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

Department of Pediatrics,¹ Department of Pathology,² Institute for Cancer Genetics,³ Department of Neurology, College of Physicians and Surgeons of Columbia University, New York, New York,⁶ Department of Biochemistry, Fukui Medical University, Fukui Japan,⁴ Lombardi Cancer Center, Department of Oncology, Georgetown University, Washington, DC⁵

Received 30 August 2004/ Returned for modification 9 November 2004/ Accepted 18 January 2005

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.

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