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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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Karakolev I, Stanilov N, Miteva L, Jovchev J, Dobreva Z, Stanilova S. Expression of Insuline-Like Growth Factor-1 Receptor mRNA in Colorectal Carcinoma Patients. BIOTECHNOL BIOTEC EQ 2014. [DOI: 10.5504/50yrtimb.2011.0017] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
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Nedić O, Robajac D, Šunderić M, Miljuš G, Đukanović B, Malenković V. Detection and identification of oxidized insulin-like growth factor-binding proteins and receptors in patients with colorectal carcinoma. Free Radic Biol Med 2013; 65:1195-1200. [PMID: 24051179 DOI: 10.1016/j.freeradbiomed.2013.09.003] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2013] [Revised: 09/06/2013] [Accepted: 09/07/2013] [Indexed: 12/26/2022]
Abstract
Colorectal cancer (CRC) is one of the most prevalent cancers worldwide and also the one with the highest mortality rate. Tumor growth is assisted by various growth factors, and insulin-like growth factors (IGFs) are among the most important. A majority of the IGFs are bound to IGF-binding proteins (IGFBPs) and their release is dependent on the rate of IGFBP proteolysis. The action of free IGFs is exerted and controlled by binding to cell membrane receptors (IGF-Rs). The objective of this work was to connect two determinants of the CRC pathology: oxidation as a process that underlies tumor development and the members of the IGF system that control it. Carbonyl groups (CO) on IGFBP-2, IGFBP-3, IGF-1R, and IGF-2R were determined in samples obtained from patients with CRC, and IGF-binding properties of these proteins were analyzed. According to our results, IGFBP-2 and IGFBP-3 in serum had increased content of CO groups due to CRC. Oxidation of IGFBP-2 increased its affinity for IGF molecules, whereas oxidation of IGFBP-3 reduced it. As for receptors, only intact CO-IGF-2R was detected on solubilized colon membranes, whereas CO-IGF-1R was degraded into fragments. Oxidative changes in the IGF axis may be regarded as part of the mechanism of its action. IGFs bound to IGFBP-3 remain in the circulation, whereas those bound to IGFBP-2 freely reach target tissues. Therefore, oxidation supports IGF distribution toward tissues and, consequently, promotes tumor growth.
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Affiliation(s)
- Olgica Nedić
- Institute for the Application of Nuclear Energy, University of Belgrade, 11080 Belgrade, Serbia.
| | - Dragana Robajac
- Institute for the Application of Nuclear Energy, University of Belgrade, 11080 Belgrade, Serbia
| | - Miloš Šunderić
- Institute for the Application of Nuclear Energy, University of Belgrade, 11080 Belgrade, Serbia
| | - Goran Miljuš
- Institute for the Application of Nuclear Energy, University of Belgrade, 11080 Belgrade, Serbia
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KUKLINSKI ADAM, KAMOCKI ZBIGNIEW, KODA MARIUSZ, PIOTROWSKI ZDZISLAW, SULKOWSKI STANISLAW, LESNIEWICZ RYSZARD, PAWLAK KRYSTYNA, MYSLIWIEC PIOTR, KEDRA BOGUSLAW. IGF-IR in patients with advanced colorectal cancer in correlation with certain clinico-morphological factors: Initial report. Oncol Lett 2011; 2:1155-1159. [PMID: 22848281 PMCID: PMC3406542 DOI: 10.3892/ol.2011.396] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2011] [Accepted: 08/03/2011] [Indexed: 02/01/2023] Open
Abstract
The insulin-like growth factor (IGF) system comprises two types of peptides (IGF-I and IGF-II), two types of receptors (IGF-IR and IGF-IIR) and six IGF-binding proteins (BP). This system is mainly responsible for the growth and division of cells in the body, regulation of the cell cycle and prevention of apoptosis. The expression of IGF-IR was assessed in the cells of resected primary colorectal tumours in 88 patients (age, 36-87 years; mean 64.78; males, 48 and females, 40) treated surgically at the Second Department of General and Gastroenterological Surgery, Medical University of Bialystok, Poland, in relation to various clinico-morphological factors. The post-operative material was analysed to find the histological type, location of lesions, lymph node involvement staging, distant metastases (pTNM classification), staging in Dukes' classification and the histopathological differentiation grade. The expression of IGF-IR in colorectal cancer cells was assessed using an immunohistochemical method. The findings were subjected to statistical analysis (Chi-square test, multivariation test and Mann-Whitney U test). A positive IGF-IR expression (in at least 10% of cancer cells) was observed in 44 patients. The mean immunoreactive cell count for IGF-IR in all of the tumours studied was 30.79%. The current study showed no correlation of IGF-IR expression in colorectal cancer cells with characteristics such as age and gender of patients, tumour location, type, histological differentiation or histopathological advancement. Immunohistological determination of IGF-IR expression in advanced colorectal cancer cells revealed controversial scores. Evaluation should be confirmed by using other methods and enhanced to include adenomas and early colorectal cancers.
