title: Polymorphic genetic control of tumor invasion in a mouse model of pancreatic neuroendocrine carcinogenesis.
abstract: Cancer is a disease subject to both genetic and environmental influences. In this study, we used the RIP1-Tag2 (RT2) mouse model of islet cell carcinogenesis to identify a genetic locus that influences tumor progression to an invasive growth state. RT2 mice inbred into the C57BL/6 (B6) background develop both noninvasive pancreatic neuroendocrine tumors (PNET) and invasive carcinomas with varying degrees of aggressiveness. In contrast, RT2 mice inbred into the C3HeB/Fe (C3H) background are comparatively resistant to the development of invasive tumors, as are RT2 C3HB6(F1) hybrid mice. Using linkage analysis, we identified a 13-Mb locus on mouse chromosome 17 with significant linkage to the development of highly invasive PNETs. A gene residing in this locus, the anaplastic lymphoma kinase (Alk), was expressed at significantly lower levels in PNETs from invasion-resistant C3H mice compared with invasion-susceptible B6 mice, and pharmacological inhibition of Alk led to reduced tumor invasiveness in RT2 B6 mice. Collectively, our results demonstrate that tumor invasion is subject to polymorphic genetic control and identify Alk as a genetic modifier of invasive tumor growth.
authors.affiliation: Department of Biochemistry and Biophysics, Diabetes Center, and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
authors.forename: Matthew G H
authors.initials: MG
authors.lastname: Chun
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Chiu
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
authors.forename: Douglas
authors.initials: D
authors.lastname: Hanahan
mesh_terms: D007516:Adenoma, Islet Cell / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D033481:Chromosomes, Mammalian; D008040:Genetic Linkage; D056426:Genetic Loci; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D011110:Polymorphism, Genetic; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D020794:Receptor Protein-Tyrosine Kinases
chemical_list: C516714:NVP-TAE684; D011743:Pyrimidines; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases