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JAMA:“癌症干细胞基因高表达”和“治疗结果差”存在很强相关性

2010年12月24日 浏览量: 评论(0) 来源:科技日报 作者:佚名 责任编辑:lwc
摘要:斯坦福大学研究人员通过对白血病干细胞的基因表达方式研究发现,癌症干细胞基因表达水平更高的病人比表达水平低的病人预后效果要差很多,该发现首次通过临床数据证明了癌症干细胞概念。

斯坦福大学研究人员通过对白血病干细胞的基因表达方式研究发现,癌症干细胞基因表达水平更高的病人比表达水平低的病人预后效果要差很多,该发现首次通过临床数据证明了癌症干细胞概念。医疗人员可据此预测群体病人的治疗结果,并帮助开发新的临床疗法。研究发表在12月22日的《美国医学会》杂志上。

几年前提出的癌症干细胞概念认为,某些癌症起源于一小撮自我更新能力很强的细胞,这一小撮细胞即是癌症干细胞。这些癌症干细胞能不断补充生成新的癌症细胞,癌症要彻底治疗,必须清除这些干细胞。癌症干细胞对抗治疗已经在一些固状肿瘤和血癌的动物模型中得到验证,虽然有大量实验室证据支持,但至今还缺乏临床证据。

论文合著者、斯坦福癌症中心医务部艾什·埃里沙德和同事拉文达·马杰提今年9月曾在实验室小鼠中,对非霍奇森淋巴瘤癌症干细胞表面发现的蛋白质CD47研究发现,CD47是癌症干细胞的“保护伞”,有了它,很多药物对这些细胞无效。CD47在其他几种癌症干细胞中也存在。马杰提认为这些动物实验中发现的证据在人体中也应该存在。

他们用两种能识别白血病干细胞的表面标记,从7个白血病患者的肿瘤样本中分离出这些白血病干细胞,将肿瘤干细胞和其他肿瘤细胞的基因表达方式进行了对比,结果有52%的基因表达不同。

癌症干细胞基因表达方式和正常的血液干细胞很相似,不仅能自我更新,还能像正常干细胞在需要时候才分裂。为了逃避那些针对迅速分裂细胞的传统治疗方法,它会选择少量分裂,潜伏着,等待机会“东山再起”。

研究人员还对来自1000多位急性骨髓白血病病人的4组肿瘤样本进行了对比研究,发现在“癌症干细胞基因高表达”和“治疗结果差”之间存在很强的相关性。在一组德国样本中,高表达病人3年内死亡的绝对风险高达78%,而低表达病人仅为57%。同样,无病生存率、某个时期再度恶化可能性、对抗初次治疗顽固性等指标也如此。

论文第一作者、斯坦福大学癌症系统生物学中心安德鲁·简托斯表示,白血病干细胞的信号越强,病人寿命越短,病情恶化得越快,治疗效果就更差。目前,研究小组正在继续研究数据,以最终从各种结合抗体疗法中确定哪些疗法对癌症干细胞高表达基因信号的病人最有效。

推荐原文出处:

JAMA.    doi: 10.1001/jama.2010.1862

Association of a Leukemic Stem Cell Gene Expression Signature With Clinical Outcomes in Acute Myeloid Leukemia

Andrew J. Gentles, PhD; Sylvia K. Plevritis, PhD; Ravindra Majeti, MD, PhD; Ash A. Alizadeh, MD, PhD

AbstractContext In many cancers, specific subpopulations of cells appear to be uniquely capable of initiating and maintaining tumors. The strongest support for this cancer stem cell model comes from transplantation assays in immunodeficient mice, which indicate that human acute myeloid leukemia (AML) is driven by self-renewing leukemic stem cells (LSCs). This model has significant implications for the development of novel therapies, but its clinical relevance has yet to be determined.

Objective To identify an LSC gene expression signature and test its association with clinical outcomes in AML.

Design, Setting, and Patients Retrospective study of global gene expression (microarray) profiles of LSC-enriched subpopulations from primary AML and normal patient samples, which were obtained at a US medical center between April 2005 and July 2007, and validation data sets of global transcriptional profiles of AML tumors from 4 independent cohorts (n = 1047).

Main Outcome Measures Identification of genes discriminating LSC-enriched populations from other subpopulations in AML tumors; and association of LSC-specific genes with overall, event-free, and relapse-free survival and with therapeutic response.

Results Expression levels of 52 genes distinguished LSC-enriched populations from other subpopulations in cell-sorted AML samples. An LSC score summarizing expression of these genes in bulk primary AML tumor samples was associated with clinical outcomes in the 4 independent patient cohorts. High LSC scores were associated with worse overall, event-free, and relapse-free survival among patients with either normal karyotypes or chromosomal abnormalities. For the largest cohort of patients with normal karyotypes (n = 163), the LSC score was significantly associated with overall survival as a continuous variable (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.08-1.22; log-likelihood P <.001). The absolute risk of death by 3 years was 57% (95% CI, 43%-67%) for the low LSC score group compared with 78% (95% CI, 66%-86%) for the high LSC score group (HR, 1.9 [95% CI, 1.3-2.7]; log-rank P = .002). In another cohort with available data on event-free survival for 70 patients with normal karyotypes, the risk of an event by 3 years was 48% (95% CI, 27%-63%) in the low LSC score group vs 81% (95% CI, 60%-91%) in the high LSC score group (HR, 2.4 [95% CI, 1.3-4.5]; log-rank P = .006). In multivariate Cox regression including age, mutations in FLT3 and NPM1, and cytogenetic abnormalities, the HRs for LSC score in the 3 cohorts with data on all variables were 1.07 (95% CI, 1.01-1.13; P = .02), 1.10 (95% CI, 1.03-1.17; P = .005), and 1.17 (95% CI, 1.05-1.30; P = .005).

Conclusion High expression of an LSC gene signature is independently associated with adverse outcomes in patients with AML.

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