypertension and Diabetes, Medical University of Gdansk, Gdansk, Poland
- Guys Richard Dimbleby Department of Cancer Research, King's College London, London, United Kingdom
- Endocard LTD, London, United Kingdom
- *Correspondence: Dorota Dworakowska
| | - Ashley B. Grossman
- Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom
- Barts and the London School of Medicine, Centre for Endocrinology, William Harvey Institute, London, United Kingdom
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12
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Predictors of colonic pathologies in active acromegaly: single tertiary center experience. Wien Klin Wochenschr 2018; 130:511-516. [DOI: 10.1007/s00508-018-1367-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Accepted: 07/13/2018] [Indexed: 02/06/2023]
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13
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Iwamuro M, Yasuda M, Hasegawa K, Fujisawa S, Ogura-Ochi K, Sugihara Y, Harada K, Hiraoka S, Okada H, Otsuka F. Colonoscopy examination requires a longer time in patients with acromegaly than in other individuals. Endocr J 2018; 65:151-157. [PMID: 29081443 DOI: 10.1507/endocrj.ej17-0322] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
This study aimed to determine the prevalence of colorectal neoplasms and to investigate the rate of and time required for cecal intubation in patients with acromegaly. A database search performed at our institution identified 29 patients with acromegaly who underwent colonoscopy. Data regarding the endoscopic, biological, and pathological examinations performed were retrospectively reviewed from the clinical records. Subsequently, the rate of and time required for cecal intubation were investigated in 23 patients with acromegaly and compared with the corresponding data of the control group. Control subjects were selected from a 2:1 matched historical control cohort, according to baseline characteristics. The mean age of the acromegaly group (17 female and 12 male) was 60.4 ± 12.6 years. Twelve patients had adenoma (41.4%), eight patients had hyperplastic polyps (27.6%), three patients had sessile serrated adenoma/polyps (10.3%), and three patients had colon cancer (10.3%). Successful cecal intubation was achieved in all patients in both groups. The difference in the time required for successful intubation between the acromegaly group (15.7 ± 9.8 minutes) and the control group (8.7 ± 6.0 minutes) was statistically significant. Linear regression analysis revealed that increased patient age was significantly related to longer colonoscope insertion times. In conclusion, although cecal intubation during colonoscopy was successful in all participants, it required a longer time in patients with acromegaly. Our results underscore the importance of and certain technical difficulties involved in colonoscopy procedures in patients with acromegaly, especially in older patients.
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Affiliation(s)
- Masaya Iwamuro
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Miho Yasuda
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Kou Hasegawa
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Satoshi Fujisawa
- Endocrine Center, Okayama University Hospital, Okayama 700-8558, Japan
| | - Kanako Ogura-Ochi
- Endocrine Center, Okayama University Hospital, Okayama 700-8558, Japan
| | - Yuusaku Sugihara
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Keita Harada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Sakiko Hiraoka
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Hiroyuki Okada
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
| | - Fumio Otsuka
- Department of General Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama 700-8558, Japan
- Endocrine Center, Okayama University Hospital, Okayama 700-8558, Japan
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14
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Ortega LS, Bradbury KE, Cross AJ, Morris JS, Gunter MJ, Murphy N. A Prospective Investigation of Body Size, Body Fat Composition and Colorectal Cancer Risk in the UK Biobank. Sci Rep 2017; 7:17807. [PMID: 29259258 PMCID: PMC5736687 DOI: 10.1038/s41598-017-17997-5] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2017] [Accepted: 12/04/2017] [Indexed: 12/26/2022] Open
Abstract
Obesity has been consistently associated with a greater colorectal cancer risk, but this relationship is weaker among women. In the UK Biobank, we investigated the associations between body size (body mass index [BMI], height, waist circumference, and waist-to-hip ratio) and body fat composition (total body fat percentage and trunk fat percentage) measurements with colorectal cancer risk among 472,526 men and women followed for 5.6 years on average. Multivariable hazard ratios (HRs) and 95% confidence intervals (95%CI) for developing colorectal cancer (2,636 incident cases) were estimated using Cox proportional hazards models. Among men, when the highest and lowest fifths were compared, BMI (HR = 1.35, 95%CI: 1.13-1.61; Ptrend < 0.0001), waist circumference (HR = 1.66, 95%CI: 1.39-1.99; Ptrend < 0.0001), waist-to-hip ratio (HR = 1.58, 95%CI: 1.31-1.91; Ptrend < 0.0001), total body fat percentage (HR = 1.27, 95%CI: 1.06-1.53; Ptrend = 0.002), and trunk fat percentage (HR = 1.31, 95%CI: 1.09-1.58; Ptrend = 0.002) were associated with greater colorectal cancer risk. For women, only waist-to-hip ratio (HR for highest versus lowest fifth = 1.33, 95%CI: 1.08-1.65; Ptrend = 0.005) was positively associated with colorectal cancer risk. Greater body size (overall and abdominal adiposity) was positively associated with colorectal cancer development in men. For women, abdominal adiposity, rather than overall body size, was associated with a greater colorectal cancer risk.
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Affiliation(s)
- Luisa Saldana Ortega
- Primary Care Clinical Trials Unit, Nuffield Department of Primary Care Health Sciences, University of Oxford, Oxford, UK
| | - Kathryn E Bradbury
- Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, UK
| | - Amanda J Cross
- School of Public Health, Imperial College London, London, UK
| | | | - Marc J Gunter
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France
| | - Neil Murphy
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
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15
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Schirripa M, Zhang W, Heinemann V, Cao S, Okazaki S, Yang D, Loupakis F, Berger MD, Ning Y, Miyamoto Y, Suenaga M, Gopez RF, West JD, Hanna D, Barzi A, Falcone A, Stintzing S, Lenz HJ. Single nucleotide polymorphisms in the IGF-IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE-3 trial. Int J Cancer 2017; 141:383-392. [PMID: 28369940 DOI: 10.1002/ijc.30715] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 03/03/2017] [Accepted: 03/14/2017] [Indexed: 12/21/2022]
Abstract
The Insulin-like growth factor (IGF)/IGF-receptor pathway with its scaffolding proteins Insulin Receptor Substrate (IRS)1 and IRS2 are crucial regulators of metabolism and progression in metastatic colorectal cancer (mCRC). The goal of the study was the identification of predictive and prognostic markers among IRS1, IRS2, IGF1 and IGF-1R SNPs in mCRC patients enrolled in the FIRE-3 trial. Four SNPs of IRS (IRS1 rs1801278, rs1801123; IRS2 rs1805097, rs2289046) and four SNPs of IGF1-IGFR1 (rs6214, rs6220, rs2946834, rs2016347) were analyzed by PCR/direct-sequencing in the FIRE-3 trial. The relation of SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test in the overall population and in subgroup according to RAS status and treatment arm. In the overall population IRS1 rs1801123 C/- carriers (N= 105) achieved significantly worse OS compared to T/T (N = 464) in univariate (HR = 1.32 [95%CI 1.03-1.70], p = 0.029) and in multivariable. Similar results were observed among RAS wild type. Patients with IGF1 rs2946834 T/- variant (N= 280) achieved improved PFS compared to C/C (N = 257) in univariate (HR = 0.77 [95%CI 0.64-0.92], p = 0.004) and in multivariable. In the RAS wild-type subgroup IGF1 rs2946834 T/- carriers showed better PFS and OS compared to C/C (univariate HR for PFS = 0.65 [95%CI 0.51-0.81], p < 0.001; multivariable HR for PFS = 0.63 [95%CI 0.50-0.81], p < 0.001). IRS1 rs1801123 SNP was identified as a new prognostic marker for mCRC. IGF1 rs2946834 was confirmed as prognostic factor in the overall population and in RAS wild type patients. Our findings underline the importance of IGF downstream signaling pathway in RAS wild-type mCRC patient.
