title: Cancer cell-secreted IGF2 instigates fibroblasts and bone marrow-derived vascular progenitor cells to promote cancer progression.
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.
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Kejizhong 2nd Rd., Hi-Tech Industrial Park, Nanshan District, Shenzhen 518057, China.
authors.forename: Wen Wen
authors.initials: WW
authors.lastname: Xu
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Kejizhong 2nd Rd., Hi-Tech Industrial Park, Nanshan District, Shenzhen 518057, China.|Centre for Cancer Research, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Centre for Cancer Research, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Xin Yuan
authors.initials: XY
authors.lastname: Guan
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Sookja K
authors.initials: SK
authors.lastname: Chung
authors.affiliation: College of Life Science and Technology, Jinan University, 601 West Huangpu Blvd., Guangzhou 510632, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Yim Ling
authors.initials: YL
authors.lastname: Yip
authors.affiliation: Centre for Cancer Research, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|Department of Surgery, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Simon Y K
authors.initials: SY
authors.lastname: Law
authors.affiliation: Centre for Cancer Research, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|Department of Surgery, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Kin Tak
authors.initials: KT
authors.lastname: Chan
authors.affiliation: Centre for Cancer Research, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|Department of Surgery, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Nikki P Y
authors.initials: NP
authors.lastname: Lee
authors.affiliation: Centre for Cancer Research, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|Department of Pathology, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Kwok Wah
authors.initials: KW
authors.lastname: Chan
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, 22 Xinling Road, Shantou, 515041 Guangdong, China.
authors.forename: Li Yan
authors.initials: LY
authors.lastname: Xu
authors.affiliation: The Key Laboratory of Molecular Biology for High Cancer Incidence Coastal Chaoshan Area, Shantou University Medical College, 22 Xinling Road, Shantou, 515041 Guangdong, China.
authors.forename: En Min
authors.initials: EM
authors.lastname: Li
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|Centre for Cancer Research, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.affiliation: College of Life Science and Technology, Jinan University, 601 West Huangpu Blvd., Guangzhou 510632, China.
authors.forename: Qing-Yu
authors.identifier: 0000-0003-0503-9492
authors.initials: QY
authors.lastname: He
authors.affiliation: School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.|The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Kejizhong 2nd Rd., Hi-Tech Industrial Park, Nanshan District, Shenzhen 518057, China.|Centre for Cancer Research, Li Ka Shing Faculty of Medicine, 21 Sassoon Road, The University of Hong Kong, Pokfulam, Hong Kong SAR, China.
authors.forename: Annie L M
authors.initials: AL
authors.lastname: Cheung
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism*; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018450:Disease Progression; D004938:Esophageal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000235:genetics / Q000378:metabolism; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D018345:Mice, Knockout; D008819:Mice, Nude; D013234:Stem Cells / Q000378:metabolism*; D014183:Transplantation, Heterologous; D042461:Vascular Endothelial Growth Factor A / Q000097:blood / Q000235:genetics / Q000378:metabolism
chemical_list: C035170:IGF2 protein, human; D051798:Inhibitor of Differentiation Protein 1; D042461:Vascular Endothelial Growth Factor A; D007335:Insulin-Like Growth Factor II