title: Repression of malignant tumor progression upon pharmacologic IGF1R blockade in a mouse model of insulinoma.
abstract: NVP-AEW541, a specific ATP-competitive inhibitor of the insulin-like growth factor-1 receptor (IGF1R) 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 β-cell carcinogenesis. In addition, we have tested NVP-AEW541 in Rip1Tag2;RipIGF1R double-transgenic mice which show accelerated tumor growth and increased tumor malignancy compared with Rip1Tag2 single-transgenic mice. Previously, we have shown that high levels of IGF-2, a high-affinity ligand for IGF1R, are required for Rip1Tag2 tumor cell survival and tumor growth. Unexpectedly, treatment of Rip1Tag2 mice with NVP-AEW541 in prevention and intervention trials neither did affect tumor growth nor tumor cell proliferation and apoptosis. Yet, it significantly repressed progression to tumor malignancy, that is, 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-2 and of the IGF-2-binding form of insulin receptor (IR-A) in tumor cells suggests a compensatory role of IR-A upon IGF1R blockade. The results indicate that inhibition of IGF1R alone is not sufficient to efficiently block insulinoma growth and imply an overlapping role of IGF1R and insulin receptor in executing mitogenic and survival stimuli elicited by IGF-2. The reduction of tumor invasion upon IGF1R blockade on the other hand indicates a critical function of IGF1R signaling for the acquisition of a malignant phenotype.
authors.affiliation: Institute of Biochemistry and Genetics, Department of Biomedicine, University of Basel, Mattenstrasse 28, Basel 4058, Switzerland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Zumsteg
authors.forename: Christoph
authors.initials: C
authors.lastname: Caviezel
authors.forename: Laura
authors.initials: L
authors.lastname: Pisarsky
authors.forename: Karin
authors.initials: K
authors.lastname: Strittmatter
authors.forename: Carlos
authors.initials: C
authors.lastname: García-Echeverría
authors.forename: Francesco
authors.initials: F
authors.lastname: Hofmann
authors.forename: Gerhard
authors.initials: G
authors.lastname: Christofori
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015151:Immunoblotting; D020287:In Situ Nick-End Labeling; D007340:Insulinoma / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000517:prevention & control*; D010766:Phosphorylation / Q000187:drug effects; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics
chemical_list: C501177:NVP-AEW541; D011743:Pyrimidines; D011758:Pyrroles; D017526:Receptor, IGF Type 1