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Affiliation(s)
- ADAM KUKLINSKI
- Second Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
| | - ZBIGNIEW KAMOCKI
- Second Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
| | - MARIUSZ KODA
- Department of General Pathomorphology, Medical University of Bialystok, Bialystok, Poland
| | - ZDZISLAW PIOTROWSKI
- Second Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
| | - STANISLAW SULKOWSKI
- Department of General Pathomorphology, Medical University of Bialystok, Bialystok, Poland
| | - RYSZARD LESNIEWICZ
- Department of Gynaecological Endocrinology, Medical University of Bialystok, Bialystok, Poland
| | - KRYSTYNA PAWLAK
- Department of Monitored Pharmacotherapy, Medical University of Bialystok, Bialystok, Poland
| | - PIOTR MYSLIWIEC
- Second Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
| | - BOGUSLAW KEDRA
- Second Department of General and Gastroenterological Surgery, Medical University of Bialystok, Bialystok, Poland
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Koda M, Reszec J, Sulkowska M, Kanczuga-Koda L, Sulkowski S. Expression of the insulin-like growth factor-I receptor and proapoptotic Bax and Bak proteins in human colorectal cancer. Ann N Y Acad Sci 2005; 1030:377-83. [PMID: 15659820 DOI: 10.1196/annals.1329.047] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Insulin-like growth factor-I (IGF-I) and IGF-I receptor (IGF-IR), despite their well-known roles in cell survival and proliferation, can also weakly enhance apoptosis. To study the relationships between the IGF-IR and Bax as well as Bak, 144 cases of colorectal cancer were examined by immunohistochemistry, using the avidin-biotin-peroxidase method. The results were correlated with selected clinicopathological features of colorectal cancer and with the expression of IGF-IR, Bax, and Bak in normal colon mucosa. In Bax-, Bak-, or IGF-IR-positive cancers, the adjacent colorectal mucosa revealed positive immunostaining for these proteins. In the majority of Bax-, Bak-, or IGF-IR-negative tumors, we observed no staining for these proteins in adjacent mucosa. The strong immunostaining for IGF-IR, Bax, and Bak was noted in 50.8, 55.5, and 49.3% of tumors, respectively. We observed positive correlations between IGF-IR and Bax (P < 0.002, r = 0.302), between IGF-IR and Bak (P < 0.0001, r = 0.407), and between Bax and Bak (P < 0.0001, r = 0.474). No relationship was noted between IGF-IR expression and tumor grade, stage, or lymph node status. We found negative associations between Bax, Bak, and tumor grade (P < 0.01 and P < 0.003, respectively), but no relationships between Bax and Bak and tumor stage or between Bax and Bak and lymph node status. Our results demonstrate that, in addition to overexpressed IGF-IR, there are relationships between IGF-IR and proapoptotic proteins in colorectal carcinomas that could contribute to increased cell turnover and the progression of colorectal cancer.
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Affiliation(s)
- Mariusz Koda
- Department of Pathology, Medical University of Bialystok, Waszyngtona 13, 15-269 Bialystok, Poland.
