Cathepsin B expression and survival in colon cancer: implications for molecular detection of neoplasia.
Cathepsin B expression and survival in colon cancer: implications for molecular detection of neoplasia.
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DOI：
10.1158/1055-9965.epi-10-0529
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发表时间：
2010-11
期刊：
影响因子：
--
通讯作者：
Ogino S
中科院分区：
文献类型：
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作者：
Chan AT;Baba Y;Shima K;Nosho K;Chung DC;Hung KE;Mahmood U;Madden K;Poss K;Ranieri A;Shue D;Kucherlapati R;Fuchs CS;Ogino S
蛋白酶在肿瘤发生中发挥关键作用，并在结直肠癌和肿瘤性息肉中上调。在动物模型中，组织蛋白酶B可激活的显像剂在肠肿瘤内表现出高酶活性。我们对558名患有结肠癌的男性和女性进行了一项前瞻性队列研究，这些肿瘤可以进行免疫组化评估。我们使用考克斯比例风险模型，按分期分层，根据组织蛋白酶B的肿瘤表达计算结肠癌特异性和总体死亡率。在558例参与者中，457例（82%）肿瘤表达组织蛋白酶B（CTSB阳性），101例（18%）肿瘤不表达组织蛋白酶B（CTSB阴性）。组织蛋白酶B表达与疾病分期无关（P=0.19）。在中位随访11.6年后，共有254人和155人死于结肠癌。与CTSB阴性肿瘤受试者相比，CTSB阳性肿瘤受试者的结肠癌特异性死亡率的多变量风险比为1.99（95%CI，1.19-3.34），总死亡率为1.71（95%CI，1.16-2.50）。组织蛋白酶B表达与KRAS（p=0.01）和BRAF突变（p=0.04）独立相关，但与MSI状态、CIMP状态、PIK 3CA突变、LINE-1甲基化、p53表达或考克斯-2表达无关。在123例腺瘤患者中，91%表达组织蛋白酶B。通过免疫组织化学评估，组织蛋白酶B在绝大多数结肠癌中表达，与分期无关，并且与结肠癌特异性和总体死亡率的较高风险显著相关。这些结果支持组织蛋白酶B作为人体肿瘤病变图像检测靶点的潜力。
Proteases play a critical role in tumorigenesis and are upregulated in colorectal cancer and neoplastic polyps. In animal models, cathepsin B activatable imaging agents demonstrate high enzyme activity within intestinal tumors. We conducted a prospective cohort study of 558 men and women with colon cancer with tumors that were accessible for immunohistochemical assessment. We used Cox proportional hazards models, stratified by stage, to compute colon cancer-specific and overall mortality according to tumoral expression of cathepsin B. Among 558 participants, 457 (82%) had tumors that expressed cathepsin B (CTSB-positive) and 101 (18%) had tumors that did not express cathepsin B (CTSB-negative). Cathepsin B expression was not associated with disease stage (P=0.19). After a median follow-up of 11.6 years, there were 254 total and 155 colon cancer-specific deaths. Compared with participants with CTSB-negative tumors, participants with CTSB-positive tumors experienced a multivariate hazard ratio for colon cancer-specific mortality of 1.99 (95% CI, 1.19–3.34) and overall mortality of 1.71 (95% CI, 1.16–2.50). Cathepsin B expression was independently associated with KRAS (p=0.01) and BRAF mutation (p=0.04), but not MSI status, CIMP status, PIK3CA mutation, LINE-1 methylation, p53 expression, or COX-2 expression. Among 123 individuals with adenomas, 91% expressed cathepsin B. As assessed by immunohistochemistry, cathepsin B is expressed in the vast majority of colon cancers, independent of stage, and is significantly associated with higher risk of colon cancer-specific and overall mortality. These results support the potential of cathepsin B as a target for image detection of neoplastic lesions in humans.