Cancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression

Wen Wen Xu, Bin Li, Xin Yuan Guan, Sookja K. Chung, Yang Wang, Yim Ling Yip, Simon Y. K. Law, Kin Tak Chan, Nikki P. Y. Lee, Kwok Wah Chan, Li Yan Xu, En Min Li, Sai Wah Tsao, Qing-Yu He () and Annie L. M. Cheung ()
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Wen Wen Xu: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
Bin Li: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
Xin Yuan Guan: Centre for Cancer Research, Li Ka Shing Faculty of Medicine
Sookja K. Chung: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
Yang Wang: College of Life Science and Technology, Jinan University
Yim Ling Yip: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
Simon Y. K. Law: Centre for Cancer Research, Li Ka Shing Faculty of Medicine
Kin Tak Chan: Centre for Cancer Research, Li Ka Shing Faculty of Medicine
Nikki P. Y. Lee: Centre for Cancer Research, Li Ka Shing Faculty of Medicine
Kwok Wah Chan: Centre for Cancer Research, Li Ka Shing Faculty of Medicine
Li Yan Xu: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College
En Min Li: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College
Sai Wah Tsao: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
Qing-Yu He: College of Life Science and Technology, Jinan University
Annie L. M. Cheung: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: Abstract Local interactions between cancer cells and stroma can produce systemic effects on distant organs to govern cancer progression. Here we show that IGF2 secreted by inhibitor of differentiation (Id1)-overexpressing oesophageal cancer cells instigates VEGFR1-positive bone marrow cells in the tumour macroenvironment to form pre-metastatic niches at distant sites by increasing VEGF secretion from cancer-associated fibroblasts. Cancer cells are then attracted to the metastatic site via the CXCL5/CXCR2 axis. Bone marrow cells transplanted from nude mice bearing Id1-overexpressing oesophageal tumours enhance tumour growth and metastasis in recipient mice, whereas systemic administration of VEGFR1 antibody abrogates these effects. Mechanistically, IGF2 regulates VEGF in fibroblasts via miR-29c in a p53-dependent manner. Analysis of patient serum samples showed that concurrent elevation of IGF2 and VEGF levels may serve as a prognostic biomarker for oesophageal cancer. These findings suggest that the Id1/IGF2/VEGF/VEGFR1 cascade plays a critical role in tumour-driven pathophysiological processes underlying cancer progression.

Date: 2017
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DOI: 10.1038/ncomms14399

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