Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in metastatic disease.
Oncosome formation in prostate cancer: association with a region of frequent chromosomal deletion in metastatic disease.
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DOI：
10.1158/0008-5472.can-08-3860
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发表时间：
2009-07-01
期刊：
影响因子：
11.2
通讯作者：
Freeman MR
中科院分区：
文献类型：
--
作者：
Di Vizio D;Kim J;Hager MH;Morello M;Yang W;Lafargue CJ;True LD;Rubin MA;Adam RM;Beroukhim R;Demichelis F;Freeman MR
癌小体最近被描述为由癌细胞分泌的膜衍生的微泡，其跨细胞边界传递致癌信号和蛋白质复合物。在这里，我们展示了DU 145和LNCaP人前列腺癌细胞癌小体的快速形成和分泌。癌小体的形成受到EGFR激活和膜靶向Akt 1过表达的刺激。从前列腺癌细胞脱落的微囊泡含有许多信号转导蛋白，并且能够激活受体肿瘤细胞中的快速磷酸酪氨酸和Akt途径信号传导，并刺激增殖和迁移。它们还在受体正常细胞中诱导基质反应。通过RNA干扰敲低肌动蛋白成核蛋白透明相关形成蛋白3（DRF 3/Dia 2）增强了癌小体形成的速率，表明这些结构类似于非凋亡膜泡，并且可能与非凋亡膜泡相同，非凋亡膜泡是细胞运动的变形虫形式的特征。使用100 K SNP阵列对原发性和转移性人前列腺肿瘤的分析显示，与器官局限性肿瘤相比，转移性肿瘤中编码DRF 3（DIAPH 3）的基因座的缺失频率显著更高（p=0.001）。荧光原位杂交（FISH）证实了不同患者队列中转移性肿瘤中DIAPH 3的染色体丢失增加（p=0.006）。这些数据表明，从前列腺癌细胞脱落的微泡可以以可能促进疾病进展的方式改变肿瘤微环境。他们还表明，DRF 3是一种生理相关的蛋白质，似乎可以调节这一过程。
Oncosomes have recently been described as membrane-derived microvesicles secreted by cancer cells, which transfer oncogenic signals and protein complexes across cell boundaries. Here we demonstrate the rapid formation and secretion of oncosomes from DU145 and LNCaP human prostate cancer cells. Oncosome formation was stimulated by EGFR activation and also by over-expression of membrane-targeted Akt1. Microvesicles shed from prostate cancer cells contained numerous signal transduction proteins and were capable of activating rapid phospho-tyrosine and Akt pathway signaling, and stimulating proliferation and migration, in recipient tumor cells. They also induced a stromal reaction in recipient normal cells. Knockdown of the actin nucleating protein Diaphanous Related Formin 3 (DRF3/Dia2) by RNA interference enhanced rates of oncosome formation, indicating that these structures resemble, and may be identical to, non-apoptotic membrane blebs, a feature of the amoeboid form of cell motility. Analysis of primary and metastatic human prostate tumors using 100K SNP arrays revealed a significantly higher frequency of deletion of the locus encoding DRF3 (DIAPH3) in metastatic tumors (p=0.001) in comparison with organ-confined tumors. Fluorescence in situ hybridization (FISH) confirmed increased chromosomal loss of DIAPH3 in metastatic tumors in a different cohort of patients (p=0.006). These data suggest that microvesicles shed from prostate cancer cells can alter the tumor microenvironment in a manner that may promote disease progression. They also show that DRF3 is a physiologically relevant protein that appears to regulate this process.