Inhibition of colon tumor progression and angiogenesis by the Ink4a/Arf locus.
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.
Gibson
Steven L
SL
Department of Medicine, Gastrointestinal Division, Department of Genetics, and Abramson Cancer Center, Philadelphia, Pennsylvania, USA.
Dai
Charlotte Y
CY
Lee
Han-Woong
HW
DePinho
Ronald A
RA
Gee
Michael S
MS
Lee
William M F
WM
Furth
Emma E
EE
Brensinger
Colleen
C
Enders
Greg H
GH
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
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