Prognostic Impact of Extracellular Matrix Metalloprotease Inducer Immunohistochemical Analyses of Colorectal Tumors and Immunocytochemical Screening of Disseminated Tumor Cells in Bone Marrow From Patients With Gastrointestinal Cancer
Prognostic Impact of Extracellular Matrix Metalloprotease Inducer Immunohistochemical Analyses of Colorectal Tumors and Immunocytochemical Screening of Disseminated Tumor Cells in Bone Marrow From Patients With Gastrointestinal Cancer
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DOI：
10.1002/cncr.24516
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发表时间：
2009-10-15
期刊：
影响因子：
6.2
通讯作者：
Allgayer, Heike
中科院分区：
文献类型：
--
作者：
Buergy, Daniel;Fuchs, Tina;Allgayer, Heike
背景技术背景：细胞外基质金属蛋白酶诱导剂（EMMPRIN）诱导基质金属蛋白酶（MMP）表达、肿瘤-基质细胞相互作用和侵袭/血管生成。本研究的目的是寻找结直肠癌细胞中总的和相对的EMMPRIN表达对预后影响的第一个证据，并分析2种不同胃肠道肿瘤实体的骨髓播散性肿瘤细胞和正常细胞中的EMMPRIN。方法：采用免疫组织化学方法对40例前瞻性随访（中位随访时间为31个月）的结直肠癌患者的肿瘤和正常组织进行EMMPRIN分析。51例患者的骨髓对13例胃癌患者和38例结直肠癌患者的肿瘤细胞和正常细胞进行EMMPRIN筛查，结果：低疾病特异性生存率与低肿瘤特异性生存率显著相关，低肿瘤特异性生存率与低肿瘤特异性生存率显著相关，（P = 0.037; Kaplan-Meier方法; Mantel-Cox对数秩检验），并且观察到肿瘤细胞中EMMPRIN相对于相应的正常上皮细胞的比率增加。此外，EMMPRIN的相对增加与总体生存率和无复发生存率下降的趋势相关。EMMPRIN的高表达与阳性转移状态（M1）（P = 0.001）和肿瘤病理分类的进展趋势显著相关。结直肠癌患者骨髓样本中16%的播散性肿瘤细胞和胃癌患者骨髓样本中48.5%的播散性肿瘤细胞EMMPRIN染色阳性，微转移细胞上的EMMPRIN与肿瘤进展参数（M状态，非治愈性可切除性）显著相关。少数正常骨髓细胞被EMMPRIN染色，表明它们适合于分子靶向。结论：据作者所知，这项研究首次表明，与正常细胞相比，肿瘤特异性细胞中EMMPRIN蛋白的相对增加预测结直肠癌患者的疾病特异性生存率较差，并且原发性和骨髓播散性肿瘤细胞中的EMMPRIN与结直肠癌/胃癌患者肿瘤进展的临床标志物相关。Cancer 2009;115：4667-78. (C)2009年美国癌症协会。
BACKGROUND: Extracellular matrix metalloprotease inducer (EMMPRIN) induces matrix metalloproteinase (MMP) expression, tumor-stroma cell interaction, and invasion/angiogenesis. The objectives of the current study were to find the first evidence of a prognostic impact of total and relative EMMPRIN expression in colorectal cancer cells and to analyze EMMPRIN in bone marrow-disseminated tumor cells and normal cells from 2 different gastrointestinal cancer entities. METHODS: Tumors and normal tissues from 40 patients with colorectal cancer who were followed prospectively (median follow-up, 31 months) were analyzed for EMMPRIN by immunohistochemistry. Bone marrow from 51 patients (13 patients with gastric cancer and 38 patients with colorectal cancer) with evidence of disseminated tumor cells was screened for EMMPRIN in tumor cells and normal cells (cytokeratin 18/EMMPRIN double immunocytochemistry), RESULTS: A significant correlation between poor disease-specific survival (P = .037; Kaplan-Meier method; Mantel-Cox log-rank tests) and an increased ratio of EMMPRIN in tumor cells versus corresponding normal epithelial cells were observed. Furthermore, the relative increase of EMMPRIN was associated with a trend toward poor overall and recurrence-free survival. High relative EMMPRIN expression was associated significantly with positive metastasis status (M1) (P = .001) and with a trend towards advanced pathologic tumor classification. Sixteen percent of disseminated tumor cells in bone marrow samples from patients with colorectal cancer and 48.5% of disseminated tumor cells in bone marrow samples from patients with gastric cancer stained positive for EMMPRIN, and EMMPRIN on micrometastatic cells was associated significantly with parameters of tumor progression (M status, noncurative resectability). A minority of normal bone marrow cells were stained for EMMPRIN, suggesting their suitability for molecular targeting. CONCLUSIONS: To the authors' knowledge, this study was the first to indicate that increased relative EMMPRIN protein in tumor-specific cells compared with normal cells predicts poor disease-specific survival in patients with colorectal cancer and that EMMPRIN in primary and bone marrow-disseminated tumor cells is associated with clinical markers of tumor progression in patients with colorectal/gastric cancer. Cancer 2009;115:4667-78. (C) 2009 American Cancer Society.