A Pilot Study Assessing the Potential Role of non-CD133 Colorectal Cancer Stem Cells as Biomarkers.
A Pilot Study Assessing the Potential Role of non-CD133 Colorectal Cancer Stem Cells as Biomarkers.
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一项试点研究评估非CD133大肠癌干细胞作为生物标志物的潜在作用。
DOI：
10.7150/jca.4542
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发表时间：
2012
影响因子：
3.9
通讯作者：
Avital I
中科院分区：
文献类型：
--
作者：
Langan RC;Mullinax JE;Ray S;Raiji MT;Schaub N;Xin HW;Koizumi T;Steinberg SM;Anderson A;Wiegand G;Butcher D;Anver M;Bilchik AJ;Stojadinovic A;Rudloff U;Avital I
简介：超过 50% 的结直肠癌 (CRC) 患者会进展和/或发生转移。需要能够预测进展、风险分层和治疗益处的生物标志物。癌症干细胞被认为是肿瘤发生、传播和治疗失败的原因。因此，我们假设 CRC 癌症干细胞标记物 (CRCSC) 将识别出一组处于进展高风险的患者。方法：将正常 (n=8)、组织病理学明确的原发性 (n=30) 和转移性 (n=10) CRC 的石蜡包埋组织核心在组织微阵列 (TMA) 上一式两份排列。通过免疫组织化学检测非 CD133 CRCSC（CD29、CD44、ALDH1A1、ALDH1B1、EpCam 和 CD166）的表达谱，并使用标准统计方法确定与临床病理数据和患者结果的关联。一位独立的病理学家对临床数据不知情，对样本进行了评分。评分包括阳性细胞百分比（0 至 4、0 = <10%、1 = 10 - 24%、2 = 25 - 49%、3 = 50 - 74%、4 = 75 - 100%）和阳性染色细胞的强度（0 至 4；0 = 无染色、1 = 低强度、2 = 低强度、3 = 中等强度、4 = 高）强度）。病理评分代表这两个值的总和，在本文中报告为组合 IHC 染色评分 (CSS)。结果：30 例患者中，7 例为 AJCC IIA 期，10 例为 IIIB 期，7 例为 IIIC 期，6 例为 IV 期。中位随访时间为 113 个月。 DFI 为 17 个月。未达到中位总生存期 (OS)。特定阶段 OS 为：II - 未达到； III——未达到； IV - 11 个月。在单变量分析中，OS 较差与 CD29 表达缺失相关。 CSS 3-7 的中位 OS 为 32 个月，未达到的 OS 为 32 个月，CSS 3-7 的中位 OS 为 >7.5；调整后，比较整条曲线，p=0.052。在 Cox 模型分析中，在调整分期影响 (p=0.0076) 后，CD29 的缺失表现出与生存相关的趋势 (p=0.098)。 ALDH1A1 的较高表达与阶段的增加相关（相对于阶段 2、3b、3c 和 4，p=0.042），而 CD29 表达的丧失则表现出与阶段 3 和 4 相关的趋势（p=0.08）。与正常结肠组织相比，原发性肿瘤与 ALDH1B1 表达增加相关（p=0.008）。 ALD1H1B1的表达水平根据肿瘤是中分化、低分化、高分化还是粘液性而不同；最高表达水平与中度或低分化肿瘤相关（p=0.011）。当比较 0、1 和 2+ 阳性淋巴结时，淋巴结转移与 EpCAM 表达下降的趋势相关 (p = 0.06)，当比较 0 和任何阳性淋巴结时，CD29 (p = 0.08) 表达也呈下降趋势。与正常结肠组织相比，来自不同患者的转移性结肠癌与 ALDH1B1 表达增加相关（p=0.001），而正常结肠组织中 CD29 表达较高（p=0.014）。结论：CD29可能与生存以及临床分期和淋巴结数量有关。 ALDH1B1 表达与分化以及评估的组织类型相关。 ALDH1A1与临床分期相关，并且在淋巴结分期晚期的患者中发现EpCAM表达降低。 CRCSC 可能是对 CRC 风险分层和估计结果有用的生物标志物。需要更大规模的前瞻性研究来验证当前的发现。
Introduction: Over 50% of patients with colorectal cancer (CRC) will progress and/or develop metastases. Biomarkers capable of predicting progression, risk stratification and therapeutic benefit are needed. Cancer stem cells are thought to be responsible for tumor initiation, dissemination and treatment failure. Therefore, we hypothesized that CRC cancer stem cell markers (CRCSC) will identify a group of patients at high risk for progression. Methods: Paraffin-embedded tissue cores of normal (n=8), and histopathologically well-defined primary (n= 30) and metastatic (n=10) CRC were arrayed in duplicate on tissue microarrays (TMAs). Expression profiles of non-CD133 CRCSC (CD29, CD44, ALDH1A1, ALDH1B1, EpCam, and CD166) were detected by immunohistochemistry and the association with clinicopathological data and patient outcomes was determined using standard statistical methodology. An independent pathologist, blinded to the clinical data scored the samples. Scoring included percent positive cells (0 