Real-time monitoring of tumorigenesis, dissemination, & drug response in a preclinical model of lymphangioleiomyomatosis/tuberous sclerosis complex.
Real-time monitoring of tumorigenesis, dissemination, & drug response in a preclinical model of lymphangioleiomyomatosis/tuberous sclerosis complex.
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DOI：
10.1371/journal.pone.0038589
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Frangioni JV
中科院分区：
文献类型：
--
作者：
Liu F;Lunsford EP;Tong J;Ashitate Y;Gibbs SL;Yu J;Choi HS;Henske EP;Frangioni JV
TSC 2缺陷细胞可在肺、肾和其他器官中增殖，引起破坏性进行性多系统疾病，如淋巴管平滑肌瘤病（LAM）和结节性硬化症（TSC）。利用LAM患者来源的细胞的临床前模型一直难以建立。我们建立了一种新的动物模型系统，以研究TSC/LAM发病和肿瘤发生的分子机制，并为药物测试提供平台。来自LAM患者血管平滑肌脂肪瘤的TSC 2缺陷型人类细胞被设计为共表达钠碘同向转运体（NIS）和绿色荧光蛋白（GFP）。将细胞经实质内、静脉内或肝内接种到无胸腺NCr nu/nu小鼠中，并使用单光子发射计算机断层扫描（SPECT）和计算机断层扫描（CT）对细胞进行跟踪和定量。令人惊讶的是，TSC 2-缺陷细胞的肠内给药导致快速扩散到全身淋巴结盆，肺组织病理学变化与LAM一致。雌激素被认为是允许肿瘤生长和传播。雷帕霉素抑制肿瘤生长，但在药物治疗停止后肿瘤重新生长。我们产生了同质NIS/GFP共表达TSC 2缺陷，患者来源的细胞，可以增殖和迁移后，体内腹膜内滴注。虽然我们所描述的动物模型有一定的局限性，我们表明，从TSC 2缺陷细胞形成的全身性肿瘤可以监测和定量随时间的推移，使用SPECT/CT非侵入性，从而提供了一个非常需要的模型系统，在体内药物测试和TSC 2缺陷细胞及其相关的临床综合征的机制研究。
TSC2-deficient cells can proliferate in the lungs, kidneys, and other organs causing devastating progressive multisystem disorders such as lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC). Preclinical models utilizing LAM patient-derived cells have been difficult to establish. We developed a novel animal model system to study the molecular mechanisms of TSC/LAM pathogenesis and tumorigenesis and provide a platform for drug testing. TSC2-deficient human cells, derived from the angiomyolipoma of a LAM patient, were engineered to co-express both sodium-iodide symporter (NIS) and green fluorescent protein (GFP). Cells were inoculated intraparenchymally, intravenously, or intratracheally into athymic NCr nu/nu mice and cells were tracked and quantified using single photon emission computed tomography (SPECT) and computed tomography (CT). Surprisingly, TSC2-deficient cells administered intratracheally resulted in rapid dissemination to lymph node basins throughout the body, and histopathological changes in the lung consistent with LAM. Estrogen was found to be permissive for tumor growth and dissemination. Rapamycin inhibited tumor growth, but tumors regrew after the drug treatment was withdrawn. We generated homogeneous NIS/GFP co-expressing TSC2-deficient, patient-derived cells that can proliferate and migrate in vivo after intratracheal instillation. Although the animal model we describe has some limitations, we demonstrate that systemic tumors formed from TSC2-deficient cells can be monitored and quantified noninvasively over time using SPECT/CT, thus providing a much needed model system for in vivo drug testing and mechanistic studies of TSC2-deficient cells and their related clinical syndromes.
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影响因子：
158.5
作者：
Krueger, Darcy A.;Care, Marguerite M.;Franz, David Neal
通讯作者：
Franz, David Neal
影响因子：
3.6
作者：
Knudson, AG
通讯作者：
Knudson, AG
影响因子：
3.7
作者：
Lesma E;Grande V;Ancona S;Carelli S;Di Giulio AM;Gorio A
通讯作者：
Gorio A
DOI：
10.1073/pnas.011528498
发表时间：
2001-01-02
影响因子：
11.1
作者：
Aoki, M;Blazek, E;Vogt, PK
通讯作者：
Vogt, PK
影响因子：
10.5
作者：
Fingar, DC;Salama, S;Blenis, J
通讯作者：
Blenis, J