Shantha Kumara H M C, Kirman I, Feingold D, Cekic V, Nasar A, Arnell T, Balik E, Hoffman A, Baxter R, Conte S, Whelan R L
Department of Surgery, Columbia University, New York Presbyterian Hospital, New York, USA.
Eur J Surg Oncol. 2009 Mar;35(3):295-301. doi: 10.1016/j.ejso.2008.07.012. Epub 2008 Sep 7.
Colorectal resection (CR) increases plasma VEGF levels which may promote residual tumor growth. This study assessed the effect of perioperative GMCSF on plasma levels of sVEGFR1, Ang-1 and Ang-2 and also the impact of post-GMCSF plasma on in vitro endothelial cell (EC) growth and invasion. Ang-2 increases while sVEGFR1 and Ang-1 impede angiogenesis.
Fifty-nine CR cancer patients were randomized to 7 perioperative doses of GMCSF or saline for 3days prior and 4days after CR. Blood samples were taken pre-drug (PreRx) and on several postoperative days (POD). Protein levels were assessed and PreRx and POD 5 plasma added to EC cultures after which branch point formation (ECBPF) and invasion (ECI) were measured.
sVEGFR1 levels were significantly higher on POD 1 and POD 5 in both groups but the GMCSF POD 5 level was twice the control value (p=0.002). Ang-2 levels were higher on PODs 1 and 5 in both groups (p<0.05) but the control POD 5 value (vs. GMCSF) was greater (p=0.03). Ang-1 decreases were noted in all (p=not significant, ns). The control group POD 5 ECBPF was 35.8% greater than Pre Rx (p=0.001) while the GMCSF result was 18.0% lower (p=ns); the control POD 5 median percent change from baseline was greater than the GMCSF result(p=0.008). The POD 5 ECI was +12.2% for the control group vs. baseline (p=ns) and -17.2% for the GMCSF group (p=ns): the control median percent change was greater than in the GMCSF group(p=0.045).
CR-related plasma changes are proangiogenic (>Ang-2) and anti-angiogenic (>sVEGFR1); the net effect is promotion of in vitro ECBPF. GMCSF limits the proangiogenic changes (higher POD 5 sVEGFR1 levels and lower Ang-2 elevations, lower POD 5 ECBPF and ECI). The clinical import of these effects is unclear; perioperative GMCSF has anti-angiogenic plasma effects that may limit tumor growth. Further investigation is warranted.
结直肠癌切除术（CR）会使血浆血管内皮生长因子（VEGF）水平升高，这可能会促进残留肿瘤生长。本研究评估了围手术期使用粒细胞-巨噬细胞集落刺激因子（GMCSF）对可溶性血管内皮生长因子受体1（sVEGFR1）、血管生成素-1（Ang-1）和血管生成素-2（Ang-2）血浆水平的影响，以及GMCSF治疗后血浆对体外内皮细胞（EC）生长和侵袭的影响。Ang-2增加，而sVEGFR1和Ang-1会阻碍血管生成。
59例CR癌症患者被随机分为两组，一组在CR术前3天和术后4天接受7个围手术期剂量的GMCSF，另一组接受生理盐水。在给药前（PreRx）和术后几天（POD）采集血样。评估蛋白质水平，并将PreRx和POD 5血浆添加到EC培养物中，然后测量分支点形成（ECBPF）和侵袭（ECI）。
两组在POD 1和POD 5时sVEGFR1水平均显著升高，但GMCSF组POD 5时的水平是对照组的两倍（p = 0.002）。两组在POD 1和POD 5时Ang-2水平均较高（p < 0.05），但对照组POD 5时的值（与GMCSF组相比）更高（p = 0.03）。所有患者的Ang-1水平均下降（p = 无显著性差异，ns）。对照组POD 5时的ECBPF比Pre Rx高35.8%（p = 0.001），而GMCSF组的结果低18.0%（p = ns）；对照组从基线开始的POD 5中位数变化百分比大于GMCSF组的结果（p = 0.008）。对照组POD 5时的ECI相对于基线增加了+12.2%（p = ns），GMCSF组为-17.2%（p = ns）：对照组的中位数变化百分比大于GMCSF组（p = 0.045）。
CR相关的血浆变化具有促血管生成作用（>Ang-2）和抗血管生成作用（>sVEGFR1）；其净效应是促进体外ECBPF。GMCSF限制了促血管生成变化（POD 5时sVEGFR1水平更高，Ang-2升高更低，POD 5时ECBPF和ECI更低）。这些效应的临床意义尚不清楚；围手术期GMCSF具有抗血管生成的血浆效应，可能会限制肿瘤生长。有必要进行进一步研究。
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