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Associations among IRS1, IRS2, IGF1, and IGFBP3 Genetic Polymorphisms and Colorectal Cancer. Cancer Epidemiol Biomarkers Prev 2004. [DOI: 10.1158/1055-9965.1206.13.7] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Abstract
Introduction: Insulin, insulin-like growth factor (IGF), and IGF binding protein (IGFBP) are involved in cell growth and proliferation and are thought to be important in the etiology of colorectal cancer. We hypothesize that genetic polymorphisms of insulin receptor substrates (IRS-1 and IRS-2), IGF-I, and IGFBP-3 alter colorectal cancer risk because of their roles in the insulin-related signaling pathway. Methods: Data from a population-based incident case-control study of 1,346 colon cancer cases and 1,544 population-based controls and 952 rectal cancer cases and 1,205 controls were used to evaluate associations. Genetic polymorphisms of four genes were investigated: an IGF1 CA repeat, the IGFBP3 −202 A > C, the IRS1 G972R, and the IRS2 G1057D. Results: Having at least one R allele (GR or RR) for IRS1 G972R was associated with an increased risk of colon cancer [odds ratio 1.4, 95% confidence interval (95% CI) 1.1-1.9]. The IRS2 G972R heterozygote GD genotype significantly reduced risk of colon cancer (odds ratio 0.8, 95% CI 0.6-0.9). Neither the IGF1 nor the IGFBP3 variants was associated independently with colon cancer, but there was an association when examined with IRS1. Individuals with an IRS1 R allele and IGF1 non-192 allele were at a 2-fold increased risk of colon cancer (95% CI 1.2-4.4). There was a 70% (95% CI 1.02-2.8) increased risk of colon cancer with an IRS1 R allele and the IGFBP3 AC or CC genotype. The IRS2 GD genotype reduced risk of colon cancer, except among those with an IRS1 R allele. No significant associations were seen in analyses of main effects or interactions of these variants and rectal cancer risk. Conclusions: Both IRS1 and IRS2 variants were associated with colon cancer risk independently. Associations were slightly stronger when polymorphisms in multiple genes were evaluated in conjunction with other genes rather than individually. These data suggest that the insulin-related pathway may be important in the etiology of colon cancer but not rectal cancer.
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Anderson MR, Jankowski JAZ. The role of receptor tyrosine kinase inhibition in treating gastrointestinal malignancy. Expert Opin Investig Drugs 2003; 12:577-92. [PMID: 12665414 DOI: 10.1517/13543784.12.4.577] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Tyrosine kinase receptors are proteins that transduce the signal from many growth factor and cytokine ligands to produce intracellular responses. As such they can activate multiple signalling cascade pathways and influence cell division, migration and survival. Many show upregulation in certain malignancies, including those of the gastrointestinal tract, and are thought to play key roles in carcinogenesis. This makes them attractive targets for drug therapy and in recent years many inhibitors have been developed. This review discusses the current situation regarding the development of inhibitors with particular reference to the erbB family, the insulin-like growth factor receptor, the Met receptor, the receptor for vascular endothelial growth factor and the Kit receptor. The evidence will be related back to cancers of the gut lumen. Clinical effectiveness in this area seems to lie in using a combinatorial approach that inhibits multiple key signalling points, and the reasons for this will be discussed.
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Affiliation(s)
- M R Anderson
- Department of Medical Sciences, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B15 2TH, UK.
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Komninou D, Ayonote A, Richie JP, Rigas B. Insulin resistance and its contribution to colon carcinogenesis. Exp Biol Med (Maywood) 2003; 228:396-405. [PMID: 12671184 DOI: 10.1177/153537020322800410] [Citation(s) in RCA: 108] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023] Open
Abstract
The insulin resistance-colon cancer hypothesis, stating that insulin resistance may be associated with the development of colorectal cancer, represents a significant advance in colon cancer, as it emphasizes the potential for this cancer to become a modifiable disease. The fact that the incidence of insulin resistance has been increasing in the United States and much of the rest of the Western world where colon cancer remains the second leading cause of cancer death makes the exploration of the interrelationship of these conditions a subject of high priority. Here, we review the salient features of insulin resistance, defined as impaired biological response to the action of insulin. Recent epidemiological studies, evaluating potential associations between colon cancer risk and diabetes mellitus, dietary intake and metabolic factors, and IGF levels in several clinical settings, provide strong support of the insulin resistance-colon cancer hypothesis (without establishing causality). Mechanistically, insulin resistance has been associated with hyperinsulinemia, increased levels of growth factors including IGF-1, and alterations in NF-kappaB and peroxisome proliferator-activated receptor signaling, which may promote colon cancer through their effects on colonocyte kinetics. It is a reasonable expectation that in the not too distant future, critical interventions to the already mapped molecular sequence of events, which link two apparently disparate entities, combined with lifestyle changes could abrogate the development of colon cancer.
