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How High Blood Cholesterol Can Promote Cancer Stemness

Oxidised bad cholesterol has been found to activate a series of pathways involved in promoting cancer stemness in non-steroid-targeted cancers like urinary bladder cancer.

With over 2 million fast food facilities, China has seen a rapid increase in obesity rates with almost half of adults and more than one-fifth of children being either overweight or obese. Current research has shown that frequent consumption of fast food is positively associated with obesity and that such individuals tend to have a metabolic disorder known as hypercholesterolemia, or high cholesterol in the blood.

A diet comprising of fried food and processed meats are high in low-density lipoprotein (LDL), or “bad cholesterol,” which can build up in the arteries and result in angina, heart attack, or stroke, among many others. High cholesterol levels have been reported as a risk factor in the development of cancers derived from steroid-targeted tissues like breast and prostate cancer. Yet, not much is known about the effects of high blood cholesterol on non-steroid-targeted cancers like urinary bladder cancer.

A team of researchers led by Yan Jun from Fudan University, Huang Ruimin from Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, and Guo Hongqian from Drum Tower Hospital, Medical School of Nanjing University endeavoured to establish the relationship between cholesterol levels and urinary bladder cancer development. In their study, published in Cancer Research, they revealed a novel mechanism where oxidised LDL (ox-LDL) links hypercholesterolemia with bladder cancer aggressiveness.

By using two different hypercholesterolemia mouse models, the researchers verified that an excess of cholesterol could control cancer stemness and fuel bladder cancer progression. On the other hand, using Ezetimibe, a medication used to treat high blood cholesterol, intestinal cholesterol absorption is inhibited, reversing diet-induced hypercholesterolemia and cancer stemness. This suggests that high cholesterol was the main cause of bladder cancer aggressiveness.

In analysing the main components in hypercholesterolemia sera, they found that ox-LDL was the key factor. By binding to receptor CD36 on the cytomembrane, ox-LDL enhanced the interaction of CD36 and JAK2, inducing the phosphorylation of JAK2, and subsequently activating STAT3 signalling pathway that is known to mediate cancer stemness. Further analyses also revealed that high ox-LDL signature in serum predicted worse survival in bladder cancer patients.

These findings establish a link between high blood cholesterol levels and bladder cancer progression. It suggests that elevated levels of ox-LDL can be a risk factor for bladder cancer and that lowering serum ox-LDL levels or targeting the CD36/JAK2/STAT3 axis might be a promising therapeutic strategy for urinary bladder cancer patients with high blood cholesterol. [APBN]

Source: Yang et al. (2021). Oxidized low-density lipoprotein links hypercholesterolemia and bladder cancer aggressiveness by promoting cancer stemness. Cancer Research.