Effects of rapamycin in the Eker rat model of tuberous sclerosis complex
Effects of rapamycin in the Eker rat model of tuberous sclerosis complex
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DOI：
10.1203/01.pdr.0000147727.78571.07
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发表时间：
2005-01-01
影响因子：
3.6
通讯作者：
Yeung, RS
中科院分区：
文献类型：
--
作者：
Kenerson, H;Dundon, TA;Yeung, RS
多发性硬化症（TSC）在儿科人群中表现为一系列良性肿瘤，影响大脑、心脏、肾脏、肺和皮肤。没有治疗显示出阻止疾病进展或预防其发作。TSC的发病机制源于两种TSC基因之一TSC 1和TSC 2的失活。这些基因的一个关键功能是调节哺乳动物雷帕霉素靶蛋白（mTOR）通路，以响应细胞能量和营养素以及生长因子的可用性。因此，TSC相关肿瘤表现出mTOR及其效应物的不受控制的活化。先前的研究表明，一种特异性mTOR抑制剂雷帕霉素可有效下调携带种系Tsc 2突变的Eker大鼠肾肿瘤中mTOR的活性。使用这个模型，我们研究了雷帕霉素对垂体和肾肿瘤的影响。我们观察到，垂体瘤大鼠的生存期明显短于那些没有垂体病理。雷帕霉素治疗有效地改善了他们的临床状态，延长了他们的生存期。雷帕霉素还导致Tsc 2相关肾肿瘤的大小显著减小。在这两种病理类型中，肿瘤反应伴随着核糖体S6激酶活性的下调、细胞大小的减小和细胞凋亡的诱导。在长期治疗后，在一小部分病变中发现了耐药性的证据。当雷帕霉素在发病前给予，随后的宏观肾肿瘤的发展减少，但微观前驱病变的数量没有影响被发现。我们得出结论，雷帕霉素敏感的mTOR活性是至关重要的肿瘤进展的Eker大鼠模型，但雷帕霉素是不可能根除所有疾病的耐药性的发展的结果。我们的数据还表明了雷帕霉素不敏感途径在肿瘤发生过程中的作用。
Tuberous sclerosis complex (TSC) presents in the pediatric population with a constellation of benign tumors that affect the brain, heart, kidney, lung, and skin. No therapy has been shown to halt disease progression or to prevent its onset. The pathogenesis of TSC stems from the inactivation of one of the two TSC genes, TSC1 and TSC2. A key function of these genes is to regulate the mammalian target of rapamycin (mTOR) pathway in response to cellular energy and nutrient and growth factor availability. Consequently, TSC-related tumors exhibit uncontrolled activation of mTOR and its effectors. Previous work has shown that a specific mTOR inhibitor, rapamycin, effectively down-regulated mTOR activity in renal tumors of Eker rats that carry a germline Tsc2 mutation. Using this model, we investigated the effects of rapamycin on pituitary and renal tumors. We observed that rats with pituitary tumors had significantly shorter survival than those without pituitary pathology. Treatment with rapamycin effectively improved their clinical state and prolonged their survival. Rapamycin also resulted in a significant decrease in the size of the Tsc2-related renal tumors. In both types of pathology, tumor response was accompanied by down-regulation of ribosomal S6 kinase activity, reduction in cell size, and induction of apoptosis. Evidence for drug resistance was found in a small percentage of lesions after prolonged therapy. When rapamycin was given before onset of disease, subsequent development of macroscopic renal tumors was reduced, but no effect on the number of microscopic precursor lesions was found. We conclude that rapamycin-sensitive mTOR activity was critical to tumor progression in the Eker rat model, but rapamycin is unlikely to eradicate all disease as a result of the development of drug resistance. Our data also suggest the role of a rapamycin-insensitive pathway during tumor initiation.