Tumorigenic stem and progenitor cells: Implications for the therapeutic index of anti-cancer agents
Tumorigenic stem and progenitor cells: Implications for the therapeutic index of anti-cancer agents
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DOI：
10.1016/j.jconrel.2007.05.005
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发表时间：
2007-10-08
影响因子：
10.8
通讯作者：
Donnenberg, Albert D.
中科院分区：
文献类型：
--
作者：
Donnenberg, Vera S.;Landreneau, Rodney J.;Donnenberg, Albert D.
对治疗有反应后的癌症复发表明耐药细胞处于休眠状态，随后重新激活。癌症干细胞范例解释了为什么肿瘤通常由一个大的治疗敏感区室和一个具有深刻内在抗性的较小区室组成。在这里，我们检查组织干细胞标志物（CD 90，CD 117，CD 133）和细胞角蛋白在以前未经治疗的非小细胞肺癌（NSCLC）的共表达。在正常肺（NL），我们分配一个临时表型的静息干细胞（低散射，细胞角蛋白和CD 90（暗淡）/CD 133+，或CD 117+）。祖细胞共享这种表型，但形态复杂，下调CD 90，因为他们获得细胞角蛋白。这种模式在高分化NSCLC中保留，但在低分化NSCLC中紊乱，最常见的模式是干细胞/祖细胞上的细胞角蛋白过表达。在NL和NSCLC中，干细胞和祖细胞分别以1%和10%的相似比例存在。构成性多药耐药（MDR）在高分化和低分化肿瘤中分别为6%和50%。我们假设，在少数能够繁殖肿瘤的肿瘤细胞中，只有那些自我保护的细胞在治疗中存活下来。在存活的细胞中，只有那些像正常干细胞一样主要处于静止状态的细胞才会在缓解后引起复发。因此，抗肿瘤塑料的治疗指数成为受相同机制保护的癌症和正常干细胞的敏感性之一。(C)2007 Elsevier B. V.保留所有权利。
Cancer recurrence following response to therapy suggests that resistant cells lay dormant and subsequently reactivate. The cancer stem cell paradigm explains why tumors typically consist of a large therapy sensitive compartment, and a smaller compartment with profound intrinsic resistance. Here we examine co-expression of tissue stem cell markers (CD90, CD117, CD133) and cytokeratin in previously untreated non-small cell lung cancer (NSCLC). In normal lung (NL), we assign a provisional phenotype to resting stem cells (low scatter, cytokeratin-and either CD90(dim)/CD133+, or CD117+). Progenitors share this phenotype but are morphologically complex, downregulating CD90 as they gain cytokeratin. This pattern is retained in well-differentiated NSCLC, but is deranged in poorly-differentiated NSCLC, the most common pattern being overexpression of cytokeratin on stem/progenitors. Stem cells and progenitors are present at similar to 1% and 10% in NL and NSCLC, respectively. Constitutive multiple drug resistance (MDR) was present in similar to 6% of well-differentiated and similar to 50% of poorly differentiated tumors. We hypothesize that among the minority of tumor cells capable of propagating a tumor, only those that self-protect survive therapy. Of surviving cells, only those which, like normal stem cells, are predominantly resting, cause recurrence after remission. The therapeutic index of antineoplastics thus becomes one of sensitivity of cancer and normal stem cells, which are protected by the same mechanisms. (C) 2007 Elsevier B.V. All rights reserved.