Tumour-endothelium interactions in co-culture: coordinated changes of gene expression profiles and phenotypic properties of endothelial cells
Tumour-endothelium interactions in co-culture: coordinated changes of gene expression profiles and phenotypic properties of endothelial cells
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DOI：
10.1242/jcs.00281
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发表时间：
2003-03-15
影响因子：
4
通讯作者：
Weichselbaum, RR
中科院分区：
文献类型：
--
作者：
Khodarev, NN;Yu, JQ;Weichselbaum, RR
肿瘤血管生成是基于肿瘤细胞和内皮细胞之间的一系列相互作用的复杂过程。为了模拟肿瘤/内皮细胞相互作用，我们将U87人胶质瘤细胞与人脐静脉内皮细胞（HUVEC）共培养。U87细胞诱导HUVECs的“活化”表型，包括增殖、迁移和网状形成的增加。在细胞直接接触和物理分离的共培养物中观察到活化，表明可溶性因子在观察到的表型和基因型变化中起重要作用。使用cDNA阵列评估肿瘤活化的内皮细胞的表达谱，并通过定量PCR确认。发现匹配的受体/配体对协同表达，包括TGF β RII与TGF β 3，FGFRII和富含半胱氨酸的成纤维细胞生长因子受体（CRF-1）与FGF 7和FGF 12，CCR 1、CCR 3、CCR 5与RANTES以及降钙素受体样基因（CALCRL）与肾上腺髓质素。与cDNA阵列数据一致，表达蛋白的免疫组织化学染色显示Tie-2受体在体外和体内上调。我们的数据表明，肿瘤诱导的静止内皮细胞的激活涉及血管生成相关受体的表达和自分泌生长环的诱导。我们认为，肿瘤细胞释放生长因子，诱导内皮细胞表达特定的配体及其同源受体协调。
Tumour angiogenesis is a complex process based upon a sequence of interactions between tumour cells and endothelial cells. To model tumour/endothelial-cell interactions, we co-cultured U87 human glioma cells with human umbilical vein endothelial cells (HUVECs). U87 cells induced an 'activated' phenotype in HUVECs, including an increase in proliferation, migration and net-like formation. Activation was observed in co-cultures where cells were in direct contact and physically separated, suggesting an important role for soluble factor(s) in the phenotypic and genotypic changes observed. Expressional profiling of tumour-activated endothelial cells was evaluated using cDNA arrays and confirmed by quantitative PCR. Matching pairs of receptors/ligands were found to be coordinately expressed, including TGFbetaRII with TGFbeta3, FGFRII and cysteine-rich fibroblast growth factor receptor (CRF-1) with FGF7 and FGF12, CCR1, CCR3, CCR5 with RANTES and calcitronin receptor-like gene (CALCRL) with adrenomedullin. Consistent with cDNA array data, immunohistochemical staining of expressed proteins revealed the upregulation of Tie-2 receptor in vitro and in vivo. Our data suggest that tumour-induced activation of quiescent endothelial cells involves the expression of angiogenesis-related receptors and the induction of autocrine growth loops. We suggest that tumour cells release growth factors that induce endothelial cells to express specific ligands and their cognate receptors coordinately.