Gut 2011 Dec;60 (12): 1635-43. [IF:10.614]
Wnt2 secreted by tumour fibroblasts promotes tumour progression in oesophageal cancer by activation of the Wnt/β-catenin signalling pathway.
Fu L , Zhang C , Zhang LY , Dong SS , Lu LH , Chen J , Dai Y , Li Y , Kong KL , Kwong DL , Guan XY .
State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Room 605, 651 Dongfeng Road East, Guangzhou 510060, China; xyguan@hkucc.hku.hk.
中山大学肿瘤中心，中山大学华南肿瘤学国家重点实验室
Abstract
Objectives Interaction between neoplastic and stromal cells plays an important role in tumour progression. It was recently found that WNT2 was frequently overexpressed in fibroblasts isolated from tumour tissue tumour fibroblasts (TF) compared with fibroblasts from non-tumour tissue normal fibroblasts in oesophageal squamous cell carcinoma (OSCC). This study aimed to investigate the effect of TF-secreted Wnt2 in OSCC development via the tumour-stroma interaction. Methods Quantitative PCR, western blotting, immunohistochemistry and immunofluorescence were used to study the expression pattern of Wnt2 and its effect on the Wnt/β-catenin pathway. A Wnt2-secreting system was established in Chinese hamster ovary cells and its conditioned medium was used to study the role of Wnt2 in cell proliferation and invasion. Results Expression of Wnt2 could only be detected in TF but not in OSCC cancer cell lines. In OSCC tissues, Wnt2(+) cells were mainly detected in the boundary between stroma and tumour tissue or scattered within tumour tissue. In this study, Wnt2-positive OSCC was defined when five or more Wnt2(+) cells were observed in 200× microscopy field. Interestingly, Wnt2-positive OSCC (22/51 cases) was significantly associated with lymph node metastases (p=0.001), advanced TNM stage (p=0.001) and disease-specific survival (p<0.0001). Functional study demonstrated that secreted Wnt2 could promote oesophageal cancer cell growth by activating the Wnt/β-catenin signalling pathway and subsequently upregulated cyclin D1 and c-myc expression. Further study found that Wnt2 could enhance cell motility and invasiveness by inducing epithelial-mesenchymal transition. Conclusions TF-secreted Wnt2 acts as a growth and invasion-promoting factor through activating the canonical Wnt/β-catenin signalling pathway in oesophageal cancer cells.
摘要：
WNT2的表达只在肿瘤纤维母细胞中可以检测，而在食管鳞状细胞癌系中却没有。在食管鳞状细胞癌组织中，WNT2（+）的细胞主要集中在基质和肿瘤组织的交界处，或者散在分布于肿瘤组织内。在这个研究中，我们是这样定义WNT2（+）的食管鳞状细胞癌的：在显微镜下200倍的视野内可见5个及5个以上的WNT2（+）细胞。有趣的是，我们发现，WNT2（+）的OSCC病人（22/51）与淋巴结的转移相关（P=0.001），与TNM分期的进展期相关（P=0.001），与疾病特异性存活率相关（P﹤0.001）。功能性研究表明，WNT2的分泌通过激活WNT2β连环蛋白信号通路，能促进食管癌细胞的生长，随后上调细胞周期蛋白D1和c-myc的表达。进一步研究表明，WNT2通过诱导上皮-间叶细胞之间的转换，从而加强细胞的运动性和侵袭力。
结论：在食管癌细胞中，肿瘤纤维母细胞分泌的WNT2通过激活WNT2β连环蛋白信号传到通路，作为一种促进生长和浸润的因子而起作用。
