Assessing tumor progression factors by somatic gene transfer into a mouse model: Bcl-xL promotes islet tumor cell invasion Journal Article
| Authors: | Du, Y. C. N.; Lewis, B. C.; Hanahan, D.; Varmus, H. |
| Article 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 ∼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. © 2007 Du et al. |
| Keywords: | controlled study; unclassified drug; promoter region; disease course; cancer growth; nonhuman; flow cytometry; lymph node metastasis; antigen expression; cell proliferation; protein analysis; animal cell; mouse; phenotype; animals; mice; actin; animal tissue; mus; cell structure; apoptosis; green fluorescent protein; animal experiment; animal model; in vitro study; protein bcl xl; bcl-x protein; cell assay; cancer model; mice, inbred c57bl; carcinogenesis; cell type; gene transfer; transgenic mouse; avian leukosis virus; genetic vectors; mice, transgenic; cancer invasion; molecular mechanics; aves; disease progression; cancer cell; measurement; neoplasm metastasis; retrovirus vector; cell migration; cell movement; insulin; down regulation; rats; neoplasm invasiveness; rattus; cell shape; mice, inbred cba; disease models, animal; pancreas islet cell hyperplasia; tumor vascularization; cadherin; cadherins; cytoskeleton; complementary dna; pancreas islet cell carcinoma; virus vector; gene transfer techniques; somatic cell genetics; islets of langerhans; cadherin 1; myosin va; pancreas adenoma; adenoma, islet cell; subgroup a |
| Journal Title: | PLoS Biology |
| Volume: | 5 |
| Issue: | 10 |
| ISSN: | 1544-9173 |
| Publisher: | Public Library of Science |
| Date Published: | 2007-10-16 |
| Start Page: | 2255 |
| End Page: | 2269 |
| Language: | English |
| DOI: | 10.1371/journal.pbio.0050276 |
| PUBMED: | 17941720 |
| PROVIDER: | scopus |
| PMCID: | PMC2020504 |
| DOI/URL: | |
| Notes: | --- - "Cited By (since 1996): 16" - "Export Date: 17 November 2011" - "CODEN: PBLIB" - "Source: Scopus" |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work