Buettner Maike, Meyer Birgit, Schreck Sabine, Niedobitek Gerald
Institute for Pathology, University Hospital of the Friedrich-Alexander-University, Erlangen-Nuremberg, Germany.
Int J Cancer. 2007 Dec 15;121(12):2703-10. doi: 10.1002/ijc.23018.
Epstein-Barr virus (EBV)-associated undifferentiated nasopharyngeal carcinoma (NPC) is characterized by a prominent nonneoplastic lymphoid stroma. The functional role of these inflammatory cells and the mechanism of their recruitment are not fully understood. In B-cells, the EBV-encoded latent membrane protein 1 (LMP1) can induce the expression of chemokines in an NF-kappaB dependent manner. We now show that LMP1 can induce the expression of RANTES and MCP-1 in an epithelial cell line, and that this effect is partially reversible by an inhibitor of NF-kappaB. Since tumor cells of virtually all NPCs show CD40 expression while many cases are LMP1-negative at the protein level, we also investigated the effect of CD40 signaling and demonstrate that CD40 stimulation can transiently induce RANTES and MCP-1 expression in LMP1-negative epithelial cells. In in situ hybridization only rare tumor cells showed expression of these chemokines unrelated to LMP1 expression, a pattern consistent with transient induction through CD40 signaling. Since RANTES and MCP-1 were also detected in the neoplastic cells of oral squamous cell carcinomas lacking a lymphoid stroma it remains uncertain to what extent these CC chemokines contribute to the attraction of inflammatory cells into the NPC microenvironment.
爱泼斯坦-巴尔病毒（EBV）相关的未分化鼻咽癌（NPC）的特征是存在显著的非肿瘤性淋巴样间质。这些炎症细胞的功能作用及其募集机制尚未完全明确。在B细胞中，EBV编码的潜伏膜蛋白1（LMP1）能够以NF-κB依赖的方式诱导趋化因子的表达。我们现在发现，LMP1能够在上皮细胞系中诱导RANTES和MCP-1的表达，并且这种效应可被NF-κB抑制剂部分逆转。由于几乎所有NPC的肿瘤细胞均表达CD40，而许多病例在蛋白水平呈LMP1阴性，我们还研究了CD40信号传导的作用，并证明CD40刺激能够在LMP1阴性的上皮细胞中瞬时诱导RANTES和MCP-1的表达。在原位杂交中，仅少数肿瘤细胞显示出这些趋化因子的表达，且与LMP1表达无关，这一模式与通过CD40信号传导的瞬时诱导一致。由于在缺乏淋巴样间质的口腔鳞状细胞癌的肿瘤细胞中也检测到RANTES和MCP-1，因此这些CC趋化因子在多大程度上有助于炎性细胞向NPC微环境的募集仍不确定。