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Affiliation(s)
- Marta Schirripa
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
| | - Wu Zhang
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
| | - Volker Heinemann
- Department of Medical Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany
| | - Shu Cao
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Satoshi Okazaki
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
| | - Dongyun Yang
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Fotios Loupakis
- Oncologia Medica 1, Istituto Oncologico Veneto, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Padova, Italy
| | - Martin D Berger
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
| | - Yan Ning
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
| | - Yuji Miyamoto
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
| | - Mitsukuni Suenaga
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
| | - Roel F Gopez
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
| | - Jordan D West
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
| | - Diana Hanna
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
| | - Afsaneh Barzi
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
| | - Alfredo Falcone
- Polo Oncologico, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy
| | - Sebastian Stintzing
- Department of Medical Oncology, Klinikum Grosshadern, Ludwig-Maximilians-University, Munich, Germany
| | - Heinz-Josef Lenz
- Medical Oncology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, 90033
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16
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Gonzalez B, Vargas G, Mendoza V, Nava M, Rojas M, Mercado M. THE PREVALENCE OF COLONIC POLYPS IN PATIENTS WITH ACROMEGALY: A CASE-CONTROL, NESTED IN A COHORT COLONOSCOPIC STUDY. Endocr Pract 2017; 23:594-599. [PMID: 28225314 DOI: 10.4158/ep161724.or] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
OBJECTIVE Acromegaly is associated with an increased risk of colonic polyps. The magnitude of such risk is controversial, and the characteristics that distinguish patients who develop polyps from those who do not are not well established. This study was performed to determine the prevalence of colonic polyps upon the diagnosis of acromegaly and to compare the clinical and biochemical features of patients with and without polyps. METHODS Out of 165 patients who underwent a full colonoscopy upon diagnosis of acromegaly, 53 were found to harbor colonic lesions (cases), whereas the remaining 112 were used as controls. Demographic, clinical, and biochemical characteristics were compared between the 2 groups. RESULTS The prevalence of colonic polyps was 32%, with an estimated relative risk of 6.21 (95% confidence interval [CI] 4.08-9.48). Adenomatous and nonadenomatous polyps were found in 22 and 31 patients, respectively. The most common location was the descending colon. Compared to patients without polyps, subjects with polyps were somewhat older and had significantly higher insulin-like growth factor-1 (IGF-1) levels and a higher prevalence of diabetes. Upon multivariate analysis, only IGF-1 level at diagnosis remained significantly associated with colonic polyps in general and with hyperplastic polyps in particular. CONCLUSION Acromegaly is associated with an elevated risk of developing colonic polyps, particularly, distally located hyperplastic lesions. Except for a higher IGF-1 level at diagnosis, no distinctive clinical or biochemical features can be found among those who develop polyps compared to those who do not. ABBREVIATIONS CI = confidence interval GH = growth hormone IGF-1 = insulin-like growth factor 1 IQR = inter-quartile range RR = relative risk ULN = upper limit of normal.
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17
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Matsunaga Y, Adachi Y, Sasaki Y, Koide H, Motoya M, Nosho K, Takagi H, Yamamoto H, Sasaki S, Arimura Y, Tokino T, Carbone DP, Imai K, Shinomura Y. The effect of forced expression of mutated K-RASgene on gastrointestinal cancer cell lines and the IGF-1R targeting therapy. Mol Carcinog 2017; 56:515-526. [PMID: 27312358 DOI: 10.1002/mc.22513] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/29/2023]
Affiliation(s)
- Yasutaka Matsunaga
- Department of Gastroenterology, Rheumatology and Clinical Immunology; Sapporo Medical University; Sapporo Japan
| | - Yasushi Adachi
- Department of Gastroenterology, Rheumatology and Clinical Immunology; Sapporo Medical University; Sapporo Japan
- Sapporo Shirakaba-Dai Hospital; Sapporo Japan
| | - Yasushi Sasaki
- Medical Genome Sciences, Research Institute of Frontier Medicine; Sapporo Medical University; Sapporo Japan
| | - Hideyuki Koide
- Department of Gastroenterology, Rheumatology and Clinical Immunology; Sapporo Medical University; Sapporo Japan
| | - Masayo Motoya
- Department of Gastroenterology, Rheumatology and Clinical Immunology; Sapporo Medical University; Sapporo Japan
| | - Katsuhiko Nosho
- Department of Gastroenterology, Rheumatology and Clinical Immunology; Sapporo Medical University; Sapporo Japan
| | - Hideyasu Takagi
- Department of Gastroenterology, Rheumatology and Clinical Immunology; Sapporo Medical University; Sapporo Japan
| | - Hiroyuki Yamamoto
- Division of Gastroenterology and Hepatology, Department of Internal Medicine; St. Marianna University School of Medicine; Kawasaki Japan
| | - Shigeru Sasaki
- Department of Gastroenterology, Rheumatology and Clinical Immunology; Sapporo Medical University; Sapporo Japan
| | - Yoshiaki Arimura
- Department of Gastroenterology, Rheumatology and Clinical Immunology; Sapporo Medical University; Sapporo Japan
| | - Takashi Tokino
- Medical Genome Sciences, Research Institute of Frontier Medicine; Sapporo Medical University; Sapporo Japan
| | - David P. Carbone
- James Cancer Center; The Ohio State University Medical Center; Columbus Ohio
| | - Kohzoh Imai
- The Institute of Medical Science Hospital; The University of Tokyo; Tokyo Japan
| | - Yasuhisa Shinomura
- Department of Gastroenterology, Rheumatology and Clinical Immunology; Sapporo Medical University; Sapporo Japan
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Overproduction of IGF-2 drives a subset of colorectal cancer cells, which specifically respond to an anti-IGF therapeutic antibody and combination therapies. Oncogene 2016; 36:797-806. [PMID: 27399333 DOI: 10.1038/onc.2016.248] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 04/15/2016] [Accepted: 05/24/2016] [Indexed: 12/28/2022]
Abstract
Colorectal cancer (CRC) is a heterogeneous disease with a broad spectrum of genetic and epigenetic changes. A comprehensive molecular characterization of CRC by The Cancer Genome Atlas Network detected the overexpression of the insulin-like growth factor 2 (IGF2) gene, encoding a ligand for the insulin-like growth factor 1 receptor (IGF-1R), in a subset of CRC tumors. In this study, we investigated the oncogenic potential of IGF-2 in IGF2-overexpressing CRC models and the efficacy of MEDI-573, an IGF-1/2-neutralizing antibody. We found that a subset of CRC cell lines express high IGF-2 levels owing to an increased DNA copy number and hypermethylation in the H19 promoter of the IGF2 gene. MEDI-573 efficiently neutralized IGF-2 and induced apoptosis, which resulted in significant tumor growth inhibition in CRC mouse models that express high levels of IGF-2. These effects were specific to CRCs overexpressing IGF-2, as MEDI-573 did not affect the growth CRC cell lines with normal levels. Moreover, blockade of IGF-2 by MEDI-573 modulated other signaling pathways, suggesting combination therapies with inhibitors of these pathways. Indeed, in vivo efficacy was significantly enhanced when MEDI-573 was used in combination with trastuzumab, AZD2014 (dual mTORC1/2i), AZD5363 (AKTi) and selumetinib (AZD6244/ARRY-142886, MEK1/2i) or cetuximab. These results demonstrate that overexpressed IGF-2 is the major tumorigenic driver in a subset of CRCs and encourage testing of MEDI-573, alone and in combinations, in IGF2-overexpressing CRC patients.
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Vigneri PG, Tirrò E, Pennisi MS, Massimino M, Stella S, Romano C, Manzella L. The Insulin/IGF System in Colorectal Cancer Development and Resistance to Therapy. Front Oncol 2015; 5:230. [PMID: 26528439 PMCID: PMC4606066 DOI: 10.3389/fonc.2015.00230] [Citation(s) in RCA: 126] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 10/01/2015] [Indexed: 12/13/2022] Open
Abstract
The insulin/insulin-like growth factor (IGF) system is a major determinant in the pathogenesis and progression of colorectal cancer (CRC). Indeed, several components of this signaling network, including insulin, IGF-1, IGF-2, the IGF-binding proteins, the insulin receptor (IR), the IGF-1 receptor (IGF-1R), and IR substrate proteins 1 and 2 contribute to the transformation of normal colon epithelial cells. Moreover, the insulin/IGF system is also implicated in the development of resistance to both chemotherapeutic drugs and epidermal growth factor receptor targeted agents. The identification of hybrid receptors comprising both the IR and IGF-1R adds further complexity to this signaling network. Thus, a comprehensive understanding of the biological functions performed by each component of the insulin/IGF system is required to design successful drugs for the treatment of CRC patients.