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Affiliation(s)
- Despina Komninou
- American Health Foundation, New York Medical College, Valhalla, New York 10595, USA
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9
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Weber MM, Fottner C, Liu SB, Jung MC, Engelhardt D, Baretton GB. Overexpression of the insulin-like growth factor I receptor in human colon carcinomas. Cancer 2002; 95:2086-95. [PMID: 12412161 DOI: 10.1002/cncr.10945] [Citation(s) in RCA: 126] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND High concentrations of insulin-like growth factor (IGF)-I and IGF-II have been demonstrated in human colonic adenocarcinomas and exert mitogenic effects through paracrine/autocrine interactions with the IGF-I receptor (IGF-IR). However, definitive studies of IGF-IR expression in these tissues have not been performed. METHODS To study changes in the levels of the IGF-IR in colorectal carcinoma, we analyzed the expression of IGF-IR in 40 paired samples of normal and carcinomatous colonic tissue by quantitative reverse-transcription-polymerase chain reaction (RT-PCR), immunohistochemistry, and ligand binding. RESULTS As measured by RT-PCR, the IGF-IR mRNA ratio in paired tumor and adjacent normal mucosa was higher than 2.0 in 32 of 40 (80%) samples. The overall mean IGF-IR mRNA level was five-fold higher in tumor versus adjacent normal mucosa (P < 0.0001). Overexpression of IGF-IR in colon carcinomas was confirmed at the protein level by immunohistochemistry and receptor-binding studies. Colon carcinoma cells exhibited a positive staining for IGF-IR in 91% of all tumors (30 of 33) whereas the adjacent normal colonic epithelial cells showed only a very faint or no significant IGF-IR immunoreactivity. Radioligand assays and Scatchard analysis in both tissue types revealed a single class of high-affinity IGF-IR-binding sites with a similar dissociation constant (K(d;) 0.14 +/- 0.02 nmol/L, n = 18). However, specific (125)IGF-I-binding and receptor concentrations were elevated in tumor membranes compared with normal mucosa (33.6 +/- 5.6 vs. 22.7 +/- 3.4 fmol/mg protein, P < 0.05). IGF-I affinity crosslinking and sodium dodecyl sulfate-polyacrylamide gel electrophoresis displayed specific bands corresponding to the size of the normal alpha-subunit of the IGF-IR that were more intense in carcinomatous samples. IGF-II mRNA levels were significantly elevated in colorectal carcinomas (P < 0.0001). The IGF-II mRNA ratio in tumor versus normal tissue was elevated more than twofold in 28 of 40 paired samples and a positive correlation was observed between the overexpression of IGF-II and IGF-IR in the tumors. CONCLUSIONS Our results demonstrate that, in addition to IGF-II, a strong overexpression of IGF-IR is found in the majority of colorectal carcinomas, supporting the hypothesis of an important role of the IGF system in the pathogenesis of colorectal carcinoma.
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Affiliation(s)
- Matthias M Weber
- Klinik II und Poliklinik für Innere Medizin der Universität zu Köln und Lehrstuhl II für Innere Medizin, Köln, Germany.
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Abstract
The growth hormone (GH)-insulin-like growth factor (IGF)-I axis is an important modulator of growth and development, but in addition to their classical role as endocrine hormones, its components also regulate a wide range of biological functions through paracrine and autocrine mechanisms. Their potent mitogenic and anti-apoptotic effects play a critical role in the regulation of rapidly renewing epithelial cell populations such as those found in the colon. Recent evidence suggests an association between inappropriate regulation of the GH-IGF-I axis and the development of colorectal cancer. However, the molecular mechanisms and signalling pathways responsible are only beginning to be unravelled, as are the relative contributions of the endocrine and autocrine or paracrine effects.
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Affiliation(s)
- S A Bustin
- Academic Department of Surgery, Barts and the London, Queen Mary's School of Medicine and Dentistry, University of London, London, UK E1 1BB.
