Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells
Identification, molecular characterization, clinical prognosis, and therapeutic targeting of human bladder tumor-initiating cells
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DOI：
10.1073/pnas.0906549106
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发表时间：
2009-08-18
影响因子：
11.1
通讯作者：
Weissman, Irving L.
中科院分区：
文献类型：
--
作者：
Chan, Keith Syson;Espinosa, Inigo;Weissman, Irving L.
膀胱癌的主要临床问题包括确定浸润性膀胱癌的预测标志物和新的治疗靶点。在目前的研究中，我们描述了原发性人膀胱癌中肿瘤起始细胞（T-IC）亚群的分离和表征，其基于与正常膀胱基底细胞（谱系-CD 44（+）CK 5（+）CK 20（-））相似的标记物的表达。膀胱T-IC亚群在功能上通过其在体内诱导异种移植肿瘤的富集能力来定义，所述异种移植肿瘤概括了原始肿瘤的异质性。此外，对300多个膀胱癌标本的分子分析揭示了T-IC中激活的致癌途径之间的异质性（例如，例如，在一个实施例中，80%Gli1、45%Stat3、10%Bmi-1和5% β-连环蛋白）。尽管这种分子异质性，我们确定了一个独特的膀胱T-IC基因的基因芯片分析签名。这种T-IC基因标签有效区分临床预后较差的肌层浸润性膀胱癌和非肌层浸润性（浅表）癌，具有重要的临床价值。它还可以预测一部分复发性非肌肉浸润性癌症的进展。最后，我们发现，CD 47，一种为巨噬细胞吞噬作用提供抑制信号的蛋白质，与肿瘤的其他部分相比，在膀胱T-IC中高度表达。通过mAb阻断CD 47导致体外巨噬细胞吞噬膀胱癌细胞。总之，我们已经确定了一个T-IC亚群的浸润性膀胱癌的潜在预后和治疗价值。
Major clinical issues in bladder cancer include the identification of prediction markers and novel therapeutic targets for invasive bladder cancer. In the current study, we describe the isolation and characterization of a tumor-initiating cell (T-IC) subpopulation in primary human bladder cancer, based on the expression of markers similar to that of normal bladder basal cells (Lineage-CD44(+)CK5(+)CK20(-)). The bladder T-IC subpopulation was defined functionally by its enriched ability to induce xenograft tumors in vivo that recapitulated the heterogeneity of the original tumor. Further, molecular analysis of more than 300 bladder cancer specimens revealed heterogeneity among activated oncogenic pathways in T-IC (e. g., 80% Gli1, 45% Stat3, 10% Bmi-1, and 5% beta-catenin). Despite this molecular heterogeneity, we identified a unique bladder T-IC gene signature by gene chip analysis. This T-IC gene signature, which effectively distinguishes muscle-invasive bladder cancer with worse clinical prognosis from non-muscle-invasive (superficial) cancer, has significant clinical value. It also can predict the progression of a subset of recurring non-muscle-invasive cancers. Finally, we found that CD47, a protein that provides an inhibitory signal for macrophage phagocytosis, is highly expressed in bladder T-ICs compared with the rest of the tumor. Blockade of CD47 by a mAb resulted in macrophage engulfment of bladder cancer cells in vitro. In summary, we have identified a T-IC subpopulation with potential prognostic and therapeutic value for invasive bladder cancer.