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Affiliation(s)
- Paolo Giovanni Vigneri
- Laboratory of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Catania , Catania , Italy
| | - Elena Tirrò
- Laboratory of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Catania , Catania , Italy
| | - Maria Stella Pennisi
- Laboratory of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Catania , Catania , Italy
| | - Michele Massimino
- Laboratory of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Catania , Catania , Italy
| | - Stefania Stella
- Laboratory of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Catania , Catania , Italy
| | - Chiara Romano
- Laboratory of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Catania , Catania , Italy
| | - Livia Manzella
- Laboratory of Experimental Oncology and Hematology, Department of Clinical and Experimental Medicine, Faculty of Medicine, University of Catania , Catania , Italy
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Lois K, Bukowczan J, Perros P, Jones S, Gunn M, James RA. The role of colonoscopic screening in acromegaly revisited: review of current literature and practice guidelines. Pituitary 2015; 18:568-74. [PMID: 25052731 DOI: 10.1007/s11102-014-0586-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Acromegaly is a chronic, debilitating and disfiguring condition with a significantly increased morbidity and mortality due to cardiovascular, as well as respiratory complications. Patients with acromegaly are usually diagnosed at the age of 40, however, the duration of symptoms can vary from 5 to 10 years before the formal diagnosis is confirmed. Recent advances in the field of acromegaly have improved survival significantly. A strong association between acromegaly and premalignant colonic lesions and colon cancer has been highlighted. Furthermore, patients with acromegaly have a greater lifetime risk of malignant transformation and a far worse overall prognosis from colorectal cancer, which is now considered a major disease related complication. MATERIALS AND METHODS A comprehensive search strategy was applied for the Medline/PubMed electronic database from its inception until April 2014. We considered all human research articles published in English, not classified as case report, editorial, comment, letter, or news. CONCLUSION Specific recommendations for large bowel endoscopic screening in patients with acromegaly have been proposed. In this comprehensive review we discuss the current state of knowledge and evidence on colonoscopic screening in patients with acromegaly illustrated by a case of aggressive colorectal cancer presenting late in a young woman with difficult to control acromegaly.
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Affiliation(s)
- K Lois
- Regional Pituitary Tumour Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, NE1 4LP, UK
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Yuen KC, Popovic V. Growth hormone replacement in patients with a history of malignancy: a review of the literature and best practice for offering treatment. Expert Rev Endocrinol Metab 2015; 10:319-326. [PMID: 30298774 DOI: 10.1586/17446651.2015.996130] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Previous studies have implicated the growth hormone (GH)/IGF-I axis as an important mediator of cancer risk in humans and animals. Evidence supporting this notion is derived from animal studies, epidemiological observations, patients with acromegaly and from therapeutic manipulation of GH and IGF-I actions. Therefore, the use of GH therapy in patients with a history of malignancy raises hypothetical safety concerns. Reassuringly, GH therapy in childhood cancer survivors has not been confirmed to increase the cancer risk. Conversely, the risk of occurrence of a second neoplasm may be increased, with meningiomas being the most common tumor. In light of these findings, we propose considering GH therapy to be based on each individual's circumstance and commenced at least 2 years after cancer remission is achieved with close monitoring during therapy. More long-term data are needed on the safety of GH replacement therapy in GH-deficient adults with a history of malignancy.
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Affiliation(s)
- Kevin Cj Yuen
- a 1 Swedish Pituitary Center, Swedish Neuroscience Institute, Seattle, WA 98122, USA
| | - Vera Popovic
- b 2 Faculty of Medicine, University of Belgrade and Clinic for Endocrinology, Diabetes and Metabolic Disease, University Clinical Center Belgrade, Dr Subotica 13, 11000 Belgrade, Serbia
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VOLKOVA EKATERINA, ROBINSON BRIDGETA, WILLIS JINNY, CURRIE MARGARETJ, DACHS GABIU. Marginal effects of glucose, insulin and insulin-like growth factor on chemotherapy response in endothelial and colorectal cancer cells. Oncol Lett 2014; 7:311-320. [PMID: 24396438 PMCID: PMC3881921 DOI: 10.3892/ol.2013.1710] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 10/24/2013] [Indexed: 12/30/2022] Open
Abstract
Resistance to chemotherapy is a major clinical issue for patients with colorectal cancer. Obesity has been associated with a poorer outcome and is a possible mechanism of resistance. The aim of the present study was to investigate the effect of obesity-related factors on the cell response to standard chemotherapy in stromal and colorectal cancer cells. Viability was measured following the treatment of colorectal cancer cell lines (WiDr and SW620) and stromal cells (human microvascular endothelial cells) in vitro with 5-fluorouracil, irinotecan and oxaliplatin under obesity-related conditions [elevated levels of insulin, insulin-like growth factor-1 (IGF-1) and glucose] and compared with non-elevated conditions. Obesity-related conditions alone increased cell viability and in selected cases, accumulation of the transcription factor, hypoxia-inducible factor-1. However, these conditions did not consistently increase resistance to the chemotherapy agents tested. The combination of IGF-1 and extremely low-dose chemotherapy significantly induced cell viability in WiDr colorectal cancer cells. These in vitro results may have clinical importance in an environment of increasing rates of obesity and colorectal cancer, and the frequent under-dosing of obese cancer patients.
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Affiliation(s)
- EKATERINA VOLKOVA
- Mackenzie Cancer Research Group, Department of Pathology, University of Otago Christchurch, Christchurch 8140, New Zealand
| | - BRIDGET A. ROBINSON
- Mackenzie Cancer Research Group, Department of Pathology, University of Otago Christchurch, Christchurch 8140, New Zealand
- Canterbury Regional Cancer and Blood Service, Canterbury District Health Board, Christchurch 8140, New Zealand
| | - JINNY WILLIS
- Lipid and Diabetes Research Group, Christchurch Hospital, Christchurch 8140, New Zealand
| | - MARGARET J. CURRIE
- Mackenzie Cancer Research Group, Department of Pathology, University of Otago Christchurch, Christchurch 8140, New Zealand
| | - GABI U. DACHS
- Mackenzie Cancer Research Group, Department of Pathology, University of Otago Christchurch, Christchurch 8140, New Zealand
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Abstract
Insulin-like growth factor 2 (IGF2) is a 7.5 kDa mitogenic peptide hormone expressed by liver and many other tissues. It is three times more abundant in serum than IGF1, but our understanding of its physiological and pathological roles has lagged behind that of IGF1. Expression of the IGF2 gene is strictly regulated. Over-expression occurs in many cancers and is associated with a poor prognosis. Elevated serum IGF2 is also associated with increased risk of developing various cancers including colorectal, breast, prostate and lung. There is established clinical utility for IGF2 measurement in the diagnosis of non-islet cell tumour hypoglycaemia, a condition characterised by a molar IGF2:IGF1 ratio >10. Recent advances in understanding of the pathophysiology of IGF2 in cancer have suggested much novel clinical utility for its measurement. Measurement of IGF2 in blood and genetic and epigenetic tests of the IGF2 gene may help assess cancer risk and prognosis. Further studies will determine whether these tests enter clinical practice. New therapeutic approaches are being developed to target IGF2 action. This review provides a clinical perspective on IGF2 and an update on recent research findings.
