Inhibition of colon tumor progression and angiogenesis by the Ink4a/Arf locus

Steven L. Gibson, Charlotte Y. Dai, Han Woong Lee, Ronald A. DePinho, Michael S. Gee, William M.F. Lee, Emma E. Furth, Colleen Brensinger, Greg H. Enders

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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 particlarly significant in light of the clinical importance of this property in the detection, recurrence, and therapy of colon tumors.

Original languageEnglish
Pages (from-to)742-746
Number of pages5
JournalCancer Research
Volume63
Issue number4
Publication statusPublished - 2003 Feb 15

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All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Gibson, S. L., Dai, C. Y., Lee, H. W., DePinho, R. A., Gee, M. S., Lee, W. M. F., Furth, E. E., Brensinger, C., & Enders, G. H. (2003). Inhibition of colon tumor progression and angiogenesis by the Ink4a/Arf locus. Cancer Research, 63(4), 742-746.