Plasticity in urokinase-type plasminogen activator receptor (uPAR) display in colon cancer yields metastable subpopulations oscillating in cell surface uPAR density--implications in tumor progression.
Plasticity in urokinase-type plasminogen activator receptor (uPAR) display in colon cancer yields metastable subpopulations oscillating in cell surface uPAR density--implications in tumor progression.
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结肠癌中尿激酶型纤溶酶原激活剂受体 (uPAR) 显示的可塑性产生细胞表面 uPAR 密度振荡的亚稳态亚群，这对肿瘤进展有影响。
DOI：
10.1158/0008-5472.can-05-3208
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发表时间：
2006
期刊：
影响因子：
11.2
通讯作者：
Boyd,DouglasD
中科院分区：
文献类型：
--
作者：
Yang,Lin;Avila,Hector;Wang,Heng;Trevino,Jose;Gallick,GaryE;Kitadai,Yasuhiko;Sasaki,Takamitsu;Boyd,DouglasD
越来越清楚的是，肿瘤的生长和发展并不完全是遗传异常造成的，也反映了肿瘤细胞的可塑性。因此，导致肿瘤进展的蛋白质在其表达上振荡，这一争论尚未显示出来。由于尿激酶型纤溶酶原激活剂受体(UPAR)促进肿瘤生长和侵袭，我们确定其表达是否本身是可塑性的。在荧光激活细胞分选(FACS)中，三个独立的结肠癌克隆群体显示细胞表面uPAR符合预期的高斯分布。然而，从FACS后缘收集的细胞的亚克隆产生了亚群，显示出较低的细胞表面uPAR数。重要的是，这些亚克隆自发地恢复到富含uPAR的细胞，这表明了一种亚稳定的表型。UPAR显示的可塑性与分化的活体行为有关，肿瘤生长和进展较弱，与受体缺乏分离。从机制上讲，uPAR表达减少并不反映基因表达受到抑制，而是反映了uPAR蛋白从膜插入到脱落的转换。据我们所知，这是第一次证明uPAR细胞表面密度是振荡的，我们认为这种事件很可能有助于肿瘤的进展。(癌症研究2006；66(16)：7957-67)
It is becoming increasingly clear that tumor growth and progression is not entirely due to genetic aberrations but also reflective of tumor cell plasticity. It follows therefore that proteins contributing to tumor progression oscillate in their expression a contention yet to be shown. Because the urokinase-type plasminogen activator receptor (uPAR) promotes tumor growth and invasion, we determined whether its expression is itself plastic. In fluorescence-activated cell sorting (FACS), three independent colon cancer clonal populations revealed the expected Gaussian distribution for cell surface uPAR display. However, subcloning of cells collected from the trailing edge of the FACS yielded subpopulations, displaying low cell surface uPAR number. Importantly, these subclones spontaneously reverted to cells enriched in uPAR display, indicating a metastable phenotype. uPAR display plasticity was associated with divergentin vivobehavior with weak tumor growth and progression segregating with receptor deficiency. Mechanistically, reduced uPAR display reflected not repressed gene expression but a switch in uPAR protein trafficking from membrane insertion to shedding. To our knowledge, this is the first demonstration that uPAR cell surface density is oscillatory and we propose that such an event might well contribute to tumor progression. (Cancer Res 2006; 66(16): 7957-67)