Compared to preoperative plasma levels post-operative urokinase-type plasminogen activator-1 levels are persistently elevated for 6 weeks after minimally invasive colorectal resection

BACKGROUND: Urokinase-type plasminogen activator-1 (uPA) is a serine protease that converts plasminogen to plasmin after binding to uPA receptor (uPAR). Plasmin catalyzes the regeneration of basement membrane, extracellular matrix, and other tissues. uPA alone and with plasmin leads to activation of angiogenic growth factors that impact tumor cell proliferation, adhesion, and migration. uPA over expression has been noted in colorectal cancer (CRC) and high tissue levels have been correlated with prognosis. uPA/uPAR promotes immune cell activation in healing surgical wounds and may alter perioperative uPA plasma levels. Postoperative (postop) plasma levels, if elevated, may impact the early growth of residual metastases. The impact of minimally invasive colorectal resection (MICR) surgery for CRC on plasma uPA levels is unknown. This study’s aim was to measure plasma uPA levels during the first postop month. METHODS: CRC patients undergoing MICR who enrolled in an Institutional Review Board (IRB) approved data/plasma bank for whom adequate plasma was available were included in the study. Patients who had chemotherapy or radiotherapy within 4 weeks, those who received blood transfusions perioperatively and immunosuppressed patients were excluded. Clinical and pathological data were prospectively collected as were blood samples preoperatively, postop day (POD) 1, 3 and at least 1 late time point between POD 7–41. Plasma was isolated and stored at −80 ℃. Late samples were bundled into 7-day blocks and considered as single time points. Total uPA levels (ng/mL) were analyzed in duplicate via enzyme-linked immunosorbent assay (ELISA) and results reported as mean ± standard deviation (SD). The Wilcoxon paired t-test was used for analysis. RESULTS: Ninety-three patients undergoing MICR for CRC [colonic 68%; rectal 32%; average age 65.6 years, laparoscopic 63%, hand-assisted minimally invasive surgery (MIS) 37%] who met criteria were studied. Cancer stage breakdown was; stage I, 30%, stage II, 29%, stage III, 34%, stage IV, 7%. The median preoperative (preop) uPA plasma level (ng/mL) was 529.8 [95% confidence interval (CI): 462.8, 601.1] (n=93). Significant elevations in median levels vs. preop were present during POD 3 (542.8, 95% CI: 518.8, 597.3, n=86, P=0.003), POD 7–13 (688.1, 95% CI: 591.7, 753.0, n=72, P<0.001), POD 14–20 (764.9, 95% CI: 704.1, 911.6, n=27, P<0.001), POD 21–27 (685.6, 95% CI: 443.8, 835.8, n=15, P<0.001), and on POD 28–41 (800.3, 95% CI: 626.9, 940.6, n=21, P<0.001). The colon cancer subgroup’s preop and POD 14–20 median results were significantly higher than the corresponding rectal cancer results; otherwise, at the other 5 postop time points there were no significant differences between the rectal and colon cancer subgroups. In addition, no association was found between cancer stage and preop uPA levels and no significant differences were found in postop uPA levels between the hand-assisted laparoscopic group and the lap assisted subgroup at any of the postop time points. CONCLUSIONS: Persistently elevated plasma uPA levels at 5/6 postop time point (P<0.05), in combination with other previously demonstrated long duration proangiogenic plasma protein changes, may render the plasma proangiogenic within the period of the first month post-surgery and may promote angiogenesis within the residual tumor foci. The clinical significance pertaining to these changes, if any, is uncertain and remains to be proven.