Claudio P P, Stiegler P, Howard C M, Bellan C, Minimo C, Tosi G M, Rak J, Kovatich A, De Fazio P, Micheli P, Caputi M, Leoncini L, Kerbel R, Giordano G G, Giordano A
Department of Pathology, Anatomy and Cell Biology, Jefferson Medical College, Philadelphia, Pennsylvania 19107, USA.
Cancer Res. 2001 Jan 15;61(2):462-8.
Angiogenesis is an essential step in the progression of tumor formation and development. The switch to an angiogenetic phenotype can occur as a distinct step before progression to a neoplastic phenotype and is linked to genetic changes such as mutations in key cell cycle regulatory genes. The pathogenesis of the angiogenetic phenotype may involve the inactivation of tumor suppressor genes such as the "guardian of the genome," p53, and the cyclin-dependent kinase inhibitor p16. Retinoblastoma family member RB2/p130 encodes a cell cycle regulatory protein and has been found mutated in different tumor types. Overexpression of RB2/p130 not only suppresses tumor formation in nude mice but also causes regression of established tumor grafts, suggesting that RB2/p130 may modulate the angiogenetic balance. We found that induction of RB2/p130 expression using a tetracycline-regulated gene expression system as well as retroviral and adenoviral-mediated gene delivery inhibited angiogenesis in vivo. This correlated with pRb2/p130-mediated down-regulation of vascular endothelial growth factor protein expression both in vitro and in vivo.
血管生成是肿瘤形成和发展过程中的一个重要步骤。向血管生成表型的转变可能发生在进展为肿瘤表型之前的一个独特阶段，并且与诸如关键细胞周期调控基因突变等遗传变化有关。血管生成表型的发病机制可能涉及肿瘤抑制基因的失活，如“基因组守护者”p53和细胞周期蛋白依赖性激酶抑制剂p16。视网膜母细胞瘤家族成员RB2/p130编码一种细胞周期调控蛋白，并且已在不同肿瘤类型中发现其发生突变。RB2/p130的过表达不仅抑制裸鼠中的肿瘤形成，还导致已建立的肿瘤移植瘤消退，这表明RB2/p130可能调节血管生成平衡。我们发现，使用四环素调控基因表达系统以及逆转录病毒和腺病毒介导的基因传递来诱导RB2/p130表达可在体内抑制血管生成。这与pRb2/p130在体外和体内介导的血管内皮生长因子蛋白表达下调相关。
