Researchers at Massachusetts General Hospital (MGH) may have discovered a new mechanism behind obesity’s ability to encourage cancer. The study, which focused on the effects of obesity on pancreatic and breast cancer, reported a relationship between obesity and an excess of PlGF (placental growth factor), and found that PlGF’s binding to its receptor VEGFR-1, which is expressed within a tumor’s immune cells, encourages cancer progression.
The study, titled “PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity,” was published in the journal Clinical Cancer Research.
Study results also indicated that targeting PlGF/VEGFR-1 signaling reprograms the tumor immune microenvironment, and inhibits obesity-induced acceleration of tumor progression.
“We found that obesity increased infiltration of tumor-promoting immune cells and the growth and metastasis of pancreatic cancers,” Dai Fukumura, MD, PhD, from the Steele Laboratory of Tumor Biology in the MGH Department of Radiation Oncology and the study’s co-senior author, said in a news release. “Blocking VEGFR-1 signaling shifted the immune environment towards prevention of tumor progression in obese but not in lean mice in both pancreatic and breast cancer models. We also found that PlGF was present in excess in obesity and that reduction of PlGF produced similar results to VEGFR-1 inhibition in the tumors of obese mice.”
With the current worldwide obesity epidemic, many pancreatic and breast cancer patients are either overweight or obese at diagnosis. Importantly, obesity is associated with a poor prognosis in these patients. Hence, uncovering the cellular mechanisms underlying such poor outcomes is imperative.
The team discovered a significant correlation between plasma PlGF and adiposity in pancreatic and breast cancer patients. Furthermore, using clinically relevant mouse models, they found that PlGF/VEGFR-1 signaling contributes to obesity-induced tumor progression, and that targeting the PlGF/VEGFR-1 interaction prevents weight gain, although it aggravates a diabetes-like condition that can be eased with metformin (a commonly used drug for diabetes).
“Uncovering potential therapeutic targets within the mechanisms that associate obesity with poor cancer prognoses is the first step towards developing remedies that could disrupt this association and significantly improve patient outcome,” said Rakesh K. Jain, PhD, director of the Steele Laboratory and a co-senior study author. “The fact that this new mechanism underlies obesity’s impact on two types of cancer suggests that it may be a common mechanism of tumor induction that could apply to other cancer types.”
Joao Incio, MD, also from the Steele lab and lead author of the study, added, “Understanding the way that obesity affects pancreatic and other cancers may help us identify biomarkers — such as body weight and increased levels of PlGF — that could identify patients for whom anti-VEGFR-1 treatment would be most beneficial. In addition, we should incorporate body weight into the design of pre-clinical studies in order to better reflect the lack of response to novel targeted therapies such as anti-VEGF. Targeting inflammation holds the promise to improve the clinical outcome of a major subset of cancer patients.”