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Playford MP, Bicknell D, Bodmer WF, Macaulay VM. Insulin-like growth factor 1 regulates the location, stability, and transcriptional activity of beta-catenin. Proc Natl Acad Sci U S A 2000; 97:12103-8. [PMID: 11035789 PMCID: PMC17301 DOI: 10.1073/pnas.210394297] [Citation(s) in RCA: 200] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/17/2000] [Indexed: 12/26/2022] Open
Abstract
The insulin-like growth factor (IGF) type 1 receptor is required for growth, transformation, and protection from apoptosis. IGFs can enhance cell migration, which is known to be influenced via regulation of the E-cadherin/beta-catenin complex. We sought to investigate whether IGF-1 modulated the interaction between E-cadherin and beta-catenin in human colorectal cancer cells. We used the C10 cell line, which we established and have previously shown to lack adenomatous polyposis coli, E-cadherin, or beta-catenin mutations. We found that IGF-1 stimulation enhanced tyrosine phosphorylation of two proteins, beta-catenin and insulin-receptor substrate 1, which formed a complex with E-cadherin. Tyrosine phosphorylation of beta-catenin was accompanied by rapid (<1 min) dissociation from E-cadherin at the plasma membrane, followed by relocation to the cellular cytoplasm. IGF-1 also enhanced the stability of beta-catenin protein. Despite this, we observed no enhancement of transcriptional activity in complex with T-cell factor 4 (Tcf-4) in human embryonic kidney 293 cells treated with IGF-1 or insulin alone. IGF-1 did, however, enhance transcriptional activity in combination with lithium chloride, an inhibitor of glycogen synthase kinase 3 beta, which also stabilizes beta-catenin. In conclusion, we have shown that IGF-1 causes tyrosine phosphorylation and stabilization of beta-catenin. These effects may contribute to transformation, cell migration, and a propensity for metastasis in vivo.
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Affiliation(s)
- M P Playford
- IGF Group, Imperial Cancer Research Fund, Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, OX3 9DS, United Kingdom
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Khandwala HM, McCutcheon IE, Flyvbjerg A, Friend KE. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 2000; 21:215-44. [PMID: 10857553 DOI: 10.1210/edrv.21.3.0399] [Citation(s) in RCA: 481] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Several decades of basic and clinical research have demonstrated that there is an association between the insulin-like growth factors (IGFs) and neoplasia. We begin with a brief discussion of the function and regulation of expression of the IGFs, their receptors and the IGF-binding proteins (IGFBPs). A number of investigational interventional strategies targeting the GH or IGFs are then reviewed. Finally, we have assembled the available scientific knowledge about this relationship for each of the major tumor types. The tumors have been grouped together by organ system and for each of the major tumors, various key elements of the relationship between IGFs and tumor growth are discussed. Specifically these include the presence or absence of autocrine IGF-I and IGF-II production; presence or absence of IGF-I and IGF-II receptor expression; the expression and functions of the IGFBPs; in vitro and in vivo experiments involving therapeutic interventions; and available results from clinical trials evaluating the effect of GH/IGF axis down-regulation in various malignancies.
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Affiliation(s)
- H M Khandwala
- Section of Endocrine Neoplasia & Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA
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Fichera E, Liang S, Xu Z, Guo N, Mineo R, Fujita-Yamaguchi Y. A quantitative reverse transcription and polymerase chain reaction assay for human IGF-II allows direct comparison of IGF-II mRNA levels in cancerous breast, bladder, and prostate tissues. Growth Horm IGF Res 2000; 10:61-70. [PMID: 10931743 DOI: 10.1054/ghir.2000.0141] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Previously, we showed by in situ hybridization that insulin-like growth factor (IGF)-II is upregulated in approximately 50% of prostate, breast, and bladder tumours. In this study, a quantitative competitive reverse transcription and polymerase chain reaction (QC RT-PCR) assay was established and used to quantify human IGF-II mRNA levels in cells and tissues. In this QC RT-PCR assay, a competitor IGF-II RNA, prepared from a newly constructed plasmid encoding the human IGF-II sequence with a 110-bp fragment inserted, was added to RNA samples prior to RT-PCR. The human IGF-II specific QC RT-PCR assay has allowed us to readily compare the levels of IGF-II mRNA in human tissues and cultured cells. Consistent with our previous observations by in situ hybridization, IGF-II mRNA was up-regulated in 50% of cancerous breast tissues examined as compared to the matching benign tissues, and IGF-II mRNA levels were higher in bladder tumours than breast and prostate tumours. In summary, we present here quantitative data confirming that a subclass of breast cancer samples has elevated levels of IGF-II transcripts by the new competitive RT-PCR assay.