to 4, 0 = <10%, 1 = 10 - 24%, 2 = 25 - 49%, 3 = 50 - 74%, 4 = 75 - 100%), and the intensity of positively stained cells (0 to 4; 0 = no staining, 1 = diminutive intensity, 2 = low intensity, 3 = intermediate intensity, 4 = high intensity). The pathologic score represents the sum of these two values, reported in this paper as a combined IHC staining score (CSS). Results: Of 30 patients 7 were AJCC stage IIA, 10 stage IIIB, 7 stage IIIC and 6 stage IV. Median follow-up was 113 months. DFI was 17 months. Median overall survival (OS) was not reached. Stage-specific OS was: II - not reached; III - not reached; IV - 11 months. In a univariate analysis, poor OS was associated with loss of CD29 expression; median OS, 32 months vs. not reached for CSS 3-7 vs. >7.5, respectively; p=0.052 comparing entire curves, after adjustment. In a Cox model analysis, loss of CD29 exhibited a trend toward association with survival (p=0.098) after adjusting for the effect of stage (p=0.0076). Greater expression of ALDH1A1 was associated with increasing stage (p=0.042 over stages 2, 3b, 3c, and 4) while loss of CD29 expression exhibited a trend toward being associated with stages 3 and 4 (p=0.08). Compared to normal colon tissue, primary tumors were associated with increased expression of ALDH1B1 (p=0.008). ALD1H1B1 expression level differed according to whether the tumor was moderately or poorly differentiated, well differentiated, or mucinous; the highest expression levels were associated with moderately or poorly differentiated tumors (p=0.011). Lymph node metastases were associated with a trend toward decreased expression of EpCAM (p = 0.06) when comparing 0 vs. 1 vs. 2+ positive lymph nodes, as was CD29 (p = 0.08) when comparing 0 vs. any positive lymph nodes. Compared to normal colon tissue metastatic colon cancers from different patients were associated with increased ALDH1B1 expression (p=0.001) whereas CD29 expression was higher in normal colonic tissue (p=0.014). Conclusion: CD29 may be associated with survival as well as clinical stage and number of lymph nodes. ALDH1B1 expression was associated with differentiation as well as type of tissue evaluated. ALDH1A1 was associated with clinical stage, and decreased EpCAM expression was found in patients with advanced lymph node stage. CRCSCs may be useful biomarkers to risk stratify, and estimate outcomes in CRC. Larger prospective studies are required to validate the current findings.
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影响因子：
8.8
作者：
通讯作者：
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影响因子：
168.9
作者：
Gastl, G;Spizzo, G;Mikuz, G
通讯作者：
Mikuz, G
影响因子：
64.8
作者：
O'Brien, Catherine A.;Pollett, Aaron;Dick, John E.
通讯作者：
Dick, John E.
影响因子：
--
作者：
Galizia, Gennaro;Gemei, Marica;Lieto, Eva
通讯作者：
Lieto, Eva
DOI：
10.1073/pnas.0703478104
发表时间：
2007-06-12
影响因子：
11.1
作者：
Dalerba, Piero;Dylla, Scott J.;Clarke, Michael F.
通讯作者：
Clarke, Michael F.