Goldberg Alexander A, Joung Kwang-Bo, Mansuri Asma, Kang Yujin, Echavarria Raquel, Nikolajev Ljiljana, Sun Yang, Yu Jane J, Laporte Stephane A, Schwertani Adel, Kristof Arnold S
Meakins-Christie Laboratories, Translational Research in Respiratory Diseases Program, Montreal, Quebec, Canada.
Department of Critical Care Medicine, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
Oncotarget. 2016 Sep 20;7(38):61152-61165. doi: 10.18632/oncotarget.10748.
Lymphangioleiomyomatosis (LAM) is a destructive lung disease that can arise sporadically or in adults suffering from the tumor syndrome tuberous sclerosis complex (TSC). Microscopic tumors ('LAM nodules') in the lung interstitium arise from lymphatic invasion and metastasis. These consist of smooth muscle-like cells (LAM cells) that exhibit markers of neural crest differentiation and loss of the tumor suppressor protein 'tuberous sclerosis complex-2' (TSC2). Consistent with a neural phenotype, expression of the neuropeptide urotensin-II and its receptor was detected in LAM nodules. We hypothesized that loss of TSC2 sensitizes cells to the oncogenic effects of urotensin-II. TSC2-deficient Eker rat uterine leiomyoma ELT3 cells were stably transfected with empty vector or plasmid for the expression of TSC2. Urotensin-II increased cell viability and proliferation in TSC2-deficient cells, but not in TSC2-reconstituted cells. When exposed to urotensin-II, TSC2-deficient cells exhibited greater migration, anchorage-independent cell growth, and matrix invasion. The effects of urotensin-II on TSC2-deficient cells were blocked by the urotensin receptor antagonist SB657510, and accompanied by activation of Erk mitogen-activated protein kinase and focal adhesion kinase. Urotensin-II-induced proliferation and migration were reproduced in TSC2-deficient human angiomyolipoma cells, but not in those stably expressing TSC2. In a mouse xenograft model, SB657510 blocked the growth of established ELT3 tumors, reduced the number of circulating tumor cells, and attenuated the production of VEGF-D, a clinical biomarker of LAM. Urotensin receptor antagonists may be selective therapeutic agents for the treatment of LAM or other neural crest-derived neoplasms featuring loss of TSC2 or increased expression of the urotensin receptor.
淋巴管平滑肌瘤病（LAM）是一种破坏性肺部疾病，可散发出现，或发生于患有肿瘤综合征结节性硬化症（TSC）的成年人中。肺间质中的微小肿瘤（“LAM结节”）由淋巴管侵袭和转移产生。这些肿瘤由平滑肌样细胞（LAM细胞）组成，这些细胞表现出神经嵴分化的标志物，并缺失肿瘤抑制蛋白“结节性硬化复合物2”（TSC2）。与神经表型一致，在LAM结节中检测到神经肽尾加压素-II及其受体的表达。我们推测TSC2的缺失使细胞对尾加压素-II的致癌作用敏感。将TSC2缺陷的Eker大鼠子宫平滑肌瘤ELT3细胞用空载体或用于表达TSC2的质粒进行稳定转染。尾加压素-II增加了TSC2缺陷细胞的活力和增殖，但在TSC2重构细胞中则没有。当暴露于尾加压素-II时，TSC2缺陷细胞表现出更大的迁移、非锚定依赖性细胞生长和基质侵袭。尾加压素-II对TSC2缺陷细胞的作用被尾加压素受体拮抗剂SB657510阻断，并伴有细胞外信号调节激酶丝裂原活化蛋白激酶和粘着斑激酶的激活。尾加压素-II诱导的增殖和迁移在TSC2缺陷的人血管平滑肌脂肪瘤细胞中重现，但在稳定表达TSC2的细胞中则没有。在小鼠异种移植模型中，SB657510阻断了已建立的ELT3肿瘤的生长，减少了循环肿瘤细胞的数量，并减弱了VEGF-D的产生，VEGF-D是LAM的一种临床生物标志物。尾加压素受体拮抗剂可能是治疗LAM或其他以TSC2缺失或尾加压素受体表达增加为特征的神经嵴源性肿瘤的选择性治疗药物。
