Markedly elevated levels of VEGF, ANG-2 & MMP-2 in wound fluid after CR resection are likely responsible for elevated plasma levels of these proteins during the 1st postop month: Preliminary results

Hmc Shantha Kumara, PhD1, Hiromichi Miyagaki, MdPhD2, Charles Petrick, BS1, Xiaohong Yan, PhD1, Linda Njoh, PhD1, Vesna Cekic, RN1, Nipa D Gandhi, MD1, Richard L Whelan, MD1. 1Department of Surgery, Mount Sinai Roosvelt Hospital, New York, USA, 2Department of Gastroenterological surgery,Osaka University,Osaka,Japan

Introduction: Persistently elevated plasma levels of proangiogenic proteins including VEGF, Angiopoietin 2 (ANG-2) and Matrix Metalloproteinase 2 (MMP2) have been noted for 3-5 weeks after colorectal cancer (CRC) resection. Whereas increases early after surgery may be due to the brief acute inflammatory response, the origin of the week 2-5 elevations is uncertain. We hypothesize that wounds are a major source since angiogenesis plays a critical role in wound healing. This study’s purpose is to determine the levels of the above 3 proteins in fluid from intra-abdominal wounds taken during the 1st month after CRC resection and compare them to previously determined postoperative plasma levels of the same proteins.

Method: The study population was CRC patients who agreed to enter an IRB approved wound fluid study. Wound fluid samples (WFS) collected via Jackson Pratt drains on postoperative day (POD) 1, 3, and a variety of later time points were centrifuged and stored at -80°C. Late samples (POD 7-20) were bundled into 7 day blocks and considered as single time points. VEGF, ANG-2 and MMP2 levels were determined in duplicate via ELISA and reported as mean± SD. The paired t-test was used for statistical analysis (significance p<0.05).

Results: Nine cancer patients were studied (8 rectal, 1 colon; mean age 65.3± 2.3 years; surgical methods used: laparoscopic-assisted, 4; hand-assisted laparoscopic, 1; and lap. converted to open, 4 (mean incision length for lap & hand, 6.4±4.3; for open 23±8.2). The mean length of stay was 7.8± 3.5 days. The cancer stage breakdown was; Stage 1, 25%, Stage 2, 38%, stage 3, 25% and stage 4, 12%. The range of wound levels noted after surgery were: VEGF, 1762-7586 pg/ml; ANG-2, 9082-17393 pg/ml; and MMP-2, 579-1216 ng/ml. Previously determined plasma levels in similar CRC patients ranged from: VEGF, 164-371 pg/ml; ANG-2, 2671-4095 pg/ml; and MMP-2, 177-262 ng/ml. Further, the POD 7-13 wound levels of VEGF, ANG-2 and MMP-2 were higher than the POD1 results.

Conclusions:  When compared to previously determined postop plasma levels, wound levels of VEGF, ANG-2, and MMP-2 were 6 to 13 times higher. Also, wound levels continued to rise and peaked during the second (ANG-2) and third weeks (VEGF, MMP-2) after surgery. These results suggest that the very high wound levels of these proangiogenic proteins contribute to the elevated plasma levels noted after surgery.  The plasma changes may promote the growth of residual tumor deposits after surgery.

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