Why does obesity increase cancer risks?

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Why does obesity increase cancer risks?

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PNAS: Why does obesity increase cancer risks? Obesity promotes angiogenesis to awaken dormant tumors.

According to the statistics of the World Health Organization (WHO) , nearly 2 billion people in the world are overweight or obese.

From 1975 to 2016, the global obesity rate has nearly tripled, and the annual death rate due to overweight or obesity is as high as 2.8 million.

Obesity will not only lead to inconvenience in life and reduced exercise capacity, but also increase the risk of metabolic diseases such as diabetes and cardiovascular and cerebrovascular diseases.

According to the US Centers for Disease Control and Prevention (CDC) , obesity increases the risk of 13 cancers including breast cancer, liver cancer, colorectal cancer, pancreatic cancer, and thyroid cancer, and is also associated with an increased risk of death from various cancers. But exactly how obesity increases cancer risk is still unclear.

In modern society, many people’s daily routines are changing rapidly. Unhealthy eating and living habits such as staying up late, drinking, overeating, and sedentary have become the norm for many people, which has led to a more prominent problem of obesity.

Recently, researchers from Boston Children’s Hospital of Harvard Medical School published a research paper entitled: Escape from breast tumor dormancy: The convergence of obesity and menopause in the Proceedings of the National Academy of Sciences (PNAS) .

The study suggests that obesity may lead to neovascularization of dormant tumors, which accelerate growth when given a blood supply . The study demonstrated in mice that drugs that inhibit angiogenesis can make breast tumors dormant.

Marsha Moses , the corresponding author of the paper , said that once blood vessels invade tumors, tumors begin to grow exponentially, and if we can delay the time for tumors to come out of dormancy or inhibit their early growth, we can reduce the challenge of treating tumors.

Watching tumors come out of dormancy

The research team constructed a sophisticated research model, including obese menopausal mice, that allowed them to observe tumor neovascularization in real time.

They then injected human mammary tumor cells carrying the Luciferase gene into the mammary fat pads of obese and lean mice to form mammary tumors.

Then, the luciferase substrate of Luciferase was injected intravenously into the mice. After the substrate met the luciferin, it could emit light under the in vivo imager, so as to observe the invasion of new blood vessels into the tumor in real time and track the growth of the tumor .

At first, the tumors were not glowing because no blood vessels had invaded the tumors, and therefore the luciferase substrate had not reached the tumors.

But within 3-6 weeks, blood vessels began to invade mammary tumors in obese mice, and these tumors began to brighten dramatically.

In contrast, tumors in non-obese mice remained dormant at 12 weeks.

Signals from fat cells

The research team further found that fat cells in obese mice secreted higher levels of substances that promote angiogenesis: lipocalin-2 (lipocalin-2) , vascular endothelial growth factor (VEGF) and basic fibroblast growth factor ( bFGF) . These factors bring tumors out of dormancy and into progression.

In response to this phenomenon, Roopali Roy, the first author of the paper , explained that in obesity, fat cells become very large in size, in which case they become more hypoxic and start to die of apoptosis, which Usually results in inflammation. To prevent this from happening, fat cells secrete vascular growth factors to promote angiogenesis and increase oxygen delivery.

At this point, if there is a dormant tumor in adipose tissue, it will be surrounded by this inflammatory angiogenic microenvironment, causing the tumor to break out of dormancy.

Next, the research team used sunitinib ( tyrosine kinase inhibitor, which can inhibit angiogenesis ) to treat obese breast cancer mouse models , which can significantly prolong the tumor dormancy period and increase the tumor-free survival period.

The research team also demonstrated that sunitinib can keep breast tumors in a dormant state.

Obesity and cancer biomarkers in urine

The research team hopes to use these findings to help breast cancer patients, who hope to screen for breast cancer by detecting biomarkers in the urine of obese women that indicate that tumors have become vascularized and started to grow. Patients who test positive may be treated with angiogenesis inhibitors or other targeted drugs to slow breast cancer progression.

The research team has now identified a panel of urine biomarkers and begun to test their effects in different cancers, including breast cancer.

Marsha Moses , the corresponding author of the paper , said that the connection between obesity and cancer has received more and more attention, and this study provides clear evidence of the mechanism behind the connection between the two, which will help us to develop drugs targeting these specific diseases. Diagnosis and treatment of cancer patients.

Paper link :
https://www.pnas.org/doi/abs/10.1073/pnas.2204758119

Why does obesity increase cancer risks?

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