Obesity “reprograms” immune cells to promote tumor formation, heightening the risk of difficult-to-treat breast cancer
Obese women are at a higher likelihood of developing triple-negative breast cancer (TNBC) – an aggressive type of breast cancer that is particularly difficult to treat. This is according to a University of Chicago study, which found that breast cancer, the most common cancer among women, poses an even greater risk to obese individuals. The researchers recommend incorporating weight loss as a component of therapy for patients with breast cancer as well as a preventative measure.
This latest research emerges following a string of similar investigations into the link between obesity and cancer, which highlights a rise in prevalence of the two closely correlated diseases – even among young adults.
“Epidemiological studies exploring the link between obesity and breast cancer are in their early days and a lot more studies are needed,” study author Lev Becker, Ph.D., Assistant Professor in the Ben May Department for Cancer Research at the University of Chicago, tells NutritionInsight. “Post-menopausal women who are obese have a 20 to 30 percent higher risk of developing breast cancer in Europe and US, and this risk is higher among Asian Pacific Women.”
Obesity has become “a global epidemic,” Becker says. The researchers note that prevalence of obesity in the US is about 36 percent for ages 20 to 39, 43 percent for ages 40 to 59, and 41 percent for those 60 and older. The US is ranked twelfth worldwide for obesity, according to the World Health Organization (WHO).
“Current treatment of breast cancer patients ignores the ongoing obesity epidemic,” says study co-author Marsha Rosner, Ph.D., the Charles B. Huggins Professor in the Ben May Department for Cancer Research. “In order to take this into consideration, we need to help patients lose weight or identify new drug targets that would be effective in obese cancer patients.”
Unfortunately, once the cancer has been detected there may not be time to lose weight prior to treatment. “So our bottom line,” Rosner says, is to “promote weight loss as a cancer prevention measure, incorporate weight loss as a component of therapy for patients with breast cancer, and develop specific drug targets that could be leveraged to address the obesity component of the disease.”
Obesity “reprograms” white blood cells, which promotes cancerous tumor growth
Breast cancers occur in adipose tissue, better known as fat. In the study, titled Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer, published May 3, 2019, in the Journal of Experimental Medicine, Becker, Rosner and colleagues examine the biological mechanisms that explain how obesity expedites the onset of TNBC. Findings show that obesity “reprograms” macrophages – scavenger white blood cells that can devour invaders such as bacteria, viruses or tumor cells – into pro-inflammatory, metabolically-activated (MMe) macrophages. Instead of fighting breast cancer, these immune cells actually promote it.
A significant challenge with TNBC, the researchers note, is that none of the three most appealing drug targets – the estrogen receptor, the progesterone receptor and human epidermal growth factor receptor 2 – are present in TNBC cells.
“Our studies, in mice and humans,” Becker adds, “implicate these metabolically-activated adipose tissue macrophages.” The corrupted white blood cells accumulate in mammary adipose tissue, which produces interleukin 6 (IL-6), a pro-inflammatory cytokine that can fuel tumorigenesis. The reprogrammed cells thrive on obesity.
IL-6 binds to a receptor on the surface of existing cancer cells, which can create “an even more aggressive stem cell phenotype,” Becker says. “These cancer stem cells are able to encourage tumor growth and metastasis, enabling them to travel to other sites.” Patients with advanced or metastatic cancer have higher levels of IL-6 in their blood, which is correlated with poor survival rates.
Future directions for research in obesity-cancer linkage
Obesity, the study authors write, is a pathological state that “facilitates tumorigenesis by creating tumor permissive conditions in multiple tissues.” This suggests that chronic inflammation and its effects on tumorigenesis may be reversed by targeted anti-inflammatory therapies or by weight loss.
In alignment with this hypothesis, the researchers found that inducing weight loss in obese mice by feeding them a healthier low-fat diet reversed macrophage inflammation and TNBC tumor formation in mammary fat, even as their body weight remained elevated. These findings highlight the potential value of weight loss, not only as a preventive intervention but even after patients develop breast cancer.
The researchers note that certain drugs that target inflammatory cytokine production by reprogramed macrophages, which were tested on obese patients, may have some value in therapeutic use for breast cancer patients. However, the therapeutic value of these drugs in treating TNBC has yet not been explored in human studies. “Our work supports the idea of testing these drugs in obese women with TNBC,” Dr. Becker tells NutritionInsight.
“We are currently developing therapeutics that inhibit inflammation in MMe macrophages. One caveat of therapeutically inhibiting inflammation in macrophages is that our body needs this inflammation to combat viral and bacterial pathogens,” Dr. Becker explains. “However, my lab is developing a therapeutic strategy that inhibits inflammation in MMe macrophages to treat obesity-associated TNBC – without interfering with the inflammation that our bodies require to combat infections.”
The researchers plan to share are looking forward to sharing their findings on this new strategy in subsequent manuscripts.
Source: Nutrition Insight
