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.
Highlights
Local interactions between cancer cells and stroma can produce systemic effects on distant organs to govern cancer progression
Our results show that insulin-like growth factor 2 (IGF2) secreted by Id1-expressing cancer cells activates the tumour microenvironment by inducing fibroblasts to secrete vascular endothelial growth factor (VEGF), but this mechanism instigates the tumour macroenvironment so that bone marrow cells primed by the presence of Id1-expressing tumours can facilitate tumour growth and distant metastatic colonization
We found that serum concentration of human VEGF in the nude mice was comparable among the three groups, remarkably higher concentration of mouse VEGF was detected in the KYSE150-Id1-shCON group, suggesting that the elevated VEGF was host-derived and likely to be stimulated by Id1-induced IGF2 (Fig. 1b)
Summary
Local interactions between cancer cells and stroma can produce systemic effects on distant organs to govern cancer progression. Our results show that IGF2 secreted by Id1-expressing cancer cells activates the tumour microenvironment by inducing fibroblasts to secrete vascular endothelial growth factor (VEGF), but this mechanism instigates the tumour macroenvironment so that bone marrow cells primed by the presence of Id1-expressing tumours can facilitate tumour growth and distant metastatic colonization. These effects can be abolished by systemic administration of VEGFR1 antibody. Our study provides evidence to support the potential clinical application of VEGFR1 antibody in the treatment of oesophageal cancer
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