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Affiliation(s)
- Callum Livingstone
- Peptide Hormones Supraregional Assay Service (SAS), Clinical Biochemistry Department, Royal Surrey County Hospital NHS Trust, Guildford, Surrey GU2 7XX, UK Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey GU2 5XH, UK
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Di Rosa M, Malaguarnera M, Zanghì A, Passaniti A, Malaguarnera L. Vitamin D3 insufficiency and colorectal cancer. Crit Rev Oncol Hematol 2013; 88:594-612. [PMID: 23941729 DOI: 10.1016/j.critrevonc.2013.07.016] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Revised: 07/03/2013] [Accepted: 07/18/2013] [Indexed: 12/15/2022] Open
Abstract
Traditionally the main recognized function of vitamin D has been calcium and phosphate homeostasis. Nevertheless, recent evidences have highlighted the importance of vitamin D3 as a protective agent against various cancers. The association between CRC and vitamin D3 was first suggested in ecologic studies, but further was confirmed by observational studies in humans and experimental studies in both animal models and cellular lines. The protective role of vitamin D3 against cancer has been attributed to its influence of on cell proliferation, differentiation, apoptosis, DNA repair mechanisms, inflammation and immune function. In its active (calcitriol) form (1,25-dihydroxyvitamin D3[1α,25-(OH)2D3]) vitamin D3 and the nuclear vitamin D receptor (VDR) regulate hundreds of genes including those coding for proteins involved in cell differentiation and cell proliferation. The current review addresses some of the key mechanisms that influence the biological actions of vitamin D and its metabolites. The insights derived from these mechanisms may aid in designing new uses for this hormone and its non-hypercalcemic derivatives in the treatment and/or prevention of CRC.
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Affiliation(s)
- Michelino Di Rosa
- Department of Bio-medical Sciences, University of Catania, Catania, Italy
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Guz NR, Leuser H, Goldman E. Process Development and Multikilogram Syntheses of XL228 Utilizing a Regioselective Isoxazole Formation and a Selective SNAr Reaction to a Pyrimidine Core. Org Process Res Dev 2013. [DOI: 10.1021/op400137m] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Affiliation(s)
- Nathan R. Guz
- Chemical Development, Exelixis, Inc., South San Francisco, California 94080,
United States
| | - Helena Leuser
- Chemical Development, CARBOGEN-AMCIS, CH-5001 Aarau, Switzerland
| | - Erick Goldman
- Chemical Development, Exelixis, Inc., South San Francisco, California 94080,
United States
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Reed ML, Merriam GR, Kargi AY. Adult growth hormone deficiency - benefits, side effects, and risks of growth hormone replacement. Front Endocrinol (Lausanne) 2013; 4:64. [PMID: 23761782 PMCID: PMC3671347 DOI: 10.3389/fendo.2013.00064] [Citation(s) in RCA: 61] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2013] [Accepted: 05/18/2013] [Indexed: 11/26/2022] Open
Abstract
Deficiency of growth hormone (GH) in adults results in a syndrome characterized by decreased muscle mass and exercise capacity, increased visceral fat, impaired quality of life, unfavorable alterations in lipid profile and markers of cardiovascular risk, decrease in bone mass and integrity, and increased mortality. When dosed appropriately, GH replacement therapy (GHRT) is well tolerated, with a low incidence of side effects, and improves most of the alterations observed in GH deficiency (GHD); beneficial effects on mortality, cardiovascular events, and fracture rates, however, remain to be conclusively demonstrated. The potential of GH to act as a mitogen has resulted in concern over the possibility of increased de novo tumors or recurrence of pre-existing malignancies in individuals treated with GH. Though studies of adults who received GHRT in childhood have produced conflicting reports in this regard, long-term surveillance of adult GHRT has not demonstrated increased cancer risk or mortality.
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Affiliation(s)
- Mary L. Reed
- Geriatrics and Extended Care, VA Puget Sound Health Care System, Madigan Health Care System, Tacoma, WA, USA
| | - George R. Merriam
- Division of Metabolism, Endocrinology, and Nutrition, VA Puget Sound Health Care System, University of Washington School of Medicine, Tacoma, WA, USA
| | - Atil Y. Kargi
- Division of Endocrinology, Diabetes, and Metabolism, University of Miami Miller School of Medicine, Miami, FL, USA
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Insulin, insulin-like growth factor 1 and insulin-like growth factor binding protein 3 serum concentrations in patients with adenomatous colon polyps. GASTROENTEROLOGY REVIEW 2013; 8:308-14. [PMID: 24868275 PMCID: PMC4027822 DOI: 10.5114/pg.2013.38734] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 02/16/2013] [Accepted: 03/19/2013] [Indexed: 11/17/2022]
Abstract
INTRODUCTION Insulin stimulates colonic mucosal cells proliferation directly and by influencing the concentration of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3). AIM To estimate serum concentrations of insulin, IGF-1, and IGFBP-3 and to determine the relationships between them and colorectal adenoma location, dysplasia grading, histological type, and size. MATERIAL AND METHODS The study included 60 patients with colorectal adenomatous polyps found on colonoscopy and confirmed pathologically. The control group consisted of 30 individuals with no positive findings on colonoscopy. All patients had their blood drawn for assessment of insulin, IGF-1, and IGFBP-3 serum concentrations. RESULTS One hundred and nine adenomas (6-40 mm in size) were found in 60 study patients. The average age of patients with multiple polyps was significantly higher than that of patients with single pathologies (61.1 vs. 56.7 years respectively (p < 0.05)). A higher adenoma incidence rate was observed in the distal portion of the colon than the proximal one (50 vs. 10 polyps respectively (p < 0.01)). Higher serum levels of IGF-1 and IGFBP-3 were found in patients with adenomatous polyps than in the control group. The average IGF-1 concentration in patients with adenomas located proximally was also significantly higher compared to those located distally (p < 0.05). The insulin concentration was similar in both groups and not related to clinical data of patients. CONCLUSIONS The results indicate the role of IGF-1 and IGFBP-3 in early carcinogenesis of the large intestine, and IGF-1 particularly in malignant transformation in the proximal part of the organ.
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Bergman D, Halje M, Nordin M, Engström W. Insulin-Like Growth Factor 2 in Development and Disease: A Mini-Review. Gerontology 2013; 59:240-9. [DOI: 10.1159/000343995] [Citation(s) in RCA: 160] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2012] [Accepted: 10/05/2012] [Indexed: 11/19/2022] Open
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Chen X, Lin X, Li M. Comprehensive modulation of tumor progression and regression with periodic fasting and refeeding circles via boosting IGFBP-3 loops and NK responses. Endocrinology 2012; 153:4622-32. [PMID: 22903617 DOI: 10.1210/en.2011-2101] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Progressive tumor-bearing patients deserve to benefit from more realistic approaches. Here, a study revealed the impact of modified periodic fasting and refeeding regimen on tumor progression or regression with little or no loss of food intake and body weight. Human A549 lung, HepG-2 liver, and SKOV-3 ovary progressive tumor-bearing mice were established and subjected to 4 wk of periodic fasting/refeeding cycles (PFRC), including periodic 1-d fasting/6-d refeeding weekly (protocol 1) and periodic 2-d fasting/5-d refeeding weekly (P2DF/5DR, protocol 2), with ad libitum (AL)-fed hosts as controls. Afterwards, PFRC groups exhibited tumor growth arrest with some tendency towards regression; especially, complete regression of progressive tumors and metastases comprised between 43.75 and 56.25% of tumor-challenged hosts in P2DF/5DR group (P < 0.05). AL controls, in contrast, showed continuous tumor progression and metastasis. Finally, 100% hosts in P2DF/5DR and 62.5-68.75% in periodic 1-d fasting/6-d refeeding weekly groups survived a 4-month study period vs. only 31.25-37.5% in AL control group. Immunological assays and Luminex microarray revealed that tumor growth remission is mainly via natural killer cell (NK) reactivity and cross-regulation of IGF-binding protein-3, IGF/IGF-receptor, and megakaryocyte growth and development factor autocrine and paracrine loops. In vivo cellular and humoral assays indicated that tumor-regressive induction by PFRC protocols could be partly terminated by NK cell and IGF-binding protein-3 blockade or replenishment of IGF-I/-II and megakaryocyte growth and development factor. These findings offer a better understanding of comprehensive modulation of periodic fasting/refeeding strategy on the balance between tumor progression and regression.
