Initial stages of tumor cell-induced angiogenesis: Evaluation via skin window chambers in rodent models
Initial stages of tumor cell-induced angiogenesis: Evaluation via skin window chambers in rodent models
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DOI：
10.1093/jnci/92.2.143
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发表时间：
2000-01-19
影响因子：
10.3
通讯作者：
Dewhirst, MW
中科院分区：
文献类型：
--
作者：
Li, CY;Shan, SQ;Dewhirst, MW
背景资料：关于肿瘤细胞被触发启动血管生成过程（新血管的形成）后立即发生的事件的信息很少。这些信息与微转移瘤何时血管化的问题有关，并且对微转移瘤对各种治疗的可及性具有影响。在本研究中，我们试图在体内肿瘤生长的最早可能阶段监测血管生成起始时的事件。用编码增强型绿色荧光蛋白（GFP）的基因稳定转染两种不同的啮齿类动物乳腺肿瘤细胞系，Fischer 344大鼠的R3230 Ac和BALB/c小鼠的4 T1。将GFP标记的R3230 Ac或4 T1细胞（约20-50个细胞）分别植入Fischer 344 fats或BALB/c小鼠的背侧皮褶窗室中。然后连续和非侵入性地监测肿瘤血管生成长达4周。结果如下：当肿瘤质量达到约60-80个细胞时，观察到宿主脉管系统修饰的明确证据，并且当肿瘤质量达到约100-300个细胞时，观察到功能性新血管。个体肿瘤细胞表现出趋化性样生长模式，朝向预先存在的宿主脉管系统。当肿瘤细胞与ex-flk 1（一种已知具有抗血管生成作用的可溶性截短的血管内皮细胞生长因子受体蛋白）一起注射时，初始的血管生成和肿瘤生长活性被显著抑制，表明血管生成抑制剂甚至可以在血管生成开始之前停止肿瘤生长。当肿瘤块包含大约100-380个细胞时。识别启动肿瘤细胞向现有脉管系统迁移的趋化信号可以为预防肿瘤进展和/或转移提供有价值的靶点。
Background: There is a paucity of information about events that follow immediately after tumor cells are triggered to initiate the process of angiogenesis (the formation of new blood vessels). Such information is relevant to the issue of when micrometastases vascularize and has implications for the accessibility of micrometastases to various treatments, In this study, we attempted to monitor events at the initiation of angiogenesis at the earliest possible stage of tumor growth in vivo, Methods: Two different rodent mammary tumor cell lines, R3230Ac from the Fischer 344 rat and 4T1 from the BALB/c mouse, were stably transfected with a gene that encodes an enhanced version of green fluorescence protein (GFP). GFP-labeled R3230Ac or 4T1 cells (about 20-50 cells) were implanted into dorsal skinfold window chambers of Fischer 344 fats or BALB/c mice, respectively. Tumor angiogenesis was then monitored serially and noninvasively for up to 4 weeks. Results: Clear evidence of modification of the host vasculature was observed when tumor mass reached approximately 60-80 cells, and functional new blood vessels were seen when tumor mass reached roughly 100-300 cells. Individual tumor cells exhibited a chemotaxis-like growth pattern toward the pre-existing host vasculature. When ex-flk1 (a soluble, truncated vascular endothelial cell growth factor receptor protein known to be antiangiogenic) was injected with the tumor cells, the initial angiogenic and tumor growth activities were inhibited considerably, indicating that angiogenesis inhibitors may halt tumor growth even before the onset of angiogenesis, Conclusion, Angiogenesis induced by tumor cells after implantation in the host begins at a very early stage, i.e., when the tumor mass contains roughly 100-380 cells. Identification of chemotactic signals that initiate tumor cell migration toward the existing vasculature may provide valuable targets for preventing tumor progression and/or metastases.