Muller Anja, Sonkoly Eniko, Eulert Christine, Gerber Peter Arne, Kubitza Robert, Schirlau Kerstin, Franken-Kunkel Petra, Poremba Christopher, Snyderman Carl, Klotz Lars-Oliver, Ruzicka Thomas, Bier Henning, Zlotnik Albert, Whiteside Theresa L, Homey Bernhard, Hoffmann Thomas K
Department of Radiation Oncology, Heinrich-Heine-University, Duesseldorf, Germany.
Int J Cancer. 2006 May 1;118(9):2147-57. doi: 10.1002/ijc.21514.
Head and neck carcinomas are histologically and clinically heterogeneous. While squamous cell carcinomas (SCC) are characterized by lymphogenous spread, adenoid cystic carcinomas (ACC) disseminate preferentially hematogenously. To study cellular and molecular mechanisms of organ-specific metastasis, we used SCC and ACC cell lines and tumor tissues, obtained from patients with primary or metastatic disease. Comprehensive analysis at the mRNA and protein level of human chemokine receptors showed that SCC and ACC cells exhibited distinct and nonrandom expression profiles for these receptors. SCC predominantly expressed receptors for chemokines homeostatically expressed in lymph nodes, including CC chemokine receptor (CCR) 7 and CXC chemokine receptor (CXCR)5. No difference in expression of chemokine receptors was seen in primary SCC and corresponding lymph node metastases. In contrast to SCC, ACC cells primarily expressed CXCR4. In chemotaxis assays, ACC cells were responsive to CXCL12, the ligand for CXCR4. Exposure of ACC cells to cisplatin resulted in upregulation of CXCR4 on the cell surface, which was repressed by the transcriptional inhibitor, alpha-amanitin. Treatment of ACC cells with CXCL12 resulted in the activation of Akt and ERK1/2 pathways. Furthermore, CXCL12 suppressed the rate of apoptosis induced by cisplatin in ACC cells, suggesting that signaling via CXCR4 may be part of a tumor cell survival program. Discrimination of the chemokine receptor profile in SCC and ACC in vitro and in tissues provided insights into their distinct biologic and clinical characteristics as well as indications that chemokine receptors might serve as future therapeutic targets in these malignancies.
头颈部癌在组织学和临床上具有异质性。鳞状细胞癌（SCC）以淋巴转移为特征，而腺样囊性癌（ACC）则优先通过血行转移。为了研究器官特异性转移的细胞和分子机制，我们使用了从原发性或转移性疾病患者获得的SCC和ACC细胞系及肿瘤组织。对人类趋化因子受体在mRNA和蛋白质水平的综合分析表明，SCC和ACC细胞对这些受体表现出独特且非随机的表达谱。SCC主要表达在淋巴结中稳态表达的趋化因子受体，包括CC趋化因子受体（CCR）7和CXC趋化因子受体（CXCR）5。原发性SCC与其相应的淋巴结转移灶中趋化因子受体的表达没有差异。与SCC相反，ACC细胞主要表达CXCR4。在趋化性分析中，ACC细胞对CXCR4的配体CXCL12有反应。将ACC细胞暴露于顺铂会导致细胞表面CXCR4上调，而转录抑制剂α-鹅膏蕈碱可抑制这种上调。用CXCL12处理ACC细胞会导致Akt和ERK1/2信号通路激活。此外，CXCL12抑制了顺铂诱导的ACC细胞凋亡率，这表明通过CXCR4的信号传导可能是肿瘤细胞存活程序的一部分。在体外和组织中区分SCC和ACC的趋化因子受体谱，有助于深入了解它们不同的生物学和临床特征，也表明趋化因子受体可能成为这些恶性肿瘤未来的治疗靶点。
