PlGF/ VEGFR-1 interaction links obesity to pancreatic, breast cancer in preclinical models

Researchers at Massachusetts General Hospital (MA, USA) have discovered a novel mechanism involving the PlGF/ VEGFR-1 pathway that may explain how obesity can contribute to breast and pancreatic cancer.

Prior to this study, the mechanism of obesity-induced pancreatic and breast cancer progression was largely unknown. However, the recent findings, published in Clinical Cancer Research, reveal that targeting VEGFR-1 disrupts this interaction and might prove to be an effective cancer therapy in obese individuals.

The research team chose to focus on pancreatic and breast cancer in particular because more than half of individuals diagnosed with pancreatic and breast tumors are overweight or obese.

In the study, the team demonstrated that obesity was associated with an overabundance of a factor termed PlGF and that PlGFs binding to its receptor VEGFR-1, which is expressed on tumor immune cells, enhanced tumor progression.

Dai Fukumura, Deputy Director of the Steele Laboratory of Tumor Biology in the Massachusetts General Hospital Department of Radiation Oncology, commented: “We found that obesity increased infiltration of tumor-promoting immune cells and the growth and metastasis of pancreatic cancers.”

“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.”

The findings reveal that targeting VEGFR-1 could prevent tumor growth by altering the immunosuppressive tumor environment in obese mice.

In addition, the team discovered that targeting the interaction of PIGF/VEGFR-1 prevented weight gain in an obese mouse model. However, this also caused worsening of a diabetes-like condition. Metformin alleviated this and resulted in beneficial antitumor effects.

Overall, the findings provide an important step towards uncovering therapeutic targets that link obesity and cancer progression. The PlGF/ VEGFR-1 pathway could also underlie associations between obesity and other types of cancer.

Lead author of the study, Joao Incio, also 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.”

Sources: Incio J, Tam J, Rahbari NN et al. PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity. Clinical Cancer Research. DOI: 10.1158/1078-0432.CCR-15-1839 (2016); Massachusetts General Hospital press release