title: Assessing tumor progression factors by somatic gene transfer into a mouse model: Bcl-xL promotes islet tumor cell invasion.
abstract: Tumors develop through multiple stages, implicating multiple effectors, but the tools to assess how candidate genes contribute to stepwise tumor progression have been limited. We have developed a novel system in which progression of phenotypes in a mouse model of pancreatic islet cell tumorigenesis can be used to measure the effects of genes introduced by cell-type-specific infection with retroviral vectors. In this system, bitransgenic mice, in which the rat insulin promoter (RIP) drives expression of both the SV40 T antigen (RIP-Tag) and the receptor for subgroup A avian leukosis virus (RIP-tva), are infected with avian viral vectors carrying cDNAs encoding candidate progression factors. Like RIP-Tag mice, RIP-Tag; RIP-tva bitransgenic mice develop isolated carcinomas by approximately 14 wk of age, after progression through well-defined stages that are similar to aspects of human tumor progression, including hyperplasia, angiogenesis, adenoma, and invasive carcinoma. When avian retroviral vectors carrying a green fluorescent protein marker were introduced into RIP-Tag; RIP-tva mice by intra-cardiac injection at the hyperplastic or early dysplastic stage of tumorigenesis, approximately 20% of the TVA-positive cells were infected and expressed green fluorescent proteins as measured by flow cytometry. Similar infection with vectors carrying cDNA encoding either of two progression factors, a dominant-negative version of cadherin 1 (dnE-cad) or Bcl-xL, accelerated the formation of islet tumors with invasive properties and pancreatic lymph node metastasis. To begin studying the mechanism by which Bcl-xL, an anti-apoptotic protein, promotes invasion and metastasis, RIP-Tag; RIP-tva pancreatic islet tumor cells were infected in vitro with RCASBP-Bcl-xL. Although no changes were observed in rates of proliferation or apoptosis, Bcl-xL altered cell morphology, remodeled the actin cytoskeleton, and down-regulated cadherin 1; it also induced cell migration and invasion, as evaluated using two-chamber transwell assays. In addition, myosin Va was identified as a novel Bcl-xL-interacting protein that might mediate the effects of Bcl-xL on tumor cell migration and invasion.
authors.affiliation: Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. duy@mskcc.org
authors.forename: Yi-Chieh Nancy
authors.initials: YC
authors.lastname: Du
authors.forename: Brian C
authors.initials: BC
authors.lastname: Lewis
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
authors.forename: Harold
authors.initials: H
authors.lastname: Varmus
mesh_terms: D007516:Adenoma, Islet Cell / Q000378:metabolism / Q000473:pathology; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D048430:Cell Shape; D004195:Disease Models, Animal; D018450:Disease Progression; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D051381:Rats; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D015820:Cadherins; D051020:bcl-X Protein