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Repression of malignant tumor progression upon pharmacological IGF-1R blockade in a mouse model of insulinoma

Zumsteg, Adrian and Strittmatter, Karin and Caviezel, Christoph and Garcia-Echeverria, Carlos and Hofmann, Francesco and Christofori, Gerhard (2012) Repression of malignant tumor progression upon pharmacological IGF-1R blockade in a mouse model of insulinoma. Molecular Cancer Research, 10 (6). pp. 800-809. ISSN 1541-7786

Abstract

NVP-AEW541, a specific inhibitor of the insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase, has been reported to interfere with tumor growth in various tumor transplantation models. We have assessed the efficacy of NVP-AEW541 in repressing tumor growth and tumor progression in the Rip1Tag2 transgenic mouse model of pancreatic beta-cell carcinogenesis. In addition, we have tested NVP-AEW541 in Rip1Tag2;RipIGF-1R double-transgenic mice which show accelerated tumor growth and increased tumor malignancy compared to Rip1Tag2 single-transgenic mice. Previously, we have shown that high levels of IGF-II, a high-affinity ligand for IGF-1R, are required for Rip1Tag2 tumor cell survival and tumor growth. Unexpectedly, treatment of Rip1Tag2 mice with NVP-AEW541 in prevention and intervention trials did neither affect tumor growth nor tumor cell proliferation and apoptosis. Yet, it significantly repressed progression to tumor malignancy, i.e. the rate of the transition from differentiated adenoma to invasive carcinoma. Treatment of Rip1Tag2;RipIGF1R double-transgenic mice resulted in moderately reduced tumor volumes and increased rates of tumor cell apoptosis. Sustained expression of IGF-II and of the IGF-II-binding form of insulin receptor (IR-A) in tumor cells suggests a compensatory role of IR-A upon IGF-1R blockade. The results indicate that inhibition of IGF-1R alone is not sufficient to efficiently block insulinoma growth and imply an overlapping role of IGF-1R and insulin receptor in executing mitogenic and survival stimuli elicited by IGF-II. The reduction of tumor invasion upon IGF-1R blockade on the other hand indicates a critical function of IGF-1R signaling for the acquisition of a malignant phenotype.

Item Type: Article
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Additional Information: author cannot archive publisher's version
Keywords: cancer, IGF, IGF receptor, metastasis, mouse models, therapy
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/6137

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