Department of Urology, New York University School of Medicine, Veterans Affairs Medical Center in Manhattan, New York, NY 10010, USA.
Cancer Res. 2009 Dec 15;69(24):9413-21. doi: 10.1158/0008-5472.CAN-09-2158.
Defects in pRb tumor suppressor pathway occur in approximately 50% of the deadly muscle-invasive urothelial carcinomas in humans and urothelial carcinoma is the most prevalent epithelial cancer in long-term survivors of hereditary retinoblastomas caused by loss-of-function RB1 mutations. Here, we show that conditional inactivation of both RB1 alleles in mouse urothelium failed to accelerate urothelial proliferation. Instead, it profoundly activated the p53 pathway, leading to extensive apoptosis, and selectively induced pRb family member p107. Thus, pRb loss triggered multiple fail-safe mechanisms whereby urothelial cells evade tumorigenesis. Additional loss of p53 in pRb-deficient urothelial cells removed these p53-dependent tumor barriers, resulting in late-onset hyperplasia, umbrella cell nuclear atypia, and rare-occurring low-grade, superficial papillary bladder tumors, without eliciting invasive carcinomas. Importantly, mice deficient in both pRb and p53, but not those deficient in either protein alone, were highly susceptible to subthreshold carcinogen exposure and developed invasive urothelial carcinomas that strongly resembled the human counterparts. The invasive lesions had a marked reduction of p107 but not p130 of the pRb family. Our data provide compelling evidence, indicating that urothelium, one of the slowest cycling epithelia, is remarkably resistant to transformation by pRb or p53 deficiency; that concurrent loss of these two tumor suppressors is necessary but insufficient to initiate urothelial tumorigenesis along the invasive pathway; that p107 may play a critical role in suppressing invasive urothelial tumor formation; and that replacing/restoring the function of pRb, p107, or p53 could be explored as a potential therapeutic strategy to block urothelial tumor progression.
RB1 抑癌基因功能丧失导致的遗传性视网膜母细胞瘤是导致长期幸存者罹患膀胱癌的主要原因，在这些膀胱癌中 pRb 肿瘤抑制通路缺陷的发生率约为 50%。在此，我们发现小鼠尿路上皮中 RB1 等位基因的条件性失活并不能加速尿路上皮的增殖。相反，它会强烈激活 p53 通路，导致广泛的细胞凋亡，并选择性地诱导 pRb 家族成员 p107。因此，pRb 的缺失触发了多种“失效安全”机制，使尿路上皮细胞能够逃避肿瘤发生。pRb 缺陷的尿路上皮细胞中 p53 的进一步缺失消除了这些依赖于 p53 的肿瘤障碍，导致晚期出现的过度增生、伞状细胞核异型性和罕见的低级别、浅表性乳头状膀胱癌，而不会引发浸润性癌。重要的是，同时缺乏 pRb 和 p53 的小鼠（而非单独缺乏这两种蛋白的小鼠）对亚阈值致癌剂暴露高度敏感，会发展为侵袭性的尿路上皮癌，这些肿瘤与人类膀胱癌具有很强的相似性。侵袭性病变中 pRb 家族的 p107 明显减少，但 p130 没有减少。我们的数据提供了令人信服的证据，表明尿路上皮是增殖最慢的上皮之一，对 pRb 或 p53 缺失导致的转化具有显著的抗性；同时缺失这两种肿瘤抑制因子是必要的，但不足以启动沿侵袭途径发生的尿路上皮肿瘤发生；p107 可能在抑制侵袭性尿路上皮肿瘤形成中发挥关键作用；并且恢复 pRb、p107 或 p53 的功能可能是阻止尿路上皮肿瘤进展的潜在治疗策略。
