Id2 Mediates Tumor Initiation, Proliferation, and Angiogenesis in Rb Mutant Mice

Abstract

The inhibitor of differentiation Id2 is a target of the retinoblastoma (Rb) protein during mouse embryogenesis. In Rb^+/− mice, LOH at the wild-type Rb allele initiates pituitary adenocarcinoma, a tumor derived from embryonic melanotropes. Here we identify a critical role for Id2 in initiation, growth, and angiogenesis of pituitary tumors from Rb^+/− mice. We show that proliferation and differentiation are intimately coupled in Rb^+/− pituitary cells before tumor initiation. In Id2-null pituitaries, premature activation of basic helix-loop-helix-mediated transcription and expression of the cdk inhibitor p27^Kip1 impairs the proliferation of melanotropes and tumor initiation. Without Id2, Rb^+/− mice have fewer early tumor lesions and a markedly decreased proliferation rate of the tumor foci. Expression of Id2 by pituitary tumor cells promotes growth and angiogenesis by functioning as a master regulator of vascular endothelial growth factor (VEGF). In human neuroblastoma, the N-Myc-driven expression of Id2 is sufficient and necessary for expression of VEGF. These results establish that aberrant Id2 activity directs initiation and progression of embryonal cancer.

ACKNOWLEDGMENTS

We are grateful to Danika Johnston for genotyping and survival studies and to John Greaves for help with p27^Kip1 immunostaining. We thank Darrell Yamashiro and Jessica Kandel for critical reading of the manuscript and for helpful discussions.

This work was supported by grants from NIH-NCI to A.L. (R01-CA101644) and A.I. (R01-CA85628).