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Affiliation(s)
- Xiancheng Chen
- National Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, High Technological Development Zone, Chengdu, Sichuan 610041, The People's Republic of China.
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Lim DY, Cho HJ, Kim J, Nho CW, Lee KW, Park JHY. Luteolin decreases IGF-II production and downregulates insulin-like growth factor-I receptor signaling in HT-29 human colon cancer cells. BMC Gastroenterol 2012; 12:9. [PMID: 22269172 PMCID: PMC3298530 DOI: 10.1186/1471-230x-12-9] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2011] [Accepted: 01/23/2012] [Indexed: 01/13/2023] Open
Abstract
Background Luteolin is a 3',4',5,7-tetrahydroxyflavone found in various fruits and vegetables. We have shown previously that luteolin reduces HT-29 cell growth by inducing apoptosis and cell cycle arrest. The objective of this study was to examine whether luteolin downregulates the insulin-like growth factor-I receptor (IGF-IR) signaling pathway in HT-29 cells. Methods In order to assess the effects of luteolin and/or IGF-I on the IGF-IR signaling pathway, cells were cultured with or without 60 μmol/L luteolin and/or 10 nmol/L IGF-I. Cell proliferation, DNA synthesis, and IGF-IR mRNA levels were evaluated by a cell viability assay, [3H]thymidine incorporation assays, and real-time polymerase chain reaction, respectively. Western blot analyses, immunoprecipitation, and in vitro kinase assays were conducted to evaluate the secretion of IGF-II, the protein expression and activation of IGF-IR, and the association of the p85 subunit of phophatidylinositol-3 kinase (PI3K) with IGF-IR, the phosphorylation of Akt and extracellular signal-regulated kinase (ERK)1/2, and cell division cycle 25c (CDC25c), and PI3K activity. Results Luteolin (0 - 60 μmol/L) dose-dependently reduced the IGF-II secretion of HT-29 cells. IGF-I stimulated HT-29 cell growth but did not abrogate luteolin-induced growth inhibition. Luteolin reduced the levels of the IGF-IR precursor protein and IGF-IR transcripts. Luteolin reduced the IGF-I-induced tyrosine phosphorylation of IGF-IR and the association of p85 with IGF-IR. Additionally, luteolin inhibited the activity of PI3K activity as well as the phosphorylation of Akt, ERK1/2, and CDC25c in the presence and absence of IGF-I stimulation. Conclusions The present results demonstrate that luteolin downregulates the activation of the PI3K/Akt and ERK1/2 pathways via a reduction in IGF-IR signaling in HT-29 cells; this may be one of the mechanisms responsible for the observed luteolin-induced apoptosis and cell cycle arrest.
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Affiliation(s)
- Do Young Lim
- Department of Food Science and Nutrition, Hallym University, Chuncheon 200-702, Korea
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Ii M, Li H, Adachi Y, Yamamoto H, Ohashi H, Taniguchi H, Arimura Y, Carbone DP, Imai K, Shinomura Y. The efficacy of IGF-I receptor monoclonal antibody against human gastrointestinal carcinomas is independent of k-ras mutation status. Clin Cancer Res 2011; 17:5048-59. [PMID: 21642381 DOI: 10.1158/1078-0432.ccr-10-3131] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal cancers. We have previously shown successful targeting therapy for colorectal, pancreatic, gastric, and esophageal carcinomas using recombinant adenoviruses expressing dominant negative IGF-IR. Mutation in k-ras is one of key factors in gastrointestinal cancers. In this study, we sought to evaluate the effect of a new monoclonal antibody for IGF-IR, figitumumab (CP-751,871), on the progression of human gastrointestinal carcinomas with/without k-ras mutation. EXPERIMENTAL DESIGN We assessed the effect of figitumumab on signal transduction, proliferation, and survival in six gastrointestinal cancer cell lines with/without k-ras mutation, including colorectal and pancreatic adenocarcinoma, esophageal squamous cell carcinoma, and hepatoma. Combination effects of figitumumab and chemotherapy were also studied. Then figitumumab was evaluated in the treatment of xenografts in nude mice. RESULTS Figitumumab blocked autophosphorylation of IGF-IR and its downstream signals. The antibody suppressed proliferation and tumorigenicity in all cell lines. Figitumumab inhibited survival by itself and up-regulated chemotherapy (5-FU and gemcitabine) induced apoptosis. Moreover, the combination of this agent and chemotherapy was effective against tumors in mice. The effect of figitumumab was not influenced by the mutation status of k-ras. Figitumumab reduced expression of IGF-IR but not insulin receptor in these xenografted tumors. The drug did not affect murine body weight or blood concentrations of glucose, insulin, IGF binding protein 3, and growth hormone. CONCLUSIONS IGF-IR might be a good molecular therapeutic target and figitumumab may thus have therapeutic value in human gastrointestinal malignancies even in the presence of k-ras mutations.
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Affiliation(s)
- Masanori Ii
- First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan
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Targeting for insulin-like growth factor-I receptor with short hairpin RNA for human digestive/gastrointestinal cancers. J Gastroenterol 2010; 45:159-70. [PMID: 19902140 DOI: 10.1007/s00535-009-0151-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2009] [Accepted: 10/06/2009] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Insulin-like growth factor (IGF)-I receptor (IGF-IR) signaling plays important parts in both the tumorigenicity and progression of digestive/gastrointestinal malignancies. In this study, we sought to test the effectiveness of a practical approach to blocking IGF-IR signaling using RNA interference delivered by recombinant adenoviruses. METHODS We constructed a recombinant adenovirus expressing short hairpin RNA targeting IGF-IR (shIGF-IR) and assessed its effect on signal transduction, proliferation, and survival in digestive/gastrointestinal cancer cell lines representing colorectal, gastric, and pancreatic adenocarcinoma, esophageal squamous cell carcinoma, and hepatoma. We analyzed the effects of shIGF-IR alone and with chemotherapy in vitro and in nude mouse xenografts, as well as on insulin signaling and hybrid receptor formation between IGF-IR and insulin receptor. RESULTS shIGF-IR blocked expression and autophosphorylation of IGF-IR and downstream signaling by the IGFs, but not by insulin. shIGF-IR suppressed proliferation and carcinogenicity in vitro and up-regulated apoptosis in a dose-dependent fashion. shIGF-IR augmented the effects of chemotherapy on in vitro growth and apoptosis induction. Moreover, the combination of shIGF-IR and chemotherapy was highly effective against tumors in mice. shIGF-IR reduced hybrid receptor formation without effect on expression of insulin receptor. CONCLUSIONS shIGF-IR may have therapeutic utility in human digestive/gastrointestinal cancers, both alone and in combination with chemotherapy.
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Macarulla T, Capdevila J, Perez-Garcia J, Ramos FJ, Elez ME, Markman B, Ruiz-Echarri M, Tabernero J. New approaches and targets in advanced colorectal cancer. Eur J Cancer 2010; 45 Suppl 1:79-88. [PMID: 19775607 DOI: 10.1016/s0959-8049(09)70019-x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Affiliation(s)
- Teresa Macarulla
- Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
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Salphati L, Plise EG, Li G. Expression and activity of the efflux transporters ABCB1, ABCC2 and ABCG2 in the human colorectal carcinoma cell line LS513. Eur J Pharm Sci 2009; 37:463-8. [PMID: 19491037 DOI: 10.1016/j.ejps.2009.04.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2008] [Revised: 03/30/2009] [Accepted: 04/01/2009] [Indexed: 11/30/2022]
Abstract
The human colorectal carcinoma cell line LS513 exhibits epithelial morphology, adherent properties and can grow subcutaneously to form tumors in nude mice. Thus, it is a potential model for mouse xenograft efficacy studies. The present study characterized the expression and activity of P-gp, BCRP and MRP2 in LS513 cells. We investigated the expression of these ATP-binding cassette transporters by Western blot and their activity was also examined using cell culture inserts, where the LS513 cells were grown to confluence for 9 days. The transport of model substrates of P-gp (amprenavir, ritonavir and topotecan), BCRP (topotecan) and MRP2 (SN-38) was studied in the apical to basolateral (A-B) and basolateral to apical (B-A) directions. P-gp, BCRP and MRP2 could be detected by western blot. The LS513 cells exhibited markedly higher transport in the B-A direction than in the A-B direction for the probe substrates tested, with efflux ratios (ERs; B-A/A-B) of 10, 21, 40 and 50 for amprenavir, ritonavir, topotecan and SN38, respectively. The ER could be significantly reduced with the addition of inhibitors of P-gp (GF120918), BCRP (FTC), and MRP2 (MK571), confirming the activity of these transporters in the LS513 cells.
