斯坦福大學(xué)研究人員通過對白血病干細(xì)胞的基因表達(dá)方式研究發(fā)現(xiàn),，癌癥干細(xì)胞基因表達(dá)水平更高的病人比表達(dá)水平低的病人預(yù)后效果要差很多,，該發(fā)現(xiàn)首次通過臨床數(shù)據(jù)證明了癌癥干細(xì)胞概念,。醫(yī)療人員可據(jù)此預(yù)測群體病人的治療結(jié)果，并幫助開發(fā)新的臨床療法。研究發(fā)表在12月22日的《美國醫(yī)學(xué)會(huì)》雜志上,。
幾年前提出的癌癥干細(xì)胞概念認(rèn)為,，某些癌癥起源于一小撮自我更新能力很強(qiáng)的細(xì)胞，這一小撮細(xì)胞即是癌癥干細(xì)胞,。這些癌癥干細(xì)胞能不斷補(bǔ)充生成新的癌癥細(xì)胞,，癌癥要徹底治療,，必須清除這些干細(xì)胞,。癌癥干細(xì)胞對抗治療已經(jīng)在一些固狀腫瘤和血癌的動(dòng)物模型中得到驗(yàn)證，雖然有大量實(shí)驗(yàn)室證據(jù)支持,，但至今還缺乏臨床證據(jù),。
論文合著者、斯坦福癌癥中心醫(yī)務(wù)部艾什·埃里沙德和同事拉文達(dá)·馬杰提今年9月曾在實(shí)驗(yàn)室小鼠中,，對非霍奇森淋巴瘤癌癥干細(xì)胞表面發(fā)現(xiàn)的蛋白質(zhì)CD47研究發(fā)現(xiàn),，CD47是癌癥干細(xì)胞的“保護(hù)傘”，有了它,，很多藥物對這些細(xì)胞無效,。CD47在其他幾種癌癥干細(xì)胞中也存在。馬杰提認(rèn)為這些動(dòng)物實(shí)驗(yàn)中發(fā)現(xiàn)的證據(jù)在人體中也應(yīng)該存在,。
他們用兩種能識(shí)別白血病干細(xì)胞的表面標(biāo)記,，從7個(gè)白血病患者的腫瘤樣本中分離出這些白血病干細(xì)胞，將腫瘤干細(xì)胞和其他腫瘤細(xì)胞的基因表達(dá)方式進(jìn)行了對比,，結(jié)果有52%的基因表達(dá)不同,。
癌癥干細(xì)胞基因表達(dá)方式和正常的血液干細(xì)胞很相似，不僅能自我更新,，還能像正常干細(xì)胞在需要時(shí)候才分裂,。為了逃避那些針對迅速分裂細(xì)胞的傳統(tǒng)治療方法，它會(huì)選擇少量分裂,，潛伏著,，等待機(jī)會(huì)“東山再起”。
研究人員還對來自1000多位急性骨髓白血病病人的4組腫瘤樣本進(jìn)行了對比研究,，發(fā)現(xiàn)在“癌癥干細(xì)胞基因高表達(dá)”和“治療結(jié)果差”之間存在很強(qiáng)的相關(guān)性,。在一組德國樣本中，高表達(dá)病人3年內(nèi)死亡的絕對風(fēng)險(xiǎn)高達(dá)78%,，而低表達(dá)病人僅為57%,。同樣，無病生存率,、某個(gè)時(shí)期再度惡化可能性,、對抗初次治療頑固性等指標(biāo)也如此。
論文第一作者、斯坦福大學(xué)癌癥系統(tǒng)生物學(xué)中心安德魯·簡托斯表示,，白血病干細(xì)胞的信號(hào)越強(qiáng),，病人壽命越短，病情惡化得越快,，治療效果就更差,。目前，研究小組正在繼續(xù)研究數(shù)據(jù),，以最終從各種結(jié)合抗體療法中確定哪些療法對癌癥干細(xì)胞高表達(dá)基因信號(hào)的病人最有效,。（生物谷Bioon.com）
生物谷推薦原文出處：
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.
