Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.
Lymphangioleiomyomatosis Biomarkers Linked to Lung Metastatic Potential and Cell Stemness.
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DOI：
10.1371/journal.pone.0132546
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Pujana MA
中科院分区：
文献类型：
--
作者：
Ruiz de Garibay G;Herranz C;Llorente A;Boni J;Serra-Musach J;Mateo F;Aguilar H;Gómez-Baldó L;Petit A;Vidal A;Climent F;Hernández-Losa J;Cordero Á;González-Suárez E;Sánchez-Mut JV;Esteller M;Llatjós R;Varela M;López JI;García N;Extremera AI;Gumà A;Ortega R;Plà MJ;Fernández A;Pernas S;Falo C;Morilla I;Campos M;Gil M;Román A;Molina-Molina M;Ussetti P;Laporta R;Valenzuela C;Ancochea J;Xaubet A;Casanova Á;Pujana MA
淋巴管平滑肌瘤病 (LAM) 是一种罕见的肺转移性肿瘤，由平滑肌样细胞增殖引起，这些细胞通常携带结节性硬化症复合体 1 或 2（TSC1 或 TSC2）基因的功能丧失突变。虽然雷帕霉素机械靶点 (mTOR) 的变构抑制已显示出巨大的临床益处，但仍需要补充疗法来改善反应和/或治疗特定患者。然而，缺乏可用于监测疾病和开发其他靶向疗法的 LAM 生物标志物。我们假设癌症转移至肺部（尤其是乳腺癌）的介质在 LAM 中也发挥着相关作用。对独立乳腺癌数据集的分析揭示了低 TSC1/2 表达、改变的 mTOR 复合物 1 (mTORC1) 通路信号传导和肺转移之间的关联。随后，对 23 个 LAM 病灶进行的免疫组织化学分析显示，所有病例的肺转移介质肌成束蛋白 1 (FSCN1) 和 DNA 结合抑制剂 1 (ID1) 均呈阳性。此外，对乳腺癌干细胞或管腔祖细胞生物标志物的评估显示，大多数 LAM 组织中乙醛脱氢酶 1 (ALDH1)、整合素-ß3 (ITGB3/CD61) 和/或性别决定区 Y-box 9 (SOX9) 蛋白呈阳性。免疫组织化学分析还提供了 LAM 病例之间和内部异质性的证据。对 Tsc2 缺陷细胞的分析揭示了 FSCN1 和 ID1 的相对过度表达；然而，Tsc2缺陷细胞对基于ID1的癌症抑制剂并没有表现出更高的敏感性。总的来说，这项研究的结果揭示了与乳腺癌肺转移和细胞干性相关的新型 LAM 生物标志物，这反过来可能指导评估 LAM 的额外或补充治疗机会。
Lymphangioleiomyomatosis (LAM) is a rare lung-metastasizing neoplasm caused by the proliferation of smooth muscle-like cells that commonly carry loss-of-function mutations in either the tuberous sclerosis complex 1 or 2 (TSC1 or TSC2) genes. While allosteric inhibition of the mechanistic target of rapamycin (mTOR) has shown substantial clinical benefit, complementary therapies are required to improve response and/or to treat specific patients. However, there is a lack of LAM biomarkers that could potentially be used to monitor the disease and to develop other targeted therapies. We hypothesized that the mediators of cancer metastasis to lung, particularly in breast cancer, also play a relevant role in LAM. Analyses across independent breast cancer datasets revealed associations between low TSC1/2 expression, altered mTOR complex 1 (mTORC1) pathway signaling, and metastasis to lung. Subsequently, immunohistochemical analyses of 23 LAM lesions revealed positivity in all cases for the lung metastasis mediators fascin 1 (FSCN1) and inhibitor of DNA binding 1 (ID1). Moreover, assessment of breast cancer stem or luminal progenitor cell biomarkers showed positivity in most LAM tissue for the aldehyde dehydrogenase 1 (ALDH1), integrin-ß3 (ITGB3/CD61), and/or the sex-determining region Y-box 9 (SOX9) proteins. The immunohistochemical analyses also provided evidence of heterogeneity between and within LAM cases. The analysis of Tsc2-deficient cells revealed relative over-expression of FSCN1 and ID1; however, Tsc2-deficient cells did not show higher sensitivity to ID1-based cancer inhibitors. Collectively, the results of this study reveal novel LAM biomarkers linked to breast cancer metastasis to lung and to cell stemness, which in turn might guide the assessment of additional or complementary therapeutic opportunities for LAM.