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Affiliation(s)
- E Fichera
- Department of Molecular Biology, Beckman Research Institute of the City of Hope, Duarte, California, 91010, USA
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Beentjes JA, van Gorkom BA, Sluiter WJ, de Vries EG, Kleibeuker JH, Dullaart RP. One year growth hormone replacement therapy does not alter colonic epithelial cell proliferation in growth hormone deficient adults. Clin Endocrinol (Oxf) 2000; 52:457-62. [PMID: 10762288 DOI: 10.1046/j.1365-2265.2000.00993.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
OBJECTIVE Increased colonic epithelial cell proliferation has been found in various conditions associated with increased risk of colorectal cancer including acromegaly. In a placebo-controlled study we determined the effect of growth hormone (GH) replacement therapy in GH deficient adults on the colonic epithelial proliferation rate. PATIENTS AND DESIGN Sixteen GH deficient adults were randomised to low dose GH therapy (1 U (0.5 mg) subcutaneously per day, n = 5), high dose GH therapy (2 U daily, n = 5) or placebo (n = 6) during 6 months. Thereafter, all patients were treated with 2 U of GH daily during a 6-months open extension period. MEASUREMENTS Plasma Insulin-like growth hormone I (IGF-I) and IGF binding protein 3 (IGF BP3) concentrations were measured using commercial RIA kits. The colonic epithelial proliferation rate, expressed as overall crypt labelling index (LI) using 5-bromo-2'-deoxyuridine (BrdU) immunostaining, was determined at baseline, after 6 months treatment and at the end of the 6 months open extension period. RESULTS IGF-I rose from 8.9 +/- 6.7 to 34.6 +/- 20.0 nmol/l after 6 months in 8 GH treated patients (P < 0.01 from baseline; P < 0.01 from change with placebo). In the extension study, plasma IGF-I was also increased in the patients who previously received placebo (P < 0.02, n = 5). LI was evaluable in 14 biopsies at baseline, in 16 after 6 months and in 14 after 12 months. Overall crypt LI did not change in 8 GH treated patients after 6 months (P > 0.40 from baseline; P > 0.80 from change with placebo). In the extension study, overall crypt LI was also unchanged in those patients who received GH after placebo (n = 5, P > 0.40) and in those who continued GH replacement (n = 9, P > 0.60; P > 0.80 from change in initially placebo treated patients). Separate evaluation of the LI at the basal, mid and luminal portions of the colonic crypts also did not reveal any effect of GH treatment on BrdU labelling. CONCLUSIONS Six to 12 months of GH replacement therapy, aimed to increase plasma IGF-I into the (high) physiological range, does not adversely affect colonic epithelial cell proliferation as a biomarker for the risk of development of colorectal cancer.
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Affiliation(s)
- J A Beentjes
- Department of Internal Medicine, Divisions of; Endocrinology, University Hospital Groningen, The Netherlands
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Zhang W, Thornton WH, MacDonald RS. Insulin-like growth factor-I and II receptor expression in rat colon mucosa are affected by dietary lipid intake. J Nutr 1998; 128:158-65. [PMID: 9446837 DOI: 10.1093/jn/128.2.158] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Epidemiologic data and animal models have demonstrated a correlation between dietary fat composition and colon cancer risk. We have previously found that dietary fat alters cell proliferation in rat colon, which may influence the risk of colon cancer. Growth factors, including insulin-like growth factor (IGF) I and II, regulate the cell cycle in most mammalian tissues. Hence, we measured IGF-I and IGF-II receptor expression in colonocytes from Sprague-Dawley rats fed diets containing either beef tallow (BT) or corn oil (CO) at 12, 30 or 37% of energy for 4 wk. Quantitative reverse transcriptase polymerase chain reaction (RT-PCR) using an internal standard was used to examine the relative expression of both IGF-I and II receptor mRNA in three sections of the colon. The IGF-I receptor protein was also measured by Western immunoblot. In the distal colon, IGF-I receptor gene expression and protein increased significantly as the percentage of CO increased. In both proximal and middle colon, an increased percentage of BT resulted in significantly increased IGF-II receptor expression. In the proximal colon, IGF-II receptor expression decreased with increasing CO concentration, whereas in the middle colon, rats fed 37% CO had significantly higher IGF-II receptor expression than rats fed 12 or 30% CO. IGF-II receptor gene expression in proximal colon decreased with increased fat quantity, independently of fat source, whereas in the middle colon, increased fat quantity resulted in increased IGF-II receptor expression. Thus IGF-I and IGF-II receptor mRNA and IGF-I receptor protein level in colon mucosa were significantly altered by dietary fat source and quantity, thereby suggesting a potential influence of dietary fat on the endocrine regulation of colon cell mitogenesis.
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Affiliation(s)
- W Zhang
- Nutritional Sciences Program, University of Missouri-Columbia, Columbia, MO 65211, USA
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