Urokinase plasminogen activator secreted by cancer-associated fibroblasts induces tumor progression via PI3K/AKT and ERK signaling in esophageal squamous cell carcinoma.
Urokinase plasminogen activator secreted by cancer-associated fibroblasts induces tumor progression via PI3K/AKT and ERK signaling in esophageal squamous cell carcinoma.
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癌症相关成纤维细胞分泌的尿激酶纤溶酶原激活剂通过 PI3K/AKT 和 ERK 信号传导诱导食管鳞状细胞癌肿瘤进展
DOI：
10.18632/oncotarget.15857
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发表时间：
2017-06-27
期刊：
影响因子：
--
通讯作者：
Hong A
中科院分区：
文献类型：
--
作者：
Tian B;Chen X;Zhang H;Li X;Wang J;Han W;Zhang LY;Fu L;Li Y;Nie C;Zhao Y;Tan X;Wang H;Guan XY;Hong A
癌症相关成纤维细胞（CAF）被认为影响肿瘤行为和临床结果。我们之前表明，来自CAF的条件培养基（CM）可诱导食管鳞状细胞癌（ESCC）细胞的增殖和运动。在这里，我们研究了CAF分泌蛋白诱导ESCC发展和进展的分子机制。使用抗体阵列，我们确定尿激酶纤溶酶原激活剂（uPA）的主要蛋白质之一，其释放增加CAFs相比，正常的成纤维细胞（NF）。病理切片免疫组化分析显示uPA阳性细胞定位于肿瘤与间质组织的交界处、肿瘤巢间的间质中以及肿瘤内。间质uPA水平升高（132/146例）与肿瘤浸润（p < 0.05）和ESCC患者的总生存率（p < 0.05）相关。体外实验表明uPA通过PI 3 K/AKT和ERK信号通路促进食管鳞癌细胞增殖、迁移和侵袭。在体内，抗uPA抗体抑制ESCC异种移植物中的肿瘤生长。提示间质尤其是CAFs释放的uPA可能是食管鳞癌诊断和预后的预测指标，也是有效的治疗靶点。
Cancer-associated fibroblasts (CAFs) are believed to influence tumor behavior and clinical outcomes. We previously showed that conditioned medium (CM) from CAFs induces proliferation and motility of esophageal squamous cell carcinoma (ESCC) cells. Here, we investigated the molecular mechanisms by which the CAF-secreted proteins induce ESCC development and progression. Using antibody arrays, we identified urokinase plasminogen activator (uPA) as one of the main proteins whose release was increased in CAFs compared to normal fibroblasts (NFs). Immunohistochemical analysis of pathological sections showed that uPA-positive cells were localized at the boundaries of tumor and stroma tissues, in stroma between tumor nests, and within the tumors. Increased stromal uPA levels (132/146 cases) correlated with tumor invasion (p < 0.05) and overall survival of ESCC patients (p < 0.05). In vitro assays showed that uPA promotes ESCC cell proliferation, migration, and invasion via PI3K/AKT and ERK signaling pathways. In vivo, anti-uPA antibody suppressed tumor growth in ESCC xenografts. These results suggest that uPA released from stroma, and especially from CAFs, might be a predictive marker for ESCC diagnosis and prognosis, as well as an effective therapeutic target.
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DOI：
10.1073/pnas.0909797107
发表时间：
2010-02-02
影响因子：
11.1
作者：
Saadi, Amel;Shannon, Nicholas B.;Fitzgerald, Rebecca C.
通讯作者：
Fitzgerald, Rebecca C.
影响因子：
29.4
作者：
Noma, Kazuhiro;Smalley, Keiran S. M.;Herlyn, Meenhard
通讯作者：
Herlyn, Meenhard
SOX6 在人食管鳞状细胞癌中的抑癌功能特征
影响因子：
11.5
作者：
Qin, Yan-Ru;Tang, Hong;Guan, Xin-Yuan
通讯作者：
Guan, Xin-Yuan
DOI：
10.1186/bcr580
发表时间：
2003
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Shekhar MP;Pauley R;Heppner G
通讯作者：
Heppner G
影响因子：
4.8
作者：
Nguyen, DHD;Hussaini, IM;Gonias, SL
通讯作者：
Gonias, SL