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Wnt2 secreted by tumour fibroblasts promotes tumour progression in oesophageal cancer by activation of the Wnt/β-catenin signalling pathway
  1. Li Fu1,2,
  2. Chunyu Zhang3,
  3. Li-Yi Zhang2,
  4. Sui-Sui Dong2,
  5. Lu-Hui Lu2,
  6. Juan Chen2,
  7. Yongdong Dai1,
  8. Yan Li1,
  9. Kar Lok Kong2,
  10. Dora L Kwong2,
  11. Xin-Yuan Guan1,2
  1. 1State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Guangzhou, China
  2. 2Department of Clinical Oncology, The University of Hong Kong, Hong Kong, China
  3. 3Medical Genetics Laboratory, Harbin Medical University, Harbin, China
  1. Correspondence to Dr Xin-Yuan Guan, State Key Laboratory of Oncology in Southern China, Sun Yat-Sen University Cancer Center, Room 605, 651 Dongfeng Road East, Guangzhou 510060, China; xyguan{at}hkucc.hku.hk

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.

  • Cell biology
  • molecular biology
  • oesophageal cancer
  • oesophageal carcinoma
  • signalling
  • tumour fibroblast
  • tumour progression
  • Wnt2

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Footnotes

  • Funding This work was supported by grants from the National Natural Science Foundation of China (no 30700462 and no 30772475), grants from the Major State Basic Research Program of China (2006CB910104), the University of Hong Kong Small Project Funding Program (200907176114), Sun Yat-Sen University ‘Hundred Talents Program’ (85000-3171311) and Research Grant Council grant (HKU 7656/07M).

  • Competing interests None to declare.

  • Ethics approval This study was conducted with the approval of the University of Hong Kong.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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