title: Inhibition of colon tumor progression and angiogenesis by the Ink4a/Arf locus.
abstract: The Ink4a/Arf locus is frequently methylated in colon carcinoma and other common human cancers, suggesting that the locus may play a broad, as yet poorly defined,role inhibiting tumor progression. We examined the influence of the locus in mice with multiple intestinal neoplasia (Min). Colon tumors in 3-month-old Min mice that were null for the Ink4a/Arf locus (-/-) were moderately larger than in Ink4a/Arf-wild-type (+/+) animals (P = 0.032). More strikingly, one-half of the -/- colon tumors were grossly red in color, whereas most of the +/+ tumors were white (P = 0.0025). This color difference remained statistically significant after normalizing for tumor area (P = 0.016). On histological analysis, -/- colon tumors displayed more RBCs near the tumor surface, twice the number of functional vessels, and features of carcinoma in situ not found in +/+ tumors. Biochemical analyses showed that red tumors had higher hemoglobin and vascular endothelial growth factor (VEGF) content than white tumors. Surprisingly, the small intestinal tumor burden was actually lower in -/- animals, and none of these tumors were red, underscoring the importance of tissue context in the function of the locus. These results provide direct evidence that the Ink4a/Arf locus inhibits colon tumor progression. The enhanced vascularity of the -/- tumors is particularly significant in light of the clinical importance of this property in the detection, recurrence, and therapy of colon tumors.
authors.affiliation: Department of Medicine, Gastrointestinal Division, Department of Genetics, and Abramson Cancer Center, Philadelphia, Pennsylvania, USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Gibson
authors.forename: Charlotte Y
authors.initials: CY
authors.lastname: Dai
authors.forename: Han-Woong
authors.initials: HW
authors.lastname: Lee
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Michael S
authors.initials: MS
authors.lastname: Gee
authors.forename: William M F
authors.initials: WM
authors.lastname: Lee
authors.forename: Emma E
authors.initials: EE
authors.lastname: Furth
authors.forename: Colleen
authors.initials: C
authors.lastname: Brensinger
authors.forename: Greg H
authors.initials: GH
authors.lastname: Enders
mesh_terms: D000818:Animals; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000502:physiology; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000378:metabolism; D005260:Female; D019942:Genes, p16 / Q000502:physiology*; D006454:Hemoglobins / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D016228:Endothelial Growth Factors; D006454:Hemoglobins; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D025803:Tumor Suppressor Protein p14ARF; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors