Inhibiting the PIGF/VEGFR-1 signaling regressed tumor growth in obese, but not in lean mice, the author report.
Obesity is a confirmed risk factor for the development of several cancers, including those of the breast, colon and rectum, endometrium, and pancreas. Now, a new study has confirmed the mechanism by which obesity promotes pancreatic and breast cancer, identifying potential targets for drug developers.
In their study published in the journal Clinical Cancer Research,1 the authors describe blocking a signaling axis that could successfully that prevented further tumor progression in obese, but not in lean mice. The researchers successfully developed a diet-induced obese mouse model. Control lean mice and the obese mice were then orthotopically implanted with pancreatic ductal adenocarcinoma or breast cancer.
Placental growth factor (PIGF) is a protein that plays an important role in obesity, and when the authors blocked signaling along the PIGF/vascular endothelial growth factor receptor 1 (VEGFR-1) pathway, it altered the activity of tumor-associated macrophages, altered the overall immunosuppressive tumor microenvironment, and reduced the rate of tumor growth in obese mice. While inhibiting VEGFR-1 signaling reduced the rate of tumor progression, the researchers also observed worsened hyperinsulinemia in those mice. This was quite easily compensated by administering metformin, which, the authors observed, further improved the anti-tumor effects.
“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,” according to one of the senior study authors Dai Fukumura, MD, PhD, of the Steele Laboratory of Tumor Biology, Department of Radiation Oncology, Massachusetts General Hospital.
This is an important finding, considering the significant increase in obesity-related cancer mortality demonstrated in multiple cancer types, including breast and pancreatic cancer.2,3
“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,” said Joao Incio, MD, also from the Steele Laboratory of Tumor Biology, and lead author on the study.
1. Incio J, Tam J, Rahbari NN, et al. PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity [published online February 9, 2016]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-15-1839.
2. Majumder K , Gupta A , Arora N , Singh PP , Singh S. Premorbid obesity and mortality in patients with pancreatic cancer: a systematic review and meta-analysis [published online October 9, 2015]. Clin Gastroenterol and Hepatol. doi: http://dx.doi.org/10.1016/j.cgh.2015.09.036.
3. Chan DS, Vieira AR, Aune D, et al. Body mass index and survival in women with breast cancer-systematic literature review and meta-analysis of 82 follow-up studies. Ann Oncol. 2014;25(10):1901-1914. doi: 10.1093/annonc/mdu042.