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Affiliation(s)
- Laurent Salphati
- Drug Metabolism and Pharmacokinetics Department, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080, United States.
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Sridhar SS, Goodwin PJ. Insulin-insulin-like growth factor axis and colon cancer. J Clin Oncol 2008; 27:165-7. [PMID: 19064959 DOI: 10.1200/jco.2008.19.8937] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Piao W, Wang Y, Adachi Y, Yamamoto H, Li R, Imsumran A, Li H, Maehata T, Ii M, Arimura Y, Lee CT, Shinomura Y, Carbone DP, Imai K. Insulin-like growth factor-I receptor blockade by a specific tyrosine kinase inhibitor for human gastrointestinal carcinomas. Mol Cancer Ther 2008; 7:1483-93. [PMID: 18566219 DOI: 10.1158/1535-7163.mct-07-2395] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Insulin-like growth factor-I receptor (IGF-IR) signaling is required for carcinogenicity and proliferation of gastrointestinal (GI) cancers. In this study, we sought to evaluate the effect of a new tyrosine kinase inhibitor of IGF-IR, NVP-AEW541, on the signal transduction and the progression of GI carcinomas. We assessed the effect of NVP-AEW541 on signal transduction, proliferation, survival, and migration in four GI cancer cells: colorectal adenocarcinoma HT29, pancreatic adenocarcinoma BxPC3, esophageal squamous cell carcinoma TE1, and hepatoma PLC/PRF/5. The effects of NVP-AEW541 alone and with chemotherapy were studied in vitro and in nude mouse xenografts. We also analyzed the effects of NVP-AEW541 on insulin signals and hybrid receptor formation between IGF-IR and insulin receptor. NVP-AEW541 blocked autophosphorylation of IGF-IR and both Akt and extracellular signal-regulated kinase activation by IGF but not by insulin. NVP-AEW541 suppressed proliferation and tumorigenicity in vitro in a dose-dependent manner in all cell lines. The drug inhibited tumor as a single agent and, when combined with stressors, up-regulated apoptosis in a dose-dependent fashion and inhibited mobility. NVP-AEW541 augmented the effects of chemotherapy on in vitro growth and induction of apoptosis. Moreover, the combination of NVP-AEW541 and chemotherapy was highly effective against tumors in mice. This compound did not influence hybrid receptor formation. Thus, NVP-AEW541 may have significant therapeutic utility in human GI carcinomas both alone and in combination with chemotherapy.
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Affiliation(s)
- Wenhua Piao
- First Department of Internal Medicine, Sapporo Medical University, Chuo-ku, Sapporo 060-8543, Japan
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Rokkas T, Pistiolas D, Sechopoulos P, Margantinis G, Koukoulis G. Risk of colorectal neoplasm in patients with acromegaly: A meta-analysis. World J Gastroenterol 2008; 14:3484-9. [PMID: 18567075 PMCID: PMC2716609 DOI: 10.3748/wjg.14.3484] [Citation(s) in RCA: 89] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To examine the risk of colorectal neoplasm in acromegalic patients by meta-analyzing all relevant controlled studies.
METHODS: Extensive English language medical literature searches for human studies, up to December 2007, were performed using suitable keywords. Pooled estimates [odds ratio (OR) with 95% confidence intervals (CI)] were obtained using either the fixed or random-effects model as appropriate. Heterogeneity between studies was evaluated with the Cochran Q test whereas the likelihood of publication bias was assessed by constructing funnel plots. Their symmetry was estimated by the adjusted rank correlation test.
RESULTS: For hyperplastic polyps the pooled ORs with 95% CI were 3.557 (2.587-4.891) by fixed effects model and 3.703 (2.565-5.347) by random effects model. The Z test values for overall effect were 7.81 and 6.984, respectively (P < 0.0001). For colon adenomas the pooled ORs with 95% CI were 2.486 (1.908-3.238) (fixed effects model) and 2.537 (1.914-3.364) (random effects model). The Z test values were 6.747 and 6.472, respectively (P < 0.0001). For colon cancer the pooled OR with 95% CI was identical for both fixed and random effects model (OR, 4.351; 95% CI, 1.533-12.354; Z = 2.762, P = 0.006). There was no significant heterogeneity and no publication bias in all the above meta-analyses.
CONCLUSION: Acromegaly is associated with an increased risk of colorectal neoplasm.
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Scamuffa N, Siegfried G, Bontemps Y, Ma L, Basak A, Cherel G, Calvo F, Seidah NG, Khatib AM. Selective inhibition of proprotein convertases represses the metastatic potential of human colorectal tumor cells. J Clin Invest 2008; 118:352-63. [PMID: 18064302 DOI: 10.1172/jci32040] [Citation(s) in RCA: 96] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2007] [Accepted: 10/17/2007] [Indexed: 01/14/2023] Open
Abstract
The proprotein convertases (PCs) are implicated in the activation of various precursor proteins that play an important role in tumor cell metastasis. Here, we report their involvement in the regulation of the metastatic potential of colorectal tumor cells. PC function in the human and murine colon carcinoma cell lines HT-29 and CT-26, respectively, was inhibited using siRNA targeting the PCs furin, PACE4, PC5, and PC7 or by overexpression of the general PC inhibitor alpha1-antitrypsin Portland (alpha1-PDX). We found that overexpression of alpha1-PDX and knockdown of furin expression inhibited processing of IGF-1 receptor and its subsequent activation by IGF-1 to induce IRS-1 and Akt phosphorylation, all important in colon carcinoma metastasis. These data suggest that the PC furin is a major IGF-1 receptor convertase. Expression of alpha1-PDX reduced the production of TNF-alpha and IL-1alpha by human colon carcinoma cells, and incubation of murine liver endothelial cells with conditioned media derived from these cells failed to induce tumor cell adhesion to activated murine endothelial cells, a critical step in metastatic invasion. Furthermore, colon carcinoma cells in which PC activity was inhibited by overexpression of alpha1-PDX when injected into the portal vein of mice showed a significantly reduced ability to form liver metastases. This suggests that inhibition of PCs is a potentially promising strategy for the prevention of colorectal liver metastasis.
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Affiliation(s)
- Nathalie Scamuffa
- INSERM U716, Equipe Avenir, Institut de Génétique Moléculaire, and Université Paris 7, Paris, France
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Melmed GY, Devlin SM, Vlotides G, Dhall D, Ross S, Yu R, Melmed S. Anti-aging therapy with human growth hormone associated with metastatic colon cancer in a patient with Crohn's colitis. Clin Gastroenterol Hepatol 2008; 6:360-3. [PMID: 18255351 PMCID: PMC2696478 DOI: 10.1016/j.cgh.2007.12.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS The nonapproved use of human growth hormone (HGH) for anti-aging has been increasing. Theoretical concerns for neoplastic potentiation by HGH have been raised, but not proven clinically. METHODS We report the case of a 68-year-old man with colonic Crohn's disease who was found to have aggressive metastatic colon cancer. The patient had been receiving HGH therapy for anti-aging purposes for 7 years before presentation. Normal and malignant colonic tissue was examined for qualitative and quantitative molecular profiles of growth hormone (GH) and its signaling molecules, using immunohistochemistry and RNA extraction with polymerase chain reaction amplification. RESULTS Immunoreactivity was more robust in tumor tissue than in normal colon for insulin-like growth factor-1 receptor (IGF-1R) but not for IGF, GH, or GH receptor. RNA extraction with quantitative polymerase chain reaction showed that IGF-1R and vascular endothelial growth factor expression, but not IGF-1, GH receptor, or suppressor of cytokine signaling-2, were higher in tumor than in normal colonic tissue. CONCLUSIONS Colorectal cancer development concurrent with administration of HGH for anti-aging purposes occurred in an individual already at increased risk for colon cancer. This underscores the need for further investigation of the proneoplastic potential of GH supplementation for anti-aging.
