Mak Baldwin C, Yeung Raymond S
Department of Surgery, University of Washington, Seattle, Washington 98195, USA.
Cancer Invest. 2004;22(4):588-603. doi: 10.1081/cnv-200027144.
The study of hereditary tumor syndromes has laid a solid foundation toward understanding the genetic basis of cancer. One of the latest examples comes from the study of tuberous sclerosis complex (TSC). As a member of the phakomatoses, TSC is characterized by the appearance of benign tumors, most notably in the central nervous system, kidney, heart, lung, and skin. While classically described as "hamartomas," the pathology of the lesions has features suggestive of abnormal cellular proliferation, size, differentiation, and migration. Occasionally, tumors progress to become malignant (i.e., renal cell carcinoma). The genetic basis of this disease has been attributed to mutations in one of two unlinked genes, TSC1 and TSC2. Cells undergo bi-allelic inactivation of either gene to give rise to tumors in a classic tumor suppressor "two-hit" paradigm. The functions of the TSC1 and TSC2 gene products, hamartin and tuberin, respectively, have remained ill defined until recently. Genetic, biochemical, and biologic analyses have highlighted their role as negative regulators of the mTOR signaling pathway. Tuberin, serving as a substrate of AKT and AMPK, mediates mTOR activity by coordinating inputs from growth factors and energy availability in the control of cell growth, proliferation, and survival. Emerging evidence also suggests that the TSC 1/2 complex may play a role in modulating the activity of beta-catenin and TGFbeta. These findings provide novel functional links between the TSC genes and other tumor suppressors responsible for Cowden's disease (PTEN), Peutz-Jeghers syndrome (LKB1), and familial polyposis (APC). Common sporadic cancers such as prostate, lung, colon, endometrium, and breast have ties to these genes, highlighting the potential role of the TSC proteins in human cancers. Rapamycin, a specific mTOR inhibitor, has potent antitumoral activities in preclinical models of TSC and is currently undergoing phase I/II clinical studies.
遗传性肿瘤综合征的研究为理解癌症的遗传基础奠定了坚实基础。最新的例子之一来自结节性硬化症（TSC）的研究。作为 phakomatoses 的一员，TSC 的特征是出现良性肿瘤，最显著的是在中枢神经系统、肾脏、心脏、肺和皮肤中。虽然传统上被描述为“错构瘤”，但病变的病理学具有提示异常细胞增殖、大小、分化和迁移的特征。偶尔，肿瘤会进展为恶性（即肾细胞癌）。这种疾病的遗传基础归因于两个不连锁基因 TSC1 和 TSC2 中的一个发生突变。细胞经历这两个基因中任何一个的双等位基因失活，以经典的肿瘤抑制“两次打击”模式产生肿瘤。直到最近，TSC1 和 TSC2 基因产物（分别为错构瘤蛋白和结节蛋白）的功能仍不清楚。遗传、生化和生物学分析突出了它们作为 mTOR 信号通路负调节因子的作用。结节蛋白作为 AKT 和 AMPK 的底物，通过协调生长因子和能量可用性的输入来介导 mTOR 活性，从而控制细胞生长、增殖和存活。新出现的证据还表明，TSC 1/2 复合物可能在调节 β-连环蛋白和 TGFβ 的活性中发挥作用。这些发现提供了 TSC 基因与其他负责考登病（PTEN）、黑斑息肉综合征（LKB1）和家族性息肉病（APC）的肿瘤抑制因子之间的新功能联系。常见的散发性癌症如前列腺癌、肺癌、结肠癌、子宫内膜癌和乳腺癌与这些基因有关，突出了 TSC 蛋白在人类癌症中的潜在作用。雷帕霉素是一种特异性 mTOR 抑制剂，在 TSC 的临床前模型中具有强大的抗肿瘤活性，目前正在进行 I/II 期临床研究。
