The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
J Natl Cancer Inst. 2010 Mar 3;102(5):340-51. doi: 10.1093/jnci/djp535. Epub 2010 Feb 17.
Specific populations of highly tumorigenic cells are thought to exist in many human tumors, including pancreatic adenocarcinoma. However, the clinical significance of these tumor-initiating (ie, cancer stem) cells remains unclear. Aldehyde dehydrogenase (ALDH) activity can identify tumor-initiating cells and normal stem cells from several human tissues. We examined the prognostic significance and functional features of ALDH expression in pancreatic adenocarcinoma.
ALDH expression was analyzed by immunohistochemistry in 269 primary surgical specimens of pancreatic adenocarcinoma and examined for association with clinical outcomes and in paired primary tumors and metastatic lesions from eight pancreatic cancer patients who had participated in a rapid autopsy program. The clonogenic growth potential of ALDH-positive pancreatic adenocarcinoma cells was assessed in vitro by a colony formation assay and by tumor growth in immunodeficient mice (10-14 mice per group). Mesenchymal features of ALDH-positive pancreatic tumor cells were examined by using quantitative reverse transcription-polymerase chain reaction and an in vitro cell invasion assay. Gene expression levels and the invasive potential of ADLH-positive pancreatic cancer cells relative to the bulk cell population were examined by reverse transcription-polymerase chain reaction and an in vitro invasion assays, respectively. All statistical tests were two-sided.
ALDH-positive tumor cells were detected in 90 of the 269 primary surgical specimens, and their presence was associated with worse survival (median survival for patients with ALDH-positive vs ALDH-negative tumors: 14 vs 18 months, hazard ratio of death = 1.28, 95% confidence interval = 1.02 to 1.68, P = .05). Six (75%) of the eight patients with matched primary and metastatic tumor samples had ALDH-negative primary tumors, and in four (67%) of these six patients, the matched metastatic lesions (located in liver and lung) contained ALDH-positive cells. ALDH-positive cells were approximately five- to 11-fold more clonogenic in vitro and in vivo compared with unsorted or ALHD-negative cells, expressed genes consistent with a mesenchymal state, and had in vitro migratory and invasive potentials that were threefold greater than those of unsorted cells.
ALDH expression marks pancreatic cancer cells that have stem cell and mesenchymal features. The enhanced clonogenic growth and migratory properties of ALDH-positive pancreatic cancer cells suggest that they play a key role in the development of metastatic disease that negatively affects the overall survival of patients with pancreatic adenocarcinoma.
人们认为，许多人类肿瘤中都存在具有高度致瘤性的特定细胞群，包括胰腺腺癌。然而，这些肿瘤起始（即癌症干细胞）细胞的临床意义尚不清楚。醛脱氢酶（ALDH）活性可以鉴定来自几种人体组织的肿瘤起始细胞和正常干细胞。我们研究了胰腺腺癌中 ALDH 表达的预后意义和功能特征。
通过免疫组织化学分析了 269 例胰腺腺癌手术标本中 ALDH 的表达情况，并与临床结果以及参加快速尸检计划的 8 例胰腺癌患者的配对原发肿瘤和转移病灶进行了关联。通过集落形成测定和免疫缺陷小鼠中的肿瘤生长（每组 10-14 只小鼠），评估 ALDH 阳性胰腺腺癌细胞的克隆生长潜力。通过定量逆转录聚合酶链反应和体外细胞侵袭测定，研究 ALDH 阳性胰腺肿瘤细胞的间充质特征。通过逆转录聚合酶链反应和体外侵袭测定，分别检测 ALDH 阳性胰腺癌细胞相对于细胞群体的基因表达水平和侵袭潜能。所有统计检验均为双侧检验。
在 269 例手术标本中，有 90 例检测到 ALDH 阳性肿瘤细胞，其存在与较差的生存相关（ALDH 阳性肿瘤患者的中位生存时间与 ALDH 阴性肿瘤患者相比：14 个月比 18 个月，死亡风险比为 1.28，95%置信区间为 1.02 至 1.68，P=0.05）。8 例配对原发和转移肿瘤样本中有 6 例（75%）患者的原发肿瘤为 ALDH 阴性，在这 6 例患者中，有 4 例（67%）的匹配转移病灶（位于肝脏和肺部）中含有 ALDH 阳性细胞。与未分选或 ALDH 阴性细胞相比，ALDH 阳性细胞在体外和体内的克隆形成能力约高 5 至 11 倍，表达与间质状态一致的基因，并且具有体外迁移和侵袭潜力，是未分选细胞的三倍。
ALDH 表达标志着具有干细胞和间充质特征的胰腺癌细胞。ALDH 阳性胰腺癌细胞增强的克隆生长和迁移特性表明，它们在发展转移疾病中发挥关键作用，这对胰腺腺癌患者的整体生存产生负面影响。
