Why does obesity increase the risk of cancer?

Three CNIO groups are investigating the relationship between obesity, diabetes and pancreatic cancer. They say that obesity could 'help' the tumor to metastasize by modifying the characteristics of blood vessels and platelets

Being obese or overweight increases the risk of developing several types of cancers, but the reason is not clear. Perhaps obesity or overweight are not even a direct cause of this increase. Some research suggests that the origin lies in the alterations they cause, or perhaps in the changes in the body derived from these physical conditions. And the truth is that understanding the relationship between obesity, overweight and cancer is key. The groups of Guadeloupe Sage, Nuria Malats y Hector Peinado.

According to the 2020 European Health Survey in Spain, in our country 16,5% of men over 18 years of age and 15,5% of women suffer from obesity, and overweight affects 44,9%. of men and 30,6% of women.

Guadalupe Wise man directs the Interaction Group between Organs in Metabolic Diseases of the CNIO, which studies the relationship between cancer and obesity: “Epidemiological studies that show a very high relationship, especially with liver and colon cancer – also with others, but with less statistical evidence – begin in 2010. Shortly after, the phenomenon in animal models and it is quickly seen that those with a high-fat diet show a propensity for liver cancer, a relationship that was also later seen with other types of tumors.”

Liver and colon cancer

One of the tissues that is most damaged by obesity is adipose – the fat, present in the usual 'love handles' -. Sabio's group discovered a certain type of proteins that are very active in obese people. If they are removed from adipose tissue, the risk of cancer is reduced. “We discovered that when we removed them from the adipose tissue of the animals, they had a lower risk of developing liver cancer. From there we began to study how these proteins are in people.”

"Men are four times more likely than women to develop a liver tumor"

Guadalupe Sabio. Interaction between Organs in Metabolic Diseases Group of the CNIO.

Sabio began to analyze these protein kinases, differentiating between “obese and thin people and, something that had not been done before, between women and men.” What they discovered was that women have this pathway less active than men. “This was a very significant fact, because men are four times more likely than women to develop a liver tumor,” explains Sabio.

This group is now investigating how fat affects other types of cancer, 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

Núria Malats, who directs the CNIO Epidemiology and Molecular Genetics Group, has led a large international study, PanGenEU, dedicated to investigating the factors associated with the risk of pancreatic cancer. The ultimate goal is to establish screening programs that allow early detection of the disease. Pancreatic cancer is usually detected in advanced stages and usually causes death within a year after diagnosis, so it is crucial to advance early detection.

«We believe that the role of obesity is much more complex and we think that there are other related factors»

Núria Malats. CNIO Epidemiology and Molecular Genetics Group.

“Pancreatic cancer is one of the most associated with obesity as a risk factor,” explains Malats. But the relationship is still not understood: "We believe that the role of obesity is much more complex and we think that there are other related factors."

Malats' group had 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 preconditions that lead to both diabetes and obesity could be the cause of the increased risk of pancreatic cancer."

Those preconditions could lead to mild, chronic inflammation of the pancreas, inducing diabetes and obesity and, eventually, 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. It is a line of research that is being explored with the CNIO Epithelial Carcinogenesis Group, directed by Paco X. Real.

Metastasis and obesity

Hector Peinado, boss of Microenvironment and Metastasis Group of the CNIO, investigates the relationship between obesity or overweight and metastasis, the process by which a primary tumor reproduces in other organs, spreading throughout the body. Little is known about this point: “It seems clear that obesity influences the spread of cancer, but research had not focused, until now, on molecularly explaining why this happens,” explains Peinado.

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

«Obesity increases what is known as vascular permeability. It also causes an increase in platelet activity."

Hector Peinado. CNIO Microenvironment and Metastasis Group.

With these data, the group established a hypothesis: “We believe that obesity affects the organs in which cancer metastasizes. On the one hand, obesity increases what is known as vascular permeability. And we have seen that in the organs in which there is metastasis, vascular permeability also increases,” says the researcher. “Another change caused by obesity is the increase in platelet activity, and we see the same thing in our mouse models, in organs with metastases. "It seems that the tumor cell takes advantage of these two circumstances to nest and form metastasis."

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

Therapeutic strategies based on diet

«We are testing therapeutic strategies in our mouse models. For example, changing from a high-fat diet to a normal diet."

Hector Peinado. CNIO Microenvironment and Metastasis Group.

Diet change strategies do work in mouse models: “We are testing therapeutic strategies in our mouse models. For example, changing from a high-fat diet to a normal diet. This, extrapolated to a patient, would mean eating healthier, eating a balanced diet instead of eating saturated fats and processed foods. The data suggest that a change in diet could reduce the ability of tumor cells to metastasize. And, on the other hand, we use platelet aggregation inhibitors that also reduce this capacity for metastatic nesting,” explains Peinado.

Advancing the knowledge of the relationship between obesity and overweight and cancer is essential in oncology. According to the National Cancer Institute of the United States, between 2011 and 2015 there were 37.670 new cases of cancer in men and 74.690 in women in that country that were related to excess body weight (in Spain there are no specific data). Additionally, between 2005 and 2014, most cancers associated with overweight and obesity increased by 7% in the US, while cancers associated with other factors decreased by 13%.

Types of cancer most related to obesity

El National Cancer Institute of the United States (NIH) recognizes that there are trec types of cancer whose risk increases with obesity or overweight in varying proportions. These are the times that the chances of suffering from each type of cancer increase, depending on whether you are severely obese, obese or overweight:

Furthermore, each increase of 5 units in the Body Mass Index (BMI), which is the indicator with which obesity and overweight are measured, increases the risk of breast cancer after menopause by 1,2 times and the risk of breast cancer after menopause by 1,1 times. times that of ovarian cancer.

Source: CNIO