Response of primary glioblastoma cells to therapy is patient specific and independent of cancer stem cell phenotype
Response of primary glioblastoma cells to therapy is patient specific and independent of cancer stem cell phenotype
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DOI：
10.1093/neuonc/not223
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发表时间：
2014-03-01
期刊：
影响因子：
15.9
通讯作者：
Costello, Joseph F.
中科院分区：
文献类型：
--
作者：
Fouse, Shaun D.;Nakamura, Jean L.;Costello, Joseph F.
背景多形性胶质母细胞瘤（GBM）含有表现出干细胞表型的细胞群体。这些癌症干细胞（CSC）可能是治疗抗性的来源，尽管对这一重要概念的支持是有限的。我们确定了早期传代GBM CSC与患者匹配的、基因型相似的非CSC相比，对临床相关的单剂量或连续剂量的替莫唑胺（TMZ）、放射治疗（XRT）或TMZ和XRT交替治疗（这是GBM患者的标准治疗）的反应是否不同。尽管存在表型差异，包括干细胞标志物的存在和颅内肿瘤的形成，但使用2项独立试验，大多数患者的CSC和匹配的非CSC对TMZ具有相同的耐药性。TMZ反应与两种培养类型中甲基化O-6-DNA甲基鸟嘌呤甲基转移酶（MGMT）和MGMT蛋白水平一致。相比之下，尽管对TMZ具有相对相等的抗性，但与来自2名患者的匹配的非CSC相比，CSC出乎意料地对XRT更有反应。然而，对于来自个体患者的大多数培养物对，CSC中的反应与非CSC培养物无区别。在我们的患者匹配的原代培养中，对TMZ的反应与个体肿瘤的MGMT状态密切相关，并且与其表型差异无关。TMZ和XRT一起显示，与单一疗法相比，任何一种培养类型都没有额外的益处，这与CSC人群对XRT更耐药的观点相反。如果体外肿瘤细胞反应反映了较大患者队列中的治疗反应，则这些原代培养物中的快速测定可以允许在患者特异性基础上经验性选择有效的治疗剂。
Background. Glioblastoma multiforme (GBM) contains a population of cells that exhibit stem cell phenotypes. These cancer stem cells (CSCs) may be a source of therapeutic resistance, although support for this important concept is limited.Methods. We determined whether early-passage GBM CSCs respond differently than patient-matched, genotypically similar non-CSCs to clinically relevant single or serial doses of temozolomide(TMZ), radiation therapy(XRT), or alternating TMZ treatment and XRT, which is the standard of care for GBM patients.Results. Despite the phenotypic differences, including the presence of stem cell markers and formation of intracranial tumors, the CSCs and matched non-CSCs were equally resistant to TMZ in a majority of patients, using 2 independent assays. TMZ response was consistent with methylated O-6-DNA methylguanine-methyltransferase (MGMT) and MGMT protein levels in both culture types. In contrast, CSCs were unexpectedly more responsive to XRT compared with matched non-CSCs from 2 patients despite having relatively equal resistance to TMZ. However, for the majority of culture pairs from individual patients, responses in CSCs were indistinguishable from non-CSC cultures.Conclusions. In our patient-matched primary cultures, response to TMZ was tightly linked to the individual tumor's MGMT status and independent of their phenotypic differences. TMZ and XRT together revealed no additive benefit compared with monotherapy for either culture type, in contrast to the notion that the CSC population is more resistant to XRT. If the tumor cell response in vitro mirrors therapeutic response in larger patient cohorts, these rapid assays in primary cultures could allow empirical selection of efficacious therapeutic agents on a patient-specific basis.