Vroling Laura, van der Veldt Astrid A M, de Haas Richard R, Haanen John B A G, Schuurhuis Gerrit Jan, Kuik Dirk J, van Cruijsen Hester, Verheul Henk M W, van den Eertwegh Alfons J M, Hoekman Klaas, Boven Epie, van Hinsbergh Victor W M, Broxterman Henk J
Department of Medical Oncology, VU University Medical Center, De Boelelaan 1117, Amsterdam, The Netherlands.
Angiogenesis. 2009;12(1):69-79. doi: 10.1007/s10456-009-9133-9. Epub 2009 Feb 11.
Mature circulating endothelial cell (CEC) as well as endothelial progenitor populations may reflect the activity of anti-angiogenic agents on tumor neovasculature or even constitute a target for anti-angiogenic therapy. We investigated the behavior of CECs in parallel with hematopoietic progenitor cells (HPCs) in the blood of renal cell cancer patients during sunitinib treatment. We analyzed the kinetics of a specific population of small VEGFR2-expressing CECs (CD45(neg)/CD34(bright)), HPCs (CD45(dim)/CD34(bright)), and monocytes in the blood of 24 renal cell cancer (RCC) patients receiving 50 mg/day of the multitargeted VEGF inhibitor sunitinib, on a 4-week-on/2-week-off schedule. Blood was taken before treatment (C1D1), on C1D14, C1D28, and on C2D1 before the start of cycle 2. Also plasma VEGF and erythropoietin (EPO) were determined. Remarkably, while CD34(bright) HPCs and monocytes decreased during treatment, CD34(bright) CECs increased from 69 cells/ml (C1D1) to 180 cells/ml (C1D14; P = 0.001) and remained high on C1D28. All cell populations recovered to near pre-treatment levels on C2D1. Plasma VEGF and EPO levels were increased on C1D14 and partly normalized to pre-treatment levels on C2D1. In conclusion, opposite kinetics of two circulating CD34(bright) cell populations, HPCs and small CECs, were observed in sunitinib-treated RCC patients. The increase in CECs is likely caused by sunitinib targeting of immature tumor vessels.
成熟循环内皮细胞（CEC）以及内皮祖细胞群体可能反映抗血管生成药物对肿瘤新生血管的作用，甚至可能成为抗血管生成治疗的靶点。我们研究了舒尼替尼治疗期间肾细胞癌患者血液中CEC与造血祖细胞（HPC）的行为。我们分析了24例接受每日50 mg多靶点VEGF抑制剂舒尼替尼治疗（按4周用药/2周停药方案）的肾细胞癌（RCC）患者血液中表达VEGFR2的小CEC（CD45阴性/CD34明亮）、HPC（CD45暗淡/CD34明亮）和单核细胞特定群体的动力学。在治疗前（C1D1）、C1D14、C1D28以及第2周期开始前的C2D1采集血液。同时测定血浆VEGF和促红细胞生成素（EPO）。值得注意的是，治疗期间CD34明亮的HPC和单核细胞减少，而CD34明亮的CEC从69个细胞/毫升（C1D1）增加到180个细胞/毫升（C1D14；P = 0.001），并在C1D28时保持高位。所有细胞群体在C2D1时恢复到接近治疗前水平。血浆VEGF和EPO水平在C1D14时升高，在C2D1时部分恢复到治疗前水平。总之，在舒尼替尼治疗的RCC患者中观察到两种循环CD34明亮细胞群体，即HPC和小CEC的相反动力学。CEC的增加可能是由于舒尼替尼靶向未成熟肿瘤血管所致。
