Authors' Affiliation: Department of Medicine, Baylor College of Medicine, Houston, Texas.
Cancer Res. 2014 Apr 1;74(7):1996-2005. doi: 10.1158/0008-5472.CAN-13-1256.
Lymphangioleiomyomatosis (LAM) is a progressive cystic lung disease affecting some women with tuberous sclerosis complex (TSC). Sporadic LAM can develop in women without TSC, owing to somatic mutations in the TSC2 gene. Accumulating evidence supports the view of LAM as a low-grade, destructive, metastasizing neoplasm. The mechanisms underlying the metastatic capability of LAM cells remain poorly understood. The observed behavior of LAM cells with respect to their infiltrative growth pattern, metastatic potential, and altered cell differentiation bears similarity to cells undergoing epithelial-mesenchymal transition. Here, we report increased levels of active Src kinase in LAM lungs and in TSC2(-/-) cells, caused by a reduction of autophagy. Furthermore, increased Src kinase activation promoted migration, invasion, and inhibition of E-cadherin expression in TSC2(-/-) cells by upregulating the transcription factor Snail. Notably, Src kinase inhibitors reduced migration and invasion properties of TSC2(-/-) cells and attenuated lung colonization of intravenously injected TSC2(-/-) cells in vivo to a greater extent than control TSC2(+/+) cells. Our results reveal mechanistic basis for the pathogenicity of LAM cells and they rationalize Src kinase as a novel therapeutic target for treatment of LAM and TSC.
淋巴管平滑肌瘤病（LAM）是一种影响部分结节性硬化症（TSC）女性的进行性囊性肺疾病。散发性 LAM 可发生于无 TSC 的女性，这归因于 TSC2 基因的体细胞突变。越来越多的证据支持将 LAM 视为一种低度、破坏性、转移性肿瘤。导致 LAM 细胞具有转移性的机制仍知之甚少。LAM 细胞浸润性生长模式、转移潜能和细胞分化改变的观察行为与经历上皮间质转化的细胞具有相似性。在这里，我们报告 LAM 肺和 TSC2(-/-)细胞中活性 Src 激酶水平升高，这是由于自噬减少所致。此外，Src 激酶的激活增加通过上调转录因子 Snail 促进了 TSC2(-/-)细胞的迁移、侵袭和 E-钙黏蛋白表达的抑制。值得注意的是，Src 激酶抑制剂降低了 TSC2(-/-)细胞的迁移和侵袭特性，并在体内比对照 TSC2(+/+)细胞更显著地减弱了静脉内注射的 TSC2(-/-)细胞对肺的定植。我们的结果揭示了 LAM 细胞致病性的机制基础，并将 Src 激酶合理化作为治疗 LAM 和 TSC 的新型治疗靶点。
