Guadalupe Sabio, Héctor Pintado and Núria Malats. Credit: Laura M. Lombardía / CNIO.
The fat in the tissues of obese people has very active proteins. When they are eliminated, the risk of liver cancer decreases.
A relationship has been seen between obesity, diabetes and pancreatic cancer. But there may be a precondition that first leads to obesity and diabetes, and then to cancer.
Obesity may ‘help’ the tumor to metastasize by modifying the characteristics of blood vessels and platelets in a way that favors the implantation of cancer in other organs.
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 Guadalupe Sabio, Nuria Malats and 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 Sabio directs the Interaction Group between Organs in Metabolic Diseases at 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 – began in 2010. Shortly after, the phenomenon was studied in animal models and it was quickly seen that those with a high-fat diet showed a propensity for liver cancer, a relationship that was also seen later 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.”
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 is continuing to search for fat-related blood biomarkers that can tell us whether a person is at higher risk of developing liver cancer.
Pancreatic cancer, obesity and the microbiome
Núria Malats, who heads the Epidemiology and Molecular Genetics Group at the CNIO, 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.
“Pancreatic cancer is one of the cancers most associated with obesity as a risk factor,” explains Malats. But the relationship is not yet understood: “We believe that the role of obesity is much more complex and we think that there are other related factors.”
Malats’ group had previously shown that long-standing type 2 diabetes is a risk factor for pancreatic cancer. “We believe that diabetes mediates the effect of obesity, and obesity the effect of diabetes, and neither factor is causally related to pancreatic cancer. This suggests that pre-existing conditions leading to both diabetes and obesity could be the cause of the increased risk of pancreatic cancer.”
These preconditions could lead to mild, chronic inflammation of the pancreas, leading to 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 inhabit our bodies,” says Malats. This is a line of research that he is exploring with the CNIO Epithelial Carcinogenesis Group, led by Paco X. Real.
Metastasis and obesity
Héctor Peinado, head of the Microenvironment and Metastasis Group at 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 she began to investigate in 2015. “We started with melanoma, and we saw that in obese mice cancer cells metastasize better. Then we moved on to breast cancer, a tumor whose risk is more closely related to obesity than melanoma. In this case, too, we found that cancer cells metastasized better in obese mice. So we already had evidence in two types of cancer: melanoma and breast.”
With this 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 organs where there is metastasis, this 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 metastasis. It seems that the tumor cell takes advantage of these two circumstances to nest and form metastases.”
Peinado’s gaze now focuses on human beings: “We are collaborating with the group of Miguel Quintelafrom the Breast Cancer Clinical Research Unit at CNIO, to try to extrapolate our observations to patients. Our hypothesis is that obesity has a systemic influence on metastasis, and we are looking for a way to control or reverse it.”
Therapeutic strategies based on diet
Diet-changing 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. Extrapolated to a patient, this 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 ability for metastatic implantation,” explains Peinado.
Advancing 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 (there are no specific data in Spain). In addition, between 2005 and 2014, the majority of 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
The National Cancer Institute (NIH) recognizes that there are thirteen types of cancer whose risk increases with obesity or overweight in varying proportions. These are the times that the probability of suffering from each type of cancer increases, depending on whether the person suffers from severe obesity, obesity or overweight:
In addition, every 5-unit increase in the Body Mass Index (BMI), which is the indicator used to measure obesity and overweight, increases the risk of breast cancer after menopause by 1.2 times and the risk of ovarian cancer by 1.1 times.
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