Oskar Eriksson, Department of Medical Sciences, Clinical Chemistry, University Hospital, Entr. 61, 3rd floor, S-751 85 Uppsala, Sweden, Tel.: +46 186114251, Fax: +46 18552562, E-mail:
Agneta Siegbahn, Department of Medical Sciences, Clinical Chemistry, University Hospital, Entr. 61, 3rd floor, S-751 85 Uppsala, Sweden, Tel.: +46 186114251, Fax: +46 18552562, E-mail:
Thromb Haemost. 2016 Nov 30;116(6):1050-1059. doi: 10.1160/TH16-04-0267. Epub 2016 Sep 22.
Colorectal cancer (CRC) is a major cause of morbidity and mortality, and the composition of the tumour stroma is a strong predictor of survival in this cancer type. Tissue factor (TF) functions as the trigger of haemostasis together with its ligand coagulation factor VII/VIIa, and TF expression has been found in tumour cells of colorectal tumours. However, TF expression in the CRC tumour stroma or its relationship to patient outcome has not yet been studied. To address this question we developed and validated a specific anti-TF antibody using standardised methods within the Human Protein Atlas project. We used this antibody to investigate TF expression in normal colorectal tissue and CRC using immunofluorescence and immunohistochemistry in two patient cohorts. TF was strongly expressed in a cell population immediately adjacent to the colorectal epithelium. These TF-positive cells were ACTA2-negative but weakly vimentin-positive, defining a specific population of pericryptal sheath cells. In colorectal tumours, TF-positive sheath cells were progressively lost after the adenoma-to-carcinoma transition, demonstrating downregulation of this source of TF in CRC. Furthermore, loss of sheath cell TF was significantly associated with poor overall and disease-specific survival in rectal but not colon cancers. In conclusion, we demonstrate that TF is a marker of a specific cell population in the large intestine, which is lost during CRC progression. Our results highlight the role of the tumour stroma in this cancer type and suggest TF to be a potential prognostic biomarker in rectal cancers through the identification of pericryptal sheath cells.
结直肠癌（CRC）是发病率和死亡率的主要原因，肿瘤基质的组成是这种癌症类型生存的强有力预测因子。组织因子（TF）与凝血因子 VII/VIIa 的配体一起作为止血的触发因素，在结直肠肿瘤的肿瘤细胞中已经发现了 TF 的表达。然而，CRC 肿瘤基质中的 TF 表达或其与患者预后的关系尚未得到研究。为了解决这个问题，我们在人类蛋白质图谱项目中使用标准化方法开发并验证了一种针对 TF 的特异性抗体。我们使用该抗体通过免疫荧光和免疫组织化学在两个患者队列中研究正常结直肠组织和 CRC 中的 TF 表达。TF 在紧邻结直肠上皮的细胞群中强烈表达。这些 TF 阳性细胞为 ACTA2 阴性但 vimentin 弱阳性，定义了特定的隐窝鞘细胞群。在结直肠肿瘤中，TF 阳性鞘细胞在腺瘤-癌转变后逐渐丢失，表明 CRC 中 TF 的这种来源下调。此外，鞘细胞 TF 的丢失与直肠癌但不是结肠癌的总生存率和疾病特异性生存率显著相关。总之，我们证明 TF 是大肠中特定细胞群的标志物，在 CRC 进展过程中丢失。我们的研究结果强调了肿瘤基质在这种癌症类型中的作用，并通过鉴定隐窝鞘细胞提示 TF 成为直肠癌潜在的预后生物标志物。
