Endothelial cell-derived IGFBP7 suppresses angiogenesis and tumor progression in colorectal cancer via the VAPA-TGF-β1 pathway.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related deaths, with the tumor microenvironment (TME) influencing disease progression and therapeutic response. Tumor endothelial cells are crucial in CRC initiation, progression, and metastasis, yet their specific mechanisms are not fully understood. METHODS: We utilized single-cell RNA sequencing, RNAscope, flow cytometry, and immunofluorescence staining to identify and characterize insulin-like growth factor binding-protein 7 (IGFBP7) secretion by tumor endothelial cells, observing a progressive decline in its expression during inflammation-driven tumorigenesis. To elucidate IGFBP7 function, bulk RNA sequencing data were integrated with in vitro and in vivo models. The molecular mechanisms by which IGFBP7 influences the TME were explored through immunoprecipitation mass spectrometry and transmission electron microscopy. RESULTS: Our findings revealed a progressive decrease in both IGFBP7 expression and secretion by tumor endothelial cells during inflammation-associated colorectal tumorigenesis. Functional analyses confirmed that endothelial-derived IGFBP7 is secreted into the TME, where it exerts anti-angiogenic effects. Moreover, CRC cells have been shown to actively internalize IGFBP7-containing vesicles. IGFBP7 suppresses tumor cell proliferation and migration by inhibiting the expression of EGR1, thereby downregulating the activity of the TGF-β1 signaling pathway. Notably, we identified Vesicle-associated membrane protein-associated protein A (VAPA) as a key mediator in the transport of IGFBP7 vesicles to lysosomes, facilitating IGFBP7 degradation and thereby attenuating its tumor-suppressive function. CONCLUSION: Endothelial cell-derived IGFBP7 suppresses CRC progression via the EGR1/TGF-β1 pathway, while VAPA-mediated lysosomal degradation limits its tumor-suppressive function. These findings highlight endothelial cell-derived IGFBP7 as a promising therapeutic target for CRC. GRAPHICAL ABSTRACT: [Image: see text] SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13046-026-03664-z.