A team led by McGill University researchers has shown that obesity contributes to the spread of breast cancer cells to the lung by "reprogramming" immune cells called neutrophils-normally considered a first line of defense against injury and infection. Once turned on, these immune cells release traps-typically seen only with infection-that weaken blood vessels, resulting in the passage of breast cancer cells into the lung.
Interestingly, the researchers demonstrated that by targeting neutrophils in diet-induced obesity mouse models, the integrity of the blood vessels could be restored, creating a stronger barrier against metastasis.
"Our work has shown that certain therapies can mitigate the impact of obesity on breast cancer metastasis, including specific antibodies or small molecule inhibitors that change the way that neutrophils behave," said Daniela F. Quail, PhD, the study's principal investigator who reported findings during a meeting on the Evolving Tumor Microenvironment in Cancer Progression," held virtually January 11-12, 2021, by the American Association for Cancer Research (AACR).
"We have also found that lifestyle factors are important," said Quail, Assistant Professor in the Rosalind and Morris Goodman Cancer Research Centre at McGill University, based in Montreal, Canada. "We found that weight loss through diet helps to normalize the immune system in individuals who are obese." That said, the researchers cautioned that weight loss is not one-size-fits-all.
"The biology is very complicated," said Sheri McDowell, BSc, a PhD candidate in Quail's lab, "and more research is needed in this area before concrete clinical recommendations can be made to patients."
Research into the potential impacts of obesity on cancer onset and spread has taken on added importance with recent statistics showing that obesity now competes with smoking tobacco as the leading preventable risk factor for cancer mortality. It's now estimated that up to 20 percent of all cancer-related deaths may be attributable to obesity, compared to about 30 percent for smoking tobacco.
About a third of adults in North America are considered obese, with another third overweight. But even these statistics may be somewhat misleading, since about one in five people who have a healthy body mass index are "metabolically obese normal weight"-meaning they are subject to the same health risks as individuals whose BMI puts them in the category of obese.
"Therefore, research that aims to understand how metabolic obesity regulates cancer progression is relevant for a significant proportion of the adult population and has the potential to dramatically impact cancer mortality statistics," said McDowell.
Studying Diet & Obesity
As outlined during the AACR meeting, the McGill team began their studies with preclinical models of diet-induced and genetically induced obesity-combined with spontaneous and experimental breast cancer metastasis assays-to help understand how obesity contributed to the spread of breast cancer to other parts of the body.
Using RNA sequencing, Quail and colleagues determined obesity activates neutrophils and as a consequence produces collateral damage in blood vessels, making them "leaky," which she noted is bad for cancer metastasis.
"Tumor cells use blood vessels to spread throughout the body, so leakier vessels can lead to easier spread," Quail said. "Therefore, as a consequence of obesity, breast cancer cells were able to spread to the lungs more easily because the vascular barrier was compromised."
In a paper published in the July 24, 2017, issue of Nature Cell Biology, Quail and colleagues found that cytokines interleukin 5 (IL-5) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are activated in obesity and, in obese mice, this leads to lung neutrophilia that supports breast cancer metastasis to the lung (https://doi.org/10.1038/ncb3578).
In unpublished work, the researchers have now found that neutrophils are "reprogrammed" by obesity within the lung to produce elevated levels of reactive oxygen species (ROS) and the release of neutrophil extracellular traps or NETs, in a process known as NETosis.
"Obesity sometimes registers as a 'problem' in the body, and makes immune cells think that they need to turn on," explained Quail. "One way that neutrophils respond to this problem is by triggering defense mechanisms that you would normally only see in the context of infection."
This includes the release of NETs, which are sticky webs of DNA and toxic factors that normally are released to trap and kill pathogens.
"The problem is there are no pathogens to kill; the neutrophils are just being tricked and this triggers a chronic cycle," explained Quail. "So as a result, these toxic DNA webs end up damaging normally bystander tissues like blood vessels."
Drug Targeting
Encouraged by these findings, Quail and colleagues sought to identify NET-targeting drugs that could potentially dampen the activation of neutrophils. Among others, the team found they could reverse the negative impact of obesity by targeting ROS via pharmacological or genetic approaches.
Several ROS or antioxidant drugs are now used in the clinic, but Quail notes the story is complicated by cancer with some reports showing antioxidants reduce tumor progression, while others show they perpetuate tumor progression.
"Our research shows that antioxidant efficacy is context-dependent. In our models, only obese hosts benefitted from ROS interventions, and not all antioxidants elicited a positive effect," she said.
Another option the team explored are inhibitors of PAD4, which prevent NETs from being released. In obese mouse models, the team confirmed that NETosis was reversed by these inhibitors.
"Importantly, we used cutting-edge technology called Imaging Mass Cytometry on human lung metastasis samples and found that neutrophils in obese cancer patients appear to have similar features as our mouse models," McDowell said. "This suggests that the therapies we have identified in mice may be relevant to patients."
In the future, Quail said she's looking forward to clinical trials testing NET-targeting drugs in cancer patients. "NET-targeting drugs have not been tested in cancer patients," she said. "However, recent work in COVID-19 patients has shown that NETs predict poor outcomes and severity of disease, and therefore NET inhibitors are now being tested in this context. This will be the first time such agents are being tested in humans, so the results of these clinical trials will have major implications in the field of cancer."
She added that her team plans to examine the impact of obesity on other common metastatic sites, including vital organs such as the brain and liver. "We have preliminary evidence that obesity enhances liver metastasis through similar mechanisms as lung, and we are working on developing therapeutic interventions in that context," Quail concluded.
Warren Froelich is a contributing writer.