p16(Ink4a) inhibits histologic progression and angiogenic signaling in min colon tumors.
The Ink4a/Arf tumor suppressor locus is widely inactivated in cancer but little is known about the tumor biology of its two products, p16(Ink4a) (p16) and Arf. Both the p16 and Arf promoters are methylated in a significant fraction of human colon carcinomas, implying a functional role. We have demonstrated previously that Ink4a/Arf-null colon tumors display increased growth and vascularity in C57Bl6 mice carrying the Min (multiple intestinal neoplasia) mutation. We present here an analysis in a mixed genetic background of Min colon tumors (N=215) in mice with or without selective deficiencies in p16 or Arf, respectively. Absence of Arf did not significantly alter tumor formation. In contrast, tumors in mice lacking p16 were moderately larger and redder. Histological analysis demonstrated that these tumors contained significantly more pockets of necrosis (p=0.02), a marker of carcinoma in situ; less apoptosis (p=0.02); and higher red blood cell density (p=0.02, 0.006 within vessels). Biochemical analyses demonstrated increased levels of vascular endothelial cell growth factor (VEGF, p<0.01). Exogenous p16 expression in human colon tumor cells in vitro inhibited VEGF production. These results suggest that p16 constrains colon tumor progression, in part through inhibiting angiogenic signaling.
Gibson
Steven L
SL
Department of Medicine, Cell and Molecular Biology Graduate Group, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6140, USA.
Boquoi
Amelie
A
Chen
Tina
T
Sharpless
Norman E
NE
Brensinger
Colleen
C
Enders
Greg H
GH
D000818:Animals; D017209:Apoptosis; D003110:Colonic Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018450:Disease Progression; D019942:Genes, p16; D019073:HT29 Cells; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D009336:Necrosis / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics* / Q000502:physiology
D025803:Tumor Suppressor Protein p14ARF