13 Feb Breast and Pancreatic Cancer: Pathway Identified That Accelerates Tumors in Obese Patients
MedicalResearch.com Interview with:
Joao Incio, MD
Edwin L. Steele Laboratory for Tumor Biology
Massachusetts General Hospital | Harvard Medical School | Boston, MA, U.S.A
Department of Internal Medicine | Hospital S. Joao | Porto, Portugal
Medical Research: What is the background for this study? What are the main findings?
Dr. Incio: The study focused on the effects of obesity on pancreatic and breast cancer, since more than half of those diagnosed with such tumors are overweight or obese. In addition, a number of large-scale studies have found that obesity leads to an increased risk of death in pancreatic, breast and other types of cancer. But prior to the current study the mechanism of obesity-induced pancreatic and breast cancer progression was unclear. We have uncovered a novel mechanism behind the ability of obesity to promote cancer progression. We found an association between obesity and an overabundance of a factor called PlGF (placental growth factor) and that PlGF’s binding to its receptor VEGFR-1, which is expressed on immune cells within tumors, promotes tumor progression.
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. We also discovered that targeting the PlGF/VEGFR-1 interaction prevents weight gain in a genetically obese mouse model but worsens a diabetes-like condition, a worsening that was alleviated by use of the common diabetes drug metformin, which also had beneficial anti-tumor effects.
Our findings in cellular and animal models, as well as in patient tumor samples, indicate that targeting the PlGF/ VEGFR-1 pathway may be particularly effective in obese patients.
Medical Research: What should clinicians and patients take away from your report?
Dr. Incio: With the majority of pancreatic and breast cancer patients being overweight or obese at diagnosis, 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. 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. 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.
Medical Research: What recommendations do you have for future research as a result of this study?
Dr. Incio: We should incorporate body weight into the design of pre-clinical studies in order to better reflect the response to novel targeted therapies such as anti-VEGFRs. Targeting inflammation holds the promise to improve the clinical outcome of a major subset of cancer patients.
Medical Research: Is there anything else you would like to add?
Dr. Incio: Fukumura, MD PhD, is an associate professor of Radiation Oncology, and Jain, PhD, is the Cook Professor of Tumor Biology at Harvard Medical School. Jain is among nine recipients of the 2016 National Medal of Science. Incio, MD, a postdoctoral fellow in the Steele Laboratories and the lead author of this study, recently received a prestigious American Association for Cancer Research (AACR) Scholar-in-Training award to present this work at the 2016 annual AACR meeting. The study also involved collaboration with researchers at other institutions, including the Dana-Farber Cancer Institute Department of Medical Oncology, the MGH Department of Radiology, Jobu University in Japan, the Vesalius Research Center in Belgium, and Porto University in Portugal.
Citation: Incio, J. Tam, N. N. Rahbari, P. Suboj, D. T. McManus, S. M. Chin, T. Vardam, A. Batista, S. Babykutty, K. Jung, A. Khachatryan, T. Hato, J. A. Ligibel, I. Krop, S. B. Puchner, C. L. Schlett, U. Hoffmman, M. Ancukiewicz, M. Shibuya, P. Carmeliet, R. Soares, D. G. Duda, R. K. Jain, D. Fukumura.
PlGF/VEGFR-1 signaling promotes macrophage polarization and accelerated tumor progression in obesity. Clinical Cancer Research, 2016;
Joao Incio, MD (2016). Breast and Pancreatic Cancer: Pathway Identified That Accelerates Tumors in Obese Patients