Effects of overexpression of ephrin-B2 on tumour growth in human colorectal cancer
Effects of overexpression of ephrin-B2 on tumour growth in human colorectal cancer
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DOI：
10.1038/sj.bjc.6601723
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发表时间：
2004-04-19
影响因子：
8.8
通讯作者：
Ellis, LM
中科院分区：
文献类型：
--
作者：
Liu, W;Jung, YD;Ellis, LM
Eph受体酪氨酸激酶（RTK）和它们的膜结合配体，肝配蛋白，是胚胎血管发育所必需的。最近，已经证明特异性Ephs和肝配蛋白的过表达与人类肿瘤的不良预后相关。我们的研究小组已经表明，EphB和ephrin-B亚家族在人结直肠癌中共表达，ephrin-B2在人结直肠癌中的表达水平高于邻近正常粘膜。由于Eph/ephrin系统参与胚胎血管发生，ephrin-B2在我们实验室研究的所有结肠癌中普遍表达，我们假设结肠癌细胞中ephrin-B2的过度表达可能诱导肿瘤血管生成并增加肿瘤生长。为了研究这一假设，我们稳定转染KM 12 L4人结肠癌细胞ephrin-B2研究其对体内肿瘤生长的影响。我们发现肝配蛋白-B2的过度表达显著降低了小鼠异种移植模型中的肿瘤生长。免疫组织化学染色显示，肝配蛋白-B2转染产生较高的肿瘤微血管密度和较低的肿瘤细胞增殖比亲本或载体转染的对照细胞。使用Cr-51标记的红细胞（RBC），以确定在肿瘤的功能血容量，我们证明了肝配蛋白-B2转染的细胞的肿瘤有显着减少的血容量相比，从父母或载体转染的对照细胞的肿瘤。细胞周期介质的体外参数的评价表明细胞周期没有改变。虽然肝配蛋白-B2转染增加了肿瘤血管密度，但血液灌注的减少表明这些血管可能是“功能障碍”的。我们得出结论，肝配蛋白-B2的过度表达抑制肿瘤细胞的生长和血管功能，在这个体内结肠癌模型。
Eph receptor tyrosine kinases (RTKs) and their membrane-bound ligands, the ephrins, are essential for embryonic vascular development. Recently, it has been demonstrated that overexpression of specific Ephs and ephrins is associated with a poor prognosis in human tumours. Our group has shown that EphB and the ephrin-B subfamilies are coexpressed in human colorectal cancer, and ephrin-B2 is expressed at higher levels in human colorectal cancer than in adjacent normal mucosa. As the Eph/ephrin system is involved in embryologic vasculogenesis and ephrin-B2 is expressed ubiquitously in all colon cancers studied in our laboratory, we hypothesised that overexpression of ephrin-B2 in colon cancer cells may induce tumour angiogenesis and increase tumour growth. To investigate this hypothesis, we stably transfected KM12L4 human colon cancer cells with ephrin-B2 to study its effect on tumour growth in vivo. We found that overexpression of ephrin-B2 markedly decreased tumour growth in a mouse xenograft model. Immunohistochemical staining showed that ephrin-B2 transfectants produced higher tumour microvessel density and lower tumour cell proliferation than did parental or vector-transfected control cells. Using Cr-51-labelled red blood cells (RBCs) to determine the functional blood volume in tumours, we demonstrated that tumours from ephrin-B2-transfected cells had significantly decreased blood volume compared with tumours from parental or vector-transfected control cells. Evaluation of in vitro parameters of cell cycle mediators demonstrated no alteration in the cell cycle. Although ephrin-B2 transfection increased tumour vessel density, the decrease in blood perfusion suggests that these vessels may be 'dysfunctional'. We conclude that overexpression of ephrin-B2 suppresses tumour cell growth and vascular function in this in vivo colon cancer model.