Department of Thoracic Oncology, Key Laboratory of Cancer Prevention and Therapy, Lung Cancer Center of Tianjin, Cancer Hospital of Tianjin Medical University, Tianjin, China.
J Cancer Res Clin Oncol. 2012 Jul;138(7):1131-44. doi: 10.1007/s00432-012-1189-z. Epub 2012 Mar 10.
Endostatin can normalize the tumor vasculature to some extent. However, exact length of its time window and corresponding markers for tumor vascular normalization are needed to be explored.
The A549 lung adenocarcinoma xenograft murine model was treated with recombinant human endostatin (rh-endostatin) for 14 days. Cisplatin was combined in different schedules. The effects of rh-endostatin on circulating endothelial cells (CECs) by flow cytometry, tumor vasculature and angiogenesis-related factors by confocal microscope and immunohistochemistry, and anti-tumor efficacy of cytotoxic drugs were observed.
The activated CECs (aCECs) were increased on day 7 and decreased on day 10, and apoptotic CECs were increased on day 10. Tumor vasculature was transiently normalized with increased collagen coverage, decreased vessel permeability, intratumoral hypoxia, and microvascular density from day 7 to 10 after rh-endostatin administration. Extracellular matrix metalloproteinase inducer, vascular endothelial growth factor, matrix metalloproteinase (MMP)-2, and MMP-9 were transiently decreased by rh-endostatin from day 4 to 10, whereas the opposite effects were observed with tissue inhibitors of matrix metalloproteinase (TIMP)-1 and TIMP-2. The maximal anti-tumor effects of cisplatin were observed on administration from day 5 to 9 after rh-endostatin initial administration.
Rh-endostatin could transiently normalize tumor vasculature, probably via regulation of both pro- and anti-angiogenesis factors. The synergistic efficacy of anti-angiogenesis and chemotherapy was found during "the normalization window". CEC could be a feasible blood biomarker for defining "vascular normalization window" and providing the evidence to make an optimizing combination therapeutic schedule in human tumor.
内皮抑素在一定程度上可以使肿瘤血管正常化。然而，需要探索其时间窗的确切长度及其相应的肿瘤血管正常化标志物。
采用重组人内皮抑素（rh-endostatin）治疗 A549 肺腺癌细胞异种移植小鼠模型 14 天。联合不同方案使用顺铂。通过流式细胞术观察 rh-endostatin 对循环内皮细胞（CECs）的影响，通过共聚焦显微镜和免疫组织化学观察肿瘤血管和血管生成相关因子，以及细胞毒性药物的抗肿瘤疗效。
第 7 天，激活的 CECs（aCECs）增加，第 10 天减少，凋亡的 CECs增加。rh-endostatin 给药后第 7 天至第 10 天，肿瘤血管短暂正常化，胶原覆盖率增加，血管通透性降低，肿瘤内缺氧，微血管密度增加。细胞外基质金属蛋白酶诱导剂、血管内皮生长因子、基质金属蛋白酶（MMP）-2 和 MMP-9 于第 4 天至第 10 天被 rh-endostatin 短暂下调，而基质金属蛋白酶组织抑制剂（TIMP）-1 和 TIMP-2 则出现相反的作用。rh-endostatin 初始给药后第 5 天至第 9 天给予顺铂，可获得最大的抗肿瘤效果。
rh-endostatin 可短暂地使肿瘤血管正常化，可能是通过调节促血管生成和抗血管生成因子。在“正常化窗口”期间发现了抗血管生成和化疗的协同疗效。CEC 可能是一种可行的血液生物标志物，用于定义“血管正常化窗口”，并为人类肿瘤提供制定优化联合治疗方案的证据。
