Obesity may be the reason that some cancers become resistant to drugs intended to stop the formation of new blood vessels that fuel tumor growth, according to recent research led by Massachusetts General Hospital in Boston.

In a paper now published in the journal Science Translational Medicine, the researchers explain how obesity and molecular factors linked to it may promote resistance to anti-angiogenic inhibitors in breast cancer.

Anti-angiogenic therapy—which is designed to prevent the growth of blood vessels that feed tumors—is showing mixed results in people with breast and other cancers.

It is also well known that obesity raises the risk of many types of cancer, including breast cancer.

The new study is the first to show a link between these two "observations." It also offers some molecular targets that might improve response to treatment with anti-angiogenic inhibitors.

"Collectively," explains lead study author Dr. Joao Incio, of the Department of Radiation Oncology at Massachusetts General Hospital, "our clinical and preclinical results indicate that obesity fuels resistance to anti-vascular endothelial growth factor therapy in breast cancer via production of several inflammatory and pro-angiogenic factors, depending on the subtype of cancer."

"Targeting these resistance factors," he continues, "may rejuvenate the use of anti-angiogenic therapy in breast cancer treatment."

Angiogenesis and its inhibition

Angiogenesis is a natural process in the body that repairs and grows blood vessels. Some chemical signals stimulate the process and some chemical signals inhibit it. Levels of these are normally kept in balance so that blood vessels are made only when and where necessary.

These processes also play a key role in cancer. Without a dedicated blood supply, tumors cannot grow and spread. However, they do so because they also generate chemical signals that trigger angiogenesis, resulting in the growth of blood vessels that keep them fed with oxygen and nutrients.

Angiogenesis inhibitors are drugs that are designed to interfere with the chemical signals involved in angiogenesis. One of these drugs blocks vascular endothelial growth factor (VEGF), a signaling molecule that triggers growth of new blood vessels when it binds to proteins on cell surfaces.

However, Dr. Incio and his colleagues found that obesity "promotes resistance to VEGF inhibitor therapy" by altering chemical signals in tumors. They note that it increases "interleukin-6 [IL-6] and possibly also fibroblast growth factor 2 [FGF-2] in the tumor microenvironment."

The team also discovered—with the help of "mouse models of cancer with and without obesity"—that resistance to VEGF inhibitors may be overcome by using the "appropriate combination therapy."

Obesity, anti-VEGF therapy in breast cancer

The researchers started their investigation by analyzing the results of a clinical trial that tested the anti-VEGF drug bevacizumab, with and without chemotherapy, in 99 people with breast cancer.

Promising results from early clinical trials had led to the accelerated approval of the drug for the treatment of metastatic breast cancer in the United States. But approval was then withdrawn after subsequent studies found no evidence of benefit to long-term survival.

The trial that Dr. Incio and his colleagues investigated had shown that bevacizumab only benefited a small percentage of people.

When the researchers analyzed the trial data, they found that people whose BMI was 25 or higher—that is, if they fell into the overweight or obese category—had larger tumors when they were diagnosed.

On average, these people had tumors that were 33% bigger than those whose BMI was under 25.

In addition, tissue samples from people who had more body fat revealed that their tumors had a smaller blood supply, which is known to reduce the effects of chemotherapy.

Further examination showed that people with a higher BMI had higher circulating levels of two molecules: IL-6, which promotes inflammation, and FGF-2, which promotes angiogenesis.

There was also evidence that these factors were present in fat cells and adjacent cells in the tumors.

The role of IL-6 and FGF-2 in mouse models

In the next stage of the study, the researchers sought to confirm these findings in mouse models of breast cancer, both with and without obesity. They used two models: one of breast cancer that is positive for the estrogen receptor (ER), and the other of triple-negative breast cancer.

They found, in the case of the obese mice, that the tumor microenvironments—which contained many fat cells and had reduced levels of oxygen—responded poorly to anti-VEGF treatment. Morever, at a molecular level, responses differed depending on the breast cancer subtype.

For example, in obese mice with ER-positive breast cancer, the fat cells and some types of immune cell had higher levels of several pro-inflammation and pro-angiogenic molecules—including IL-6.

The researchers found that when they blocked IL-6 in the ER-positive obese mice, the animals' responses to anti-VEGF therapy improved and matched that of the lean mice.

Obese mice with triple-negative breast cancer, on the other hand, showed higher levels of FGF-2 but not of IL-6. In their case, blocking FGF-2 raised their response to treatment to that of the lean mice.

Blocking either of those molecules in lean mice with either type of breast cancer did not improve their response to anti-VEGF treatment.

"This is the first study to propose that markers such as BMI could help personalize anti-VEGF therapy, with blockade of molecules like IL-6 or FGF-2 for overweight or obese cancer patients."

Dr. Joao Incio

The researchers note that there are several inhibitors of the two pathways already available. For example, to inhibit FGF-2 in their experiments, they used the widely used diabetes drug metformin, which has been showing promise in slowing the growth of some cancers.