Plasma angiopoietin-2 is persistently elevated after non-small cell lung cancer surgery and stimulates angiogenesis in vitro

Angiopoietin-2 (Ang2) is a key proangiogenic factor, but its role in surgery-induced angiogenesis, a possible cause of cancer recurrence, is still elusive.We measured the plasma Ang2 levels in healthy controls (n = 42) and stage I-IV perioperative nonsmall cell lung cancer (NSCLC) patients (n = 227) with enzyme-linked immunosorbent assay, and examined the impact of Ang2 in the plasmas on in vitro angiogenesis and proliferation of human umbilical vein endothelial cells and human microvascular endothelial cells.Ang2 plasma levels are significantly increased in untreated NSCLC patients (2697 ± 1354 pg/mL) compared to control (1473 ± 560.6 pg/mL) and positively associated with disease stage but not with histology. Ang2 plasma levels in stage I-IIIA NSCLC patients (n = 154) are elevated after the standard open thoracic surgery, following an approximate pattern to increase quickly in the 1st postoperative days (PODs, from preoperative 2342 ± 1084 to POD1: 4485 ± 1617 and POD3: 5370 ± 1879 pg/mL), reach the peak about 2 weeks later (POD14: 6099 ± 2280 pg/mL), drop slowly thereafter (POD28: 3877 ± 1388 and POD42: 3365 ± 1189 pg/mL), and remain significantly higher than preoperative 8 weeks after the procedure (POD56: 2937 ± 943.3 pg/mL). The postoperative plasmas enhance in vitro angiogenesis and Ang2 removal from the plasmas can counteract the effect. The postoperative plasmas stimulate endothelial proliferation independently of Ang2.These results suggest that plasma Ang2 increases after NSCLC surgery and contributes to the proangiogenic property of the postoperative plasmas, thus supporting the possible administration of anti-Ang2 therapy for NSCLC in postoperative adjuvant setting.