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Affiliation(s)
| | | | | | - Deepti Dhall
- Departments of Medicine and Anatomic Pathology, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California, Los Angeles, CA
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Yang SY, Sales KM, Fuller BJ, Seifalian AM, Winslet MC. Inducing apoptosis of human colon cancer cells by an IGF-I D domain analogue peptide. Mol Cancer 2008; 7:17. [PMID: 18261206 PMCID: PMC2276513 DOI: 10.1186/1476-4598-7-17] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2007] [Accepted: 02/08/2008] [Indexed: 11/23/2022] Open
Abstract
Background The resistance of tumour cells to apoptosis is a major contributor to the limited effectiveness of chemotherapies. Insulin-like growth factor I (IGF-I) has potential to protect cancer cells from variety of apoptotic challenges. This study was carried out to investigate the effect of a novel IGF-I receptor antagonist on apoptosis in colon cancer cells. Results We have designed and synthesised a novel antagonist of IGF-I receptor. The effect of this antagonist on human colon cancer cell proliferation was examined by a non-radioactive assay; the apoptosis was revealed by determining the activities of cellular caspases3/7, 8 and 9. The apoptosis pathways were investigated by examining the levels of pro-apoptosis proteins with Western blotting. Following 40 hours treatment with the novel antagonist peptide, colon cancer cell Caspase 3/7 activities increased 2–7 times; Caspase 8 activities increased 2–5 times and Caspase 9 increased 1.2–1.6 times. The proliferation of cancer cell was inhibited by 14–15%. The data showed that the antagonist induced colon cancer cell apoptosis and inhibited cancer cell proliferation. The different changes of Caspase 3/7, 8 and 9 activities suggested that the extrinsic pathways may play a major role in the antagonist peptide-induced apoptosis. Conclusion This is the first report on this novel antagonist to induce human colon cancer cell apoptosis and inhibit cancer cell proliferation. These results suggest that IGF-I receptor antagonists may have the potential to be developed as a novel therapy for colon cancers in the future.
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Affiliation(s)
- Shi Yu Yang
- University Department of Surgery, Royal Free & University College Medical School, University College London, Rowland Hill Street, London NW3 2PF, UK.
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42
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Similar Biological Medicinal Products Containing Recombinant Human Growth Hormone: European Regulation. Horm Res Paediatr 2007; 69:14-21. [DOI: 10.1159/000111790] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2007] [Accepted: 10/02/2007] [Indexed: 02/02/2023] Open
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Diehl D, Oesterle D, Elmlinger MW, Hoeflich A, Wolf E, Lahm H. IGF-II transgenic mice display increased aberrant colon crypt multiplicity and tumor volume after 1,2-dimethylhydrazine treatment. J Carcinog 2006; 5:24. [PMID: 17118177 PMCID: PMC1660565 DOI: 10.1186/1477-3163-5-24] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2006] [Accepted: 11/21/2006] [Indexed: 01/27/2023] Open
Abstract
In colorectal cancer insulin-like growth factor II (IGF-II) is frequently overexpressed. To evaluate, whether IGF-II affects different stages of tumorigenesis, we induced neoplastic alterations in the colon of wild-type and IGF-II transgenic mice using 1,2-dimethylhydrazine (DMH). Aberrant crypt foci (ACF) served as markers of early lesions in the colonic mucosa, whereas adenomas and carcinomas characterized the endpoints of tumor development. DMH-treatment led initially to significantly more ACF in IGF-II transgenic than in wild-type mice. This increase in ACF was especially prominent for those consisting of > or =three aberrant crypts (AC). Nevertheless, adenomas and adenocarcinomas of the colon, present after 34 weeks in both genetic groups, were not found at different frequency. Tumor volumes, however, were significantly higher in IGF-II transgenic mice and correlated with serum IGF-II levels. Immunohistochemical staining for markers of proliferation and apoptosis revealed increased cell proliferation rates in tumors of IGF-II transgenic mice without significant affection of apoptosis. Increased proliferation was accompanied by elevated localization of beta-catenin in the cytosol and cell nuclei and reduced appearance at the inner plasma membrane. In conclusion, we provide evidence that IGF-II, via activation of the beta-catenin signaling cascade, promotes growth of ACF and tumors without affecting tumor numbers.
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Affiliation(s)
- Daniela Diehl
- Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians University, Feodor-Lynen-Str. 25, D-81377 Munich, Germany
| | - Doris Oesterle
- Institute of Toxicology, GSF-National Research Center for Environment and Health, Ingolstädter Landstr.1, D-85764 Neuherberg, Germany
| | - Martin W Elmlinger
- Pediatric Endocrinology, Children's Hospital, University of Tübingen, Hoppe-Seyler-Str.1, D-72076 Tübingen, Germany
| | - Andreas Hoeflich
- Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians University, Feodor-Lynen-Str. 25, D-81377 Munich, Germany
| | - Eckhard Wolf
- Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians University, Feodor-Lynen-Str. 25, D-81377 Munich, Germany
| | - Harald Lahm
- Institute of Molecular Animal Breeding and Biotechnology, Ludwig-Maximilians University, Feodor-Lynen-Str. 25, D-81377 Munich, Germany
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Bouvy ND, Marquet RL, Jeekel J, Bonjer HJ. Laparoscopic surgery is associated with less tumour growth stimulation than conventional surgery: An experimental study. Br J Surg 2005. [DOI: 10.1046/j.1365-2168.1997.02590.x] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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45
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Remacle-Bonnet M, Garrouste F, Baillat G, Andre F, Marvaldi J, Pommier G. Membrane rafts segregate pro- from anti-apoptotic insulin-like growth factor-I receptor signaling in colon carcinoma cells stimulated by members of the tumor necrosis factor superfamily. THE AMERICAN JOURNAL OF PATHOLOGY 2005; 167:761-73. [PMID: 16127155 PMCID: PMC1698735 DOI: 10.1016/s0002-9440(10)62049-4] [Citation(s) in RCA: 48] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
In the tumor microenvironment, autocrine/paracrine loops of insulin-like growth factors (IGFs) contribute to cancer cell survival. However, we report here that IGF-I can send contradictory signals that interfere with cell death induced by different ligands of the tumor necrosis factor (TNF) superfamily. IGF-I protected human colon carcinoma cells from TNF-alpha-induced apoptosis, but it enhanced the apoptotic response to anti-Fas antibody and TNF-related apoptosis inducing ligand stimulation. This proapoptotic effect of IGF-I, observed in several but not all tested colon cancer cell lines, was mediated via the phosphatidylinositol 3'-kinase (PI3K)/Akt pathway. Furthermore, IGF-I receptors (IGF-IR) were located in and out of membrane lipid rafts and were tyrosine autophosphorylated in response to IGF-I. However, disruption of rafts by acute cholesterol depletion shifted IGF-IR to non-raft domains, abolished the IGF-I-mediated proapoptotic effect, and inhibited the IGF-I-dependent IRS-1 and Akt recruitment into and phosphorylation/activation within lipid rafts. Replenishing cell membranes with cholesterol reversed these effects. Activation of extracellular-regulated kinase-1/2 and p38 mitogen-activated protein kinase, which convey the IGF-I anti-apoptotic effect, occurred independently of lipid rafts. Thus, we propose that segregation of IGF-IR in and out of lipid rafts may dynamically regulate the pro- and anti-apoptotic effects of IGF-I on apoptosis induced by TNF superfamily members.
