Buergy Daniel, Fuchs Tina, Kambakamba Patryk, Mudduluru Giridhar, Maurer Gabriele, Post Stefan, Tang Yi, Nakada Marian T, Yan Li, Allgayer Heike
Department of Experimental Surgery, Medical Faculty Mannheim, University Heidelberg, Heidelberg, Germany.
Cancer. 2009 Oct 15;115(20):4667-78. doi: 10.1002/cncr.24516.
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.
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).
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.
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.
细胞外基质金属蛋白酶诱导剂（EMMPRIN）可诱导基质金属蛋白酶（MMP）表达、肿瘤-基质细胞相互作用以及侵袭/血管生成。本研究的目的是首次发现结直肠癌细胞中EMMPRIN总表达量和相对表达量的预后影响证据，并分析来自2种不同胃肠道癌实体的骨髓播散肿瘤细胞和正常细胞中的EMMPRIN。
对40例接受前瞻性随访（中位随访时间为31个月）的结直肠癌患者的肿瘤组织和正常组织进行免疫组织化学分析，检测EMMPRIN。对51例有肿瘤细胞播散证据的患者（13例胃癌患者和38例结直肠癌患者）的骨髓进行检测，采用细胞角蛋白18/EMMPRIN双重免疫细胞化学法筛查肿瘤细胞和正常细胞中的EMMPRIN。
观察到疾病特异性生存率低（P = 0.037；Kaplan-Meier法；Mantel-Cox对数秩检验）与肿瘤细胞中EMMPRIN与相应正常上皮细胞的比例增加之间存在显著相关性。此外，EMMPRIN的相对增加与总体生存率和无复发生存率差的趋势相关。EMMPRIN相对高表达与转移阳性状态（M1）显著相关（P = 0.001），并与病理肿瘤分期进展趋势相关。结直肠癌患者骨髓样本中16%的播散肿瘤细胞和胃癌患者骨髓样本中48.5%的播散肿瘤细胞EMMPRIN染色呈阳性，微转移细胞上的EMMPRIN与肿瘤进展参数（M状态、非根治性可切除性）显著相关。少数正常骨髓细胞EMMPRIN染色阳性，表明它们适合进行分子靶向治疗。
据作者所知，本研究首次表明，与正常细胞相比，肿瘤特异性细胞中EMMPRIN相对蛋白增加预示着结直肠癌患者疾病特异性生存率低，并且原发性和骨髓播散肿瘤细胞中的EMMPRIN与结直肠癌/胃癌患者的肿瘤进展临床标志物相关。
