Elevated levels of IGF-1 receptor convey invasive and metastatic capability in a mouse model of pancreatic islet tumorigenesis.
In a prototypical model of multistage tumorigenesis involving pancreatic islets in RIP1-Tag2 transgenic mice, activation of insulin-like growth factor II (IGF-II) was previously shown to serve as a survival factor that inhibited apoptosis. Now IGF-1R, the receptor tyrosine kinase for IGF-II, has been found to be variably upregulated, first uniformly in dysplastic and angiogenic progenitors and then focally at the margins and in invasive regions of carcinomas. When the levels of IGF-1R were forcibly elevated throughout islet tumorigenesis, progression was accelerated at all stages in the pathway, although apoptosis was not differentially suppressed. Notably, encapsulated tumors were absent; instead, invasive carcinomas with downregulated E-cadherin were prevalent, and the majority of mice had local lymph node metastasis.
Lopez
Theresa
T
Department of Biochemistry & Biophysics and the UCSF Diabetes and Comprehensive Cancer Centers, University of California, San Francisco, 94143, USA.
Hanahan
Douglas
D
D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001973:Bromodeoxyuridine; D015820:Cadherins / Q000378:metabolism; D018273:Carcinoma, Islet Cell / Q000378:metabolism* / Q000556:secondary; D002455:Cell Division; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D018450:Disease Progression; D005434:Flow Cytometry; D006801:Humans; D020287:In Situ Nick-End Labeling; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D017526:Receptor, IGF Type 1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation; D001617:beta-Glucosidase / Q000235:genetics / Q000378:metabolism
D015820:Cadherins; D004268:DNA-Binding Proteins; C489892:IGHMBP2 protein, human; C081225:Ighmbp2 protein, mouse; D014157:Transcription Factors; D017526:Receptor, IGF Type 1; D001617:beta-Glucosidase; D001973:Bromodeoxyuridine