P3-08-03: Exercise Increases Soluble Vascular Endothelial Growth Factor Receptor-1 (sFlt-1) in the Circulation of Adult Women.
Authors: K Makey, SG Patterson, J Robinson, M Loftin, DE Waddell, L Miele, E Chinchar, M Huang, AD Smith, M Weber, J-W Gu
Journal: Cancer Research (2011)

Abstract Background: Physical inactivity increases the risk of several different cancers, including breast cancer. Soluble fms-like tyrosine kinase-1 (sFlt-1) is an extra-cellular Ig-like domain of the VEGF receptor-1 that is released into the extracellular space and circulation where it inhibits the activities of VEGF. Over-expression of sFlt-1 has been shown to inhibit ovarian tumor growth in gene therapy experiments. The present study tests the hypothesis that exercise can increase sFlt-1 in the circulation of adult women. Material and Methods: 63 African American and Caucasian adult woman volunteers aged 18–44 were enrolled into a prospective exercise study. All the participants walked on a treadmill for 30 minutes at a moderate intensity (40-60% heart rate reserve), and oxygen consumption (VO2) was quantified by utilizing a metabolic cart. Blood samples were collected before and immediately after exercise. The exercise test was conducted between the first and seventh day of the participant's menstrual cycle. The plasma concentrations of sFlt-1, unbound VEGF, and endostatin were measured using ELISA kits from R and D Systems. Results: Plasma levels of sFlt-1 were 67.8±3.7 pg/ml immediately after exercise (30 minutes), significantly higher than basal levels of 54.5±3.3 pg/ml before exercise (P&amp;lt;0.01; n=63). The % increase in sFlt-1 levels before and after exercise in adult women was 54%. There was no significant difference in the % increase of sFlt-1 levels between African American and Caucasian groups (P=0.5334). There was no significant difference in plasma levels of endostatin before (92.4±4.4 ng/ml) and immediately after (93.8±4.4 ng/ml; P=0.8216) exercise. The basal plasma levels of unbound VEGF (21.5±4.3 pg/ml) ware similar to the plasma levels of VEGF (22.5±4.6 pg/ml; P=0.8652) immediately after exercise. Discussion: We previously reported that plasma levels of sFlt-1 significantly increased 30 minutes after exercise in adult men, in which plasma levels of unbound-VEGF significantly decreased and plasma levels of endostatin significantly increased 2 hours after exercise. Until now, there has been no data on whether exercise increases plasma sFlt-1 levels in women. Our study is the first to show that exercise in adult women significantly increases plasma levels of sFlt-1. VEGF pathways have both autocrine and paracrine effects for promoting breast cancer progression. Previous studies have demonstrated that sFlt-1 inhibits the activities of VEGF and suppresses ovarian tumor growth in mice. Exercise-induced plasma levels of sFlt-1 could be an important clinical biomarker to explore the mechanisms of exercise training in reducing breast cancer progression. The sFtl-1 is produced in the microvascular and macrovascular endothelial cells that exist throughout the skeletal muscle tissues. It is therefore plausible that release of sFlt-1 from the skeletal muscles into the circulation might be due to exercise-dependent reductions in oxygen tension in the skeletal muscle. In future studies, we will determine whether sFlt-1 can be released directly from the exercised muscle. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-08-03.