The INK4a/ARF locus encodes two overlapping but non-homologous and independently functioning tumor suppressors, p161NK4a (p16) and p19ARF (ARF). Although deleted frequently in human tumors, the settings, contexts, and regulation of p16 and ARF are uncertain. Recent evidence indicates that the INK4a/ARF locus may influence the growth of tumors of , colon epithelium, which progress rapidly through well- defined, accessible neoplastic stages. Colon carcinoma is the second most common fatal malignancy in humans, and 50% of humans develop colon tumors by age 70. We investigated whether the INK4a/ARF locus suppresses colon neoplasia in the Multiple intestinal neoplasia (MIN) mouse, which is predisposed genetically to colon neoplasia. MIN mice, when crossed with a strain lacking functional p16 and ARF (INK4a/ARF-/- mice), demonstrate a greater mean tumor area (p<0.03) and a striking increase in red coloration of the colon tumors (p<0.00005), consistent with increased intratumor vascularity. We hypothesize that the INK4a/ARF locus inhibits angiogenesis in mouse colon neoplasias. To investigate further, tumors from INK4a/ARF-/- MIN mice will be assayed for content of angiogenic factors, hemoglobin, and endothelial cells. MIN mice will be crossed with INK4a- and ARF-specific knockout mice to determine whether p16, ARF, or both contribute to the anti-angiogenic effect. Implantation of Matrigel impregnated with angiogenic factors into INK4a/ARF-/- and wild type mice will investigate whether the antiangiogenic effect is intrinsic to the endothelial or the neoplastic cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA094831-01
Application #
6451539
Study Section
Special Emphasis Panel (ZRG1-RPHB-3 (20))
Program Officer
Bini, Alessandra M
Project Start
2001-09-29
Project End
Budget Start
2001-09-29
Budget End
2002-09-28
Support Year
1
Fiscal Year
2001
Total Cost
$19,000
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104