A research group led by Professor Kyoko Hida, Assistant Professor Nako Maishi, and graduate student Takuya Tsumita at the Graduate School of Dental Medicine at Hokkaido University, and Associate Professor Yasuhiro Hida at Hokkaido University Hospital has successfully demonstrated that the oxidized LDL/LOX-1 pathway in tumor endothelial cells may induce neutrophils to enter cancer tissue and form a metastasis-promoting cancer microenvironment.
Prevention and control of cancer metastasis is an important therapeutic issue, and cancer metastasis is greatly affected by the cancer microenvironment, which is composed of blood vessels and immune cells. Using a transplantation model of low-metastatic and high-metastatic cancer cells, the research group tested the importance of the accumulation of low-density lipoprotein (LDL) in tumor tissue in the formation of a metastasis-promoting cancer microenvironment.
They found neutrophils infiltrated highly metastatic tumor tissue and higher LDL/oxidized LDL. In addition, the oxidized LDL receptor LOX-1 was highly expressed in highly metastatic tumor vessels. Moreover, they observed a marked neutrophil infiltration in highly metastatic tumor tissue, and that overexpression of LOX-1 in vascular endothelial cells promoted neutrophil migration. Conversely, co-transplantation of tumor vascular endothelial cells with cancer cells in which LOX-1 expression was suppressed inhibited lung metastasis.
These findings suggest that activation of the LOX-1/oxidized LDL pathway in tumor vessels is involved in the formation of a metastasis-promoting cancer microenvironment, including the promotion of neutrophil migration.
"Until now, the famous LDL vessel wall accumulation in atherosclerosis has rarely been reported in cancer," explains Professor Hida. "In this study, we found for the first time the accumulation of oxidized LDL around blood vessels in highly metastatic cancers. Our research suggests that LOX-1, a receptor for oxidized LDL in blood vessels, may be a promising therapeutic target that could simultaneously reduce cancer malignancy and the risk of cardiovascular disease."
■ Tumor vascular endothelial cells: A single layer of flat cells lining the lumen of blood vessels (tumor blood vessels) induced within tumor tissue.
■ Oxidized LDL: Low-density lipoprotein (LDL) that has been oxidized. It is a known risk factor for cardiovascular disease, including atherosclerosis.
■ LOX-1: A type of receptor for oxidized LDL. It has been reported to have a relationship with various pathological conditions, including cardiovascular disease and cancer.
Journal Information
Publication: International Journal of Cancer (IJC)
Title: The oxidized-LDL/LOX-1 axis in tumor endothelial cells enhances metastasis by recruiting neutrophils and cancer cells
DOI: 10.1002/ijc.34134
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