Why does obesity increase the risk of developing cancer and possibly metastases? Three CNIO teams are involved in the investigation.

Guadalupe Sabio, Hector Pintado and Nuria Malats. Photo: Laura M. Lombardia / CNIO. Guadalupe Sabio, Hector Pintado and Nuria Malats. Photo: Laura M. Lombardia/CNIO.

The fat in the tissues of obese people contains very active proteins. Removing them reduces the risk of liver cancer.

A link has been seen between obesity, diabetes and pancreatic cancer. But there may be a prerequisite that first leads to obesity and diabetes, and then to cancer.

Obesity can “help” tumor metastasis by changing the characteristics of blood vessels and platelets in a way that allows cancer to spread to other organs.

Being obese or overweight increases the risk of developing some types of cancer, but the reason is not clear. Obesity or overweight may not even be the direct cause of the increase. Some studies suggest that the reason lies in the changes they cause, or perhaps in changes in the body caused by these physical conditions. And the truth is that understanding the relationship between obesity, overweight and cancer is key. Groups Guadalupe Sabio, Nuria Malac And Hector Peinado.

According to the European Health Survey 2020 in Spain, in our country 16.5% of men over 18 years of age and 15.5% of women are obese, while 44.9% of men and 30.6% of women are overweight.

Guadalupe Sabio heads the Organ Interaction Group in Metabolic Diseases at the CNIO, which studies the relationship between cancer and obesity: “Epidemiological studies that show a very high association, especially with liver and colon cancer – also with others, but with fewer statistics – started in 2010. Soon after, this phenomenon was studied in animal models, and it was quickly discovered that people eating a high-fat diet showed a predisposition to liver cancer, an association that was later observed with other types of tumors.”

Liver and colon cancer

One of the tissues that is most damaged by obesity is adipose tissue—the fat found in common love handles. Sabio’s group discovered a certain type of protein that is highly active in obese people. If they are removed from adipose tissue, the risk of cancer is reduced. “We found that when we removed them from the fat tissue of animals, they had a lower risk of developing liver cancer. After that, we began to study how these proteins are contained in humans.”

Sabio began analyzing these protein kinases, distinguishing between “obese and lean people and, something that had not been done before, between women and men.” They found that this pathway is less active in women than in men. “This was a very important finding because men are four times more likely than women to develop liver tumors,” explains Sabio.

The group is now investigating how fat affects other cancers, such as breast cancer, and continues to look for fat-related blood biomarkers that can tell us whether a person is at greater risk of developing liver cancer.

Pancreatic cancer, obesity and the microbiome

Nuria Malats, who heads the Epidemiology and Molecular Genetics Group at the CNIO, led a large international study, PanGenEU, examining factors associated with the risk of developing pancreatic cancer. The ultimate goal is to create screening programs that allow early detection of the disease. Pancreatic cancer is usually detected in advanced stages and usually results in death within a year of diagnosis, so early detection is essential.

“Pancreatic cancer is one of the most commonly associated risk factors with obesity,” explains Malats. But the connection is still unclear: “We think the role of obesity is much more complex, and we think there are other factors involved.”

Malat’s group has already shown that long-term type 2 diabetes is a risk factor for pancreatic cancer. “We believe that diabetes mediates the effect of obesity, and obesity mediates the effect of diabetes, and neither factor has a causal relationship with pancreatic cancer. “This suggests that the underlying conditions that lead to both diabetes and obesity may be responsible for the increased risk of pancreatic cancer.”

These preconditions can lead to mild chronic inflammation of the pancreas, causing diabetes and obesity and ultimately pancreatic cancer. “The causes of this inflammation may be genetic or related to the microbiome, the community of microorganisms that live in our bodies,” says Malats. This line of research is carried out in collaboration with the Epithelial Carcinogenesis Group of the CNIO, led by Paco X. Real.

Metastasis and obesity

Héctor Peinado, head of the Microenvironment and Metastasis Group at CNIO, is investigating the relationship between obesity or excess weight and metastasis, the process by which a primary tumour replicates in other organs, spreading throughout the body. Little is known about this: “It seems obvious that obesity influences the spread of cancer, but until now research has not focused on the molecular explanation of why this happens,” explains Peinado.

This is what he began researching in 2015. “We started with melanoma and saw that cancer cells metastasized better in obese mice. We then move on to breast cancer, a tumor whose risk is more closely related to obesity than to melanoma. Also in this case, we found that cancer cells metastasize better in obese mice. So we already had evidence of two types of cancer: melanoma and breast cancer.”

Based on these data, the team hypothesized: “We believe that obesity affects the organs to which cancer metastasizes. On the one hand, obesity increases what is called vascular permeability. And we saw that in organs with metastases, vascular permeability also increases,” says the researcher. “Another change caused by obesity is an increase in platelet activity, and we see the same thing in our mouse models, in organs with metastases. “It seems that the tumor cell uses these two circumstances to nest and form metastases.”

Peinado’s gaze is now focused on people: “We are collaborating with a group Miguel Quintela, from the CNIO Breast Cancer Clinical Research Unit, to try to extrapolate our observations to patients. Our hypothesis is that obesity systemically affects metastasis, and we are looking for a way to control or reverse it.”

Diet-based therapeutic strategies

Dietary modification strategies do work in mouse models: “We test therapeutic strategies in our mouse models. For example, switching from a high-fat diet to a normal diet. If we extrapolate this to the patient, it would mean a healthier diet, a balanced diet instead of saturated fats and processed foods. The data shows that dietary modification can reduce the ability of tumor cells to metastasize. And on the other hand, we use platelet aggregation inhibitors, which also reduce the ability to metastasize,” explains Peinado.

Increasing knowledge about the relationship between obesity, overweight and cancer is important in oncology. According to the National Cancer Institute in the United States, between 2011 and 2015, there were 37,670 new cases of cancer in men and 74,690 in women related to excess body weight (no specific data are available for Spain). In addition, between 2005 and 2014, the number of cancer cases related to overweight and obesity increased by 7% in the United States, while the number of cancer cases related to other factors decreased by 13%.

Types of cancer most associated with obesity

The National Cancer Institute (NIH) recognizes that there are thirteen types of cancer that are increased in varying proportions by obesity or overweight. At this time, the likelihood of developing each type of cancer increases depending on whether you are severely obese, obese, or overweight:

In addition, for every 5 unit increase in body mass index (BMI), which is a measure of obesity and overweight, the risk of postmenopausal breast cancer increases by 1.2 times, and the risk of postmenopausal breast cancer increases by 1.1 times, compared with ovarian cancer.

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