Oxidized LDL in Cancer Metastasis

LDL particles carry cholesterol from the liver throughout the body via the circulatory system. As the prevalence of oxidative molecules rises with age, a consequence of inflammation and mitochondrial dysfunction, ever more of these LDL particles become oxidized. This allows them to interact with cells in novel ways that contribute to atherosclerosis, the formation of fatty deposits in blood vessel walls, either by overwhelming them with additional cholesterol uptake, aggravating the lysosomal recycling system, or interacting with specialized receptors such as LOX-1 in ways that spur inflammatory behavior. Here, researchers report that one of the receptors known to be involved in these processes is also important to cancer metastasis - and so the same oxidative stress of aging that contributes to atherosclerosis is also contributing to a greater risk of severe cancer via this mechanism.

Cancer is the uncontrolled growth of body cells leading to the formation of tumors, triggered by the accumulation of mutations in a cell's genome. In order to become malignant, metastasizing cancer, tumor cells go through a series of transformations involving interactions between the body's immune system and the tumor. However, many mechanistic details in this process are still unclear, making the prevention and treatment of cancer notoriously difficult. However, there is growing evidence that in tumor progression to metastasis, inflammation of blood vessel-lining endothelial cells is a key process.

Researchers showed that metastasizing tumors, in contrast to non-metastasizing ones, accumulate proteoglycan molecules; these, in turn, attach to and accumulate LDL to the walls of blood vessels. The bound LDL becomes oxidized. There are also high levels of its receptor, called LOX-1, in the endothelial cells of metastasizing tumors. This, they found, causes these cells to produce inflammation signals that attract neutrophils. They then proved that in mice, the suppression of LOX-1 can significantly reduce tumor malignancy, and also that LOX-1 overexpression caused an increase in signaling molecules attracting neutrophils.

The study also points to a promising approach for treating and preventing malignant cancer - and cardiovascular disease - by targeting neutrophil recruitment to endothelial cells. "The number of patients with cancer who die not of cancer, but of cardiovascular events, is increasing. Targeting the LOX-1/oxidized LDL axis might be a promising strategy for the treatment of the two diseases concomitantly."

Link: https://www.global.hokudai.ac.jp/blog/a-common-mechanism-for-cancer-metastasis-and-atherosclerosis/

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