Yoong K F, Afford S C, Randhawa S, Hubscher S G, Adams D H
MRC Centre for Immune Regulation at University of Birmingham Liver Research Labóratories, Queen Elizabeth Hospital, Birmingham, United Kingdom.
Am J Pathol. 1999 Mar;154(3):693-703. doi: 10.1016/S0002-9440(10)65316-3.
This study demonstrates a novel role for the Fas pathway in the promotion of local tumor growth by inducing apoptotic cell death in normal hepatocytes at the tumor margin in colorectal hepatic metastases. Our results show that >85% of lymphocytes infiltrating colorectal liver cancer express high levels of Fas-ligand (Fas-L) by flow cytometry. Using immunohistochemistry of tumor tissue we showed strong Fas expression in noninvolved hepatocytes, whereas Fas-L expression was restricted to tumor cells and infiltrating lymphocytes at the tumor margin. Apoptosis was observed in 45 +/- 13% of the Fas(high) hepatocytes at the tumor margin whereas only 7 +/- 3% tumor cells were apoptotic (n = 10). In vitro, primary human hepatocytes expressed Fas receptor and crosslinking with anti-Fas antibody induced apoptosis in 44 +/- 5% of the cells compared with 4. 6 +/- 1.0% in untreated controls (P = 0.004). Both tumor-infiltrating lymphocytes (TIL) and human metastatic colon cancer cells cells are able to induce Fas-mediated apoptosis of primary human hepatocytes in coculture cytotoxic assays. TIL induced apoptosis in 47 +/- 9% hepatocytes compared with control 4.3 +/- 1. 0% (P = 0.009) and this effect was reduced by anti-human Fas-L mAb (18.7 +/- 1.3%, P = 0.009). SW620 cells induced apoptosis in 26 +/- 2% hepatocytes compared with control 5.6 +/- 1.7% (P = 0.004) and this was reduced to 11.2 +/- 1.8% (P = 0.004) in the presence of anti-human Fas-L mAb. These data suggest that the inflammatory response at the margin of colorectal liver metastases induces Fas expression in surrounding hepatocytes, allowing them to be killed by Fas-L-bearing TIL or tumor cells and facilitating the invasion of the tumor into surrounding liver tissue.
本研究证明了Fas通路在促进结直肠癌肝转移瘤边缘正常肝细胞凋亡从而促进局部肿瘤生长方面的新作用。我们的结果显示，通过流式细胞术检测，浸润结直肠癌肝转移灶的淋巴细胞中>85%表达高水平的Fas配体（Fas-L）。利用肿瘤组织免疫组化，我们发现未受累肝细胞中有强烈的Fas表达，而Fas-L表达局限于肿瘤细胞及肿瘤边缘浸润的淋巴细胞。在肿瘤边缘，45±13%的Fas（高表达）肝细胞发生凋亡，而仅有7±3%的肿瘤细胞凋亡（n = 10）。在体外，原代人肝细胞表达Fas受体，与抗Fas抗体交联后，44±5%的细胞发生凋亡，而未处理对照中为4.6±1.0%（P = 0.004）。在共培养细胞毒性试验中，肿瘤浸润淋巴细胞（TIL）和人转移性结肠癌细胞均能够诱导原代人肝细胞发生Fas介导的凋亡。TIL诱导47±9%的肝细胞凋亡，而对照为4.3±1.0%（P = 0.009），抗人Fas-L单克隆抗体可降低该效应（18.7±1.3%，P = 0.009）。SW620细胞诱导26±2%的肝细胞凋亡，对照为5.6±1.7%（P = 0.004），在抗人Fas-L单克隆抗体存在时，该比例降至11.2±1.8%（P = 0.004）。这些数据表明，结直肠癌肝转移灶边缘的炎症反应诱导周围肝细胞表达Fas，使其被携带Fas-L的TIL或肿瘤细胞杀伤，从而促进肿瘤向周围肝组织浸润。