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Affiliation(s)
- Maryse Remacle-Bonnet
- FRE CNRS 27.37, Faculté de Pharmacie, 27 Bd. Jean Moulin, 13385 Marseille Cedex 5, France.
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Yakar S, Leroith D, Brodt P. The role of the growth hormone/insulin-like growth factor axis in tumor growth and progression: Lessons from animal models. Cytokine Growth Factor Rev 2005; 16:407-20. [PMID: 15886048 DOI: 10.1016/j.cytogfr.2005.01.010] [Citation(s) in RCA: 132] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2005] [Accepted: 01/20/2005] [Indexed: 02/08/2023]
Abstract
Over the past two decades it has become widely appreciated that a relationship exists between the insulin-like growth factors (IGFs) and cancer. Many cancers have been shown to overexpress the IGF-I receptor and produce the ligands (IGF-I or IGF-II) and some combinations of the six IGF-binding proteins. With the recent demonstration by epidemiological studies that an elevated serum IGF-I level is associated with an increased relative risk of developing a number of epithelial cancers, interest has been sparked in this area of research with the possibility of targeting the IGF-I receptor in cancer treatment protocols. This review highlights many of the most relevant studies in this exciting area of research, focusing in particular on lessons learned from animal models of cancer.
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Affiliation(s)
- Shoshana Yakar
- Diabetes Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892-1758, USA.
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López de Cicco R, Bassi DE, Zucker S, Seidah NG, Klein-Szanto AJP. Human Carcinoma Cell Growth and Invasiveness Is Impaired by the Propeptide of the Ubiquitous Proprotein Convertase Furin. Cancer Res 2005; 65:4162-71. [PMID: 15899807 DOI: 10.1158/0008-5472.can-04-2820] [Citation(s) in RCA: 44] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Furin, a potent proprotein convertase involved in activation of several cancer-related substrates, is synthesized as an inactive zymogen, thus minimizing the occurrence of premature enzymatic activity that would lead to inappropriate protein activation or degradation. This natural inhibitory mechanism is based on the presence of an inactivating prosegment at the NH2 terminal of the zymogen. After initial autocatalytic cleavage, the prosegment remains tightly associated with the convertase until it reaches the trans-Golgi network where the dissociation of the prosegment and activation of furin occurs. We hypothesized that the inhibitory properties of the preprosegment of furin (ppFur) could be beneficial if ectopically expressed in tumor cells. Transfection of four human head and neck squamous cell carcinoma cell lines with the complete ppFur cDNA sequence (pIRES-EGFP-ppFur) or with the empty expression vector (pIRES-EGFP) was done. The inhibitory effect was evaluated using in vivo tumorigenicity, invasion, anchorage-independent growth in soft agar, and proliferation assays, as well as by investigating impairment of furin substrates processing. Following transfection of ppFur, a significant reduction in cell proliferation, tumorigenicity, and invasiveness was observed in vitro and in vivo. These biological changes are directly related to the inhibition of furin-mediated activation of crucial cancer-related substrates, such as membrane type 1 matrix metalloproteinase, transforming growth factor-beta, insulin-like growth factor-1 receptor, and vascular endothelial growth factor-C. PpFur expression in head and neck squamous cell carcinoma cell lines showed a mechanistic link between furin inhibition, decreased substrate processing, cell proliferation, and invasive ability. These findings suggest that furin inhibition is a feasible approach to ameliorate and even abolish the malignant phenotype of various malignancies.
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Miyamoto S, Nakamura M, Shitara K, Nakamura K, Ohki Y, Ishii G, Goya M, Kodama K, Sangai T, Maeda H, Shi-Chuang Z, Chiba T, Ochiai A. Blockade of Paracrine Supply of Insulin-Like Growth Factors Using Neutralizing Antibodies Suppresses the Liver Metastasis of Human Colorectal Cancers. Clin Cancer Res 2005; 11:3494-502. [PMID: 15867252 DOI: 10.1158/1078-0432.ccr-04-1701] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Environmental stimuli, such as organ-specific growth factors, can influence the metastatic potential of a tumor. The liver is the main source of insulin-like growth factors (IGFs). The importance of IGF signal in hepatic metastasis has been clarified mainly by IGF-I receptor targeting strategies. This study aims to confirm these precedent reports by novel tool, neutralizing antibodies against IGFs and to show that IGFs are promising therapeutic targets for hepatic metastasis in vivo. Hepatic metastasis was induced by intrasplenic injection of human colorectal cancer cell line, HT29. The antimetastatic effects of three antibodies (anti-mouse IGF-I, anti-mouse IGF-II, and anti-human/mouse IGF-II designated KM1468) were tested singly or in combination in the early phase of metastasis. The dose escalation effect of KM1468 and its survival benefit were examined in the early and late phases of metastasis. The mechanism of IGF neutralization was investigated with immunohistochemistry. Dual neutralization of paracrine IGF-I and IGF-II showed modest additive antimetastatic effects than single neutralization of IGF-I or IGF-II. In any phase of metastasis, neutralization led to significant tumor growth inhibition and longer survival. Dose escalation of KM1468 influenced survival only in the late phase of metastasis. Apoptosis increased significantly in the antibody-treated group compared with the control group (P = 0.0025) In conclusion, IGFs are promising therapeutic targets for hepatic metastases of colorectal cancers. However, the IGF dependency is probably variable in the metastatic process.
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Affiliation(s)
- Shin'ichi Miyamoto
- Pathology Division, National Cancer Center Research Institute East, Chiba, Japan
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Zhang H, Yee D. The therapeutic potential of agents targeting the type I insulin-like growth factor receptor. Expert Opin Investig Drugs 2005; 13:1569-77. [PMID: 15566314 DOI: 10.1517/13543784.13.12.1569] [Citation(s) in RCA: 108] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
The type I insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase that mediates insulin-like growth factor I (IGF-1) and IGF-2 signalling. Increased expression levels and/or enhanced activity of IGF-1R have been observed in many types of cancer. It is well documented that IGF-1R plays important roles in the proliferation, transformation, motility and metastasis of cancer cells. Therefore, IGF-1R has surfaced as an attractive target for cancer therapy. There are several aspects of this receptor that need to be considered when thinking about inhibitory strategies. In this review, several points relevant to targeting IGF-1R will be discussed, including the signalling pathways downstream of the receptor, the potential role for the insulin receptor in regulating IGF action and multiple cancer phenotypes regulated by this receptor. In addition, there are several strategies that could be used to inhibit IGF action. Inhibition of receptor function by lowering protein expression, decreasing kinase activity by small-molecule inhibitors, disrupting receptor function by monoclonal antibody blockade and neutralising circulating ligand all represent potential therapeutic strategies. As these strategies move forward to clinical trial, several important considerations need to be incorporated into the clinical trial design.
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Affiliation(s)
- Hua Zhang
- University of Minnesota Cancer Center, MMC 806, 420 Delaware Street SE, Minneapolis, MN 55455, USA
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50
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Ibrahim YH, Yee D. Insulin-like growth factor-I and cancer risk. Growth Horm IGF Res 2004; 14:261-269. [PMID: 15231294 DOI: 10.1016/j.ghir.2004.01.005] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2004] [Accepted: 01/14/2004] [Indexed: 02/04/2023]
Abstract
Growth factor pathways are fundamental in normal tissue regulation and development. In many tissues, factors that function in normal growth and development also have important regulatory roles in transformed malignant cells. The insulin-like growth factor (IGF) system is implicated in the regulation of the malignant phenotype by its effects on proliferation, differentiation, and apoptosis. IGF-I has also been linked to malignant transformation. The role of the IGF-I in cancer has been recognized in both experimental and clinical settings, suggesting that the enhancement of growth factor pathways potentially could increase the risk for cancer development. In this paper, the role of IGF-I signaling in tumor regulation, and the impact of IGF-I modulation using growth hormone replacement therapy are discussed.
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Affiliation(s)
- Yasir H Ibrahim
- University of Minnesota Cancer Center, MMC 806, 420 Delaware Street SE, Minneapolis, MN 55455, USA
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