Role of insulin-like growth factor-1R system in colorectal carcinogenesis

Donovan, Erin A.; Kummar, Shivaani

doi:10.1016/j.critrevonc.2007.09.003

Cited by 55 publications

(33 citation statements)

References 51 publications

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“…In experimental models of CRC an autocrine release was demonstrated in all IGF system components including IGF-1, suggesting that the IGF signalling pathway plays a role in colorectal carcinogenesis (1,45). The number of IGFs produced reflects the type of epithelial cells and the type of cellular growth (45).…”

Section: Discussionmentioning

confidence: 99%

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Differential expression of IGF-1 mRNA isoforms in colorectal carcinoma and normal colon tissue

et al. 2012

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Abstract. The insulin-like growth factor (IGF)-1 gene consists of 6 exons resulting in the expression of 6 variant forms of mRNA (IA, IB, IC, IIA, IIB and IIC) due to an alternative splicing. The mechanisms of IGF-1 gene splicing and the role of local expression manifested by IGF-1 mRNA variants in colorectal carcinoma (CRC) have not been extensively investigated. Therefore, the aim of our study was to analyse the expression of IGF-1 mRNA isoforms [A, B, C, P1 (class I) and P2 (class II)], as well as the protein expression in CRC and control samples isolated from 28 patients. The expression of Ki-67 was also analysed and clinical data were obtained. For this purpose, we used quantitative real-time PCR (qPCR) and immunocytochemistry. The expression of mRNAs coding for all splicing isoforms of IGF-1 was observed in every tissue sample studied, with a significantly lower expression noted in the CRC as compared to the control samples. The cytoplasmic expression of IGF-1 protein was found in 50% of the CRC and in ~40% of the non-tumor tissues; however, no significant quantitative inter-group differences were observed. The expression of the IGF-1 gene in the 2 groups of tissues was controlled by the P1 and P2 promoters in a similar manner. No significant differences were detected in the expression of the IGF-1 A and B isoforms; however, their expression was significantly higher compared to that of isoform C. No significant differences were observed between the expression of Ki-67 mRNA in the CRC and control tissue even though the expression of the Ki-67 protein was higher in the CRC compared to the control samples. Ki-67 protein expression was associated with the macroscopic and microscopic aspects of CRC. A significant positive correlation was found between the local production of total mRNA and isoform A and the expression of Ki-67 mRNA, although only in the non-tumor tissues. In CRC samples, the local expression of the total IGF-1 mRNA and all splicing isoforms of IGF-1 mRNA decreased as compared to the normal colon tissues, although however, with conservation of both gene promoter activities and with the continued principal splicing IGF-1 mRNA isoforms.

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Section: Discussionmentioning

confidence: 99%

“…The role of the insulin-like growth factor (IGF) system in carcinogenesis, including colorectal cancer (CRC) has been extensively described in the literature (1)(2)(3)(4). The local overproduction of IGF-1 and IGF-2 has been found in 'endocrine-dependent' cancers (breast and prostate) and other tumors (lung, colon).…”

Section: Introductionmentioning

confidence: 99%

Differential expression of IGF-1 mRNA isoforms in colorectal carcinoma and normal colon tissue

et al. 2012

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“…In particular, IGF-IR is the most promising target, and many IGF-IR-targeting agents have been developed (19)(20)(21). Some of these agents are in ongoing clinical trials, and a few positive data have been obtained (38,39).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, IGF-IR is the most attractive target, and many IGF-IR-targeting strategies, including monoclonal antibodies and small-molecule tyrosine kinase inhibitors, have been developed (19)(20)(21). In contrast, few reports have been published on IGF-ligand-targeting strategies (22).…”

Section: Introductionmentioning

confidence: 99%

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Matsunaka

Miyamoto

Shitara

et al. 2010

Molecular Cancer Therapeutics

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Insulin-like growth factors (IGF-I and IGF-II) play important roles in intestinal tumorigenesis. To investigate the effectiveness of IGF-targeting strategies, we conducted an in vivo study using anti-mouse neutralizing antibodies IGF-I (KM3168) and IGF-II (KM1468). Six-and 10-week-old Apc +/− mice were given KM3168 and/or KM1468 i.p. at two doses (0.01 or 0.1 μg/g weight) once or twice weekly for 4 weeks. To clarify the source of IGFs in vivo, we evaluated the expression levels of IGFs in the liver, normal small intestine, and polyps of the small intestine of Apc +/− mice. The phosphorylation status of IGF signalrelated molecules was examined using immunostaining to understand the mechanism underlying the effects of IGF-neutralizing antibody. The plasma half-life was 168 for KM3168 and 85 hours for KM1468. In two lineages of Apc +/− mice (Apc 1309 and Apc Min/+ ), a low dose (0.01 μg/g weight) of KM3168 and KM1468 significantly reduced the number of polyps when given once and twice weekly, respectively. Combined administration of the effective dose of each antibody had an additive effect. The liver was the main source of IGF-I, whereas the polyps of the small intestine and normal small intestine were the main source of IGF-II. IGF-neutralizing antibodies decreased the phosphorylation of IGF type 1 receptor and inhibited the signal transduction of the Akt pathway. These results suggest that IGF-I and IGF-II play important roles in polyp formation in Apc +/− mice and that specific antibodies to IGF-I and IGF-II may be promising antitumor agents. Mol Cancer Ther; 9(2); 419-28. ©2010 AACR.

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“…[31][32][33] Insulin growth factor-1R is currently being tested as a new therapeutic target in clinical trials, in combination with other targeted agents and cytotoxics.…”

Section: Genetic Alterations In Tumor Tissuesmentioning

confidence: 99%

Pharmacogenetics and biomarkers in colorectal cancer

2009

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The prognosis of patients with colorectal cancer (CRC) is affected by various factors at the time of diagnosis, including location of the tumor, gender, age and overall performance status of the patient. Predicting response and limiting drug-induced toxicity for patients with CRC are also critical. Interpatient differences in tumor response and drug toxicity are common during chemotherapy. Genomic variability of key metabolic enzyme complexes, drug targets and drug transport molecules are important contributing factors. At present, there is inconsistent and rather low use of pharmacogenetic testing in the clinical setting because of a lack of robust evidence or of resources. Patients' selection and tailored treatments by the introduction of genetic testing will hopefully allow better response prediction and limit drug-induced toxicity leading to improved patient outcomes in the most cost-effective way. Here, we review the main genetic alterations observed in familial and sporadic CRC and their associations with the metabolism, efficacy and toxicities of drugs used in this disease.

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Role of insulin-like growth factor-1R system in colorectal carcinogenesis

Cited by 55 publications

References 51 publications

Differential expression of IGF-1 mRNA isoforms in colorectal carcinoma and normal colon tissue

Differential expression of IGF-1 mRNA isoforms in colorectal carcinoma and normal colon tissue

Ligand-Specific Antibodies to Insulin-Like Growth Factors Suppress Intestinal Polyp Formation in Apc+/− Mice

Pharmacogenetics and biomarkers in colorectal cancer

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