Targeting JAML promotes normalization of tumour blood vessels to antagonize tumour progression via FAK/SRC and VEGF/VEGFR2 signalling pathways

Abstract

Background

Angiogenesis is a crucial process in tumour growth and metastasis. Junctional adhesion molecule-like protein (JAML) plays an important role in cancer proliferation; however, its expression and role in tumour angiogenesis remains unexplored.

Methods

We collected colorectal cancer from Jinan Central Hospital, using immunofluorescence staining to confirm the expression of JAML in vascular endothelial cells of cancer and adjacent tissue. Then we used the endothelial-specific knockout of JAML mice and human umbilical vein endothelial cells (HUVECs) to clarify the role of JAML in vivo and in vitro.

Result

Our findings indicated a significant upregulation of JAML in vascular endothelial cells of colorectal cancer tissues compared to adjacent tissues. Endothelial-specific knockout of JAML effectively inhibited tumour growth through normalization of tumour blood vessels in multiple mice tumour models. The deletion of JAML in endothelial cells facilitated tumour vascular normalization, which was evident from increased pericyte coverage, vessel perfusion and T lymphocytes infiltration, decreased hypoxia, vessel density and leakage in tumour tissues. Further analysis showed that the phosphorylation of FAK/SRC/AKT/ERK pathway and VEGFR2 were suppressed in JAML^endo−/− mice with tumour.

Conclusion

This study concluded that JAML is specifically highly expressed in the vascular endothelial cells of tumour, promoting tumour progression by angiogenesis through the activation of the FAK/SRC/ERK/AKT pathway and VEGF/VEGFR2 pathway. JAML might be a new target for antiangiogenesis and provide valuable insights into the development of novel therapeutic approaches for cancer patients.