Development of head and neck squamous cell carcinoma is associated with altered cytokine responsiveness.
Development of head and neck squamous cell carcinoma is associated with altered cytokine responsiveness.
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DOI：
10.1158/1541-7786.585.2.10
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发表时间：
2004-10
期刊：
影响因子：
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通讯作者：
W. Douglas;E. Tracy;D. Tan;Jihnhee Yu;W. Hicks;N. Rigual;T. Loree;Yanping Wang;H. Baumann
中科院分区：
文献类型：
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作者：
W. Douglas;E. Tracy;D. Tan;Jihnhee Yu;W. Hicks;N. Rigual;T. Loree;Yanping Wang;H. Baumann
头颈部鳞状细胞癌（HNSCC）的生长通常与炎症成分相关。据推测，这些肿瘤细胞发展机制，以逃避肿瘤微环境中存在的细胞因子的生长抑制作用。本研究确定了伴随正常上皮细胞向转化上皮细胞转变的炎症细胞因子反应性的变化。从16例患者中建立正常上皮细胞（NEC）和SCC细胞的配对原代培养物。通过免疫印迹分析鉴定了响应于细胞因子处理的受体介导的信号转导子和转录激活子以及细胞外信号调节激酶途径的激活。胸苷掺入确定细胞因子对DNA合成的影响。HNNEC和HNSCC显示出对制瘤素M、白细胞介素-6、IFN-γ和表皮生长因子的显著信号传导。与HNNEC相比，未经治疗的HNSCC显示磷酸化信号转导子和转录激活子3以及细胞外信号调节激酶的水平升高（P < 0.001），表明组成性激活的途径。此外，HNSCC细胞在抑瘤素M（P = 0.002）和IFN-γ（P = 0.018）处理后磷酸化的信号转导子和转录激活子1显著增加。内毒素刺激巨噬细胞产生的细胞因子对SCC细胞DNA合成的抑制作用低于NEC细胞（P = 0.016）。低剂量抑瘤素M对SCC的增殖有轻度促进作用，而对NEC的增殖有抑制作用（P = 0.016）。这项研究确定了细胞因子参与的信号转导途径的显著改变，这些改变与HNSCC生长抑制的丧失有关。HNSCC中信号转导子和转录激活子磷酸化水平的增加，沿着细胞外信号调节激酶的组成性磷酸化，提示这些信号通路作为分子标志物在HNSCC的恶性转化过程中是重要的，是潜在的治疗靶点。
Growth of head and neck squamous cell carcinoma (HNSCC) is generally associated with an inflammatory component. It is hypothesized that these tumor cells develop mechanisms to evade the growth inhibitory effects of cytokines that are present in the tumor microenvironment. This study determined the changes in responsiveness to inflammatory cytokines that accompany the transition of normal to transformed epithelial cells. Paired primary cultures of normal epithelial cells (NEC) and SCC cells were established from 16 patients. Receptor-mediated activation of signal transducer and activator of transcription and extracellular signal-regulated kinase pathways in response to cytokine treatments was identified by immunoblot analysis. Thymidine incorporation determined the impact of the cytokines on DNA synthesis. HNNEC and HNSCC displayed a prominent signaling in response to oncostatin M, interleukin-6, IFN-gamma, and epidermal growth factor. Untreated HNSCC showed an elevated level of phosphorylated signal transducer and activator of transcription 3 and extracellular signal-regulated kinase (P < 0.001) compared with HNNEC, suggesting constitutively activated pathways. Moreover, HNSCC cells phosphorylated significantly more signal transducer and activator of transcription 1 in response to oncostatin M (P = 0.002) and IFN-gamma (P = 0.018) treatments. DNA synthesis of SCC cells was less inhibited by cytokines produced by endotoxin-stimulated macrophages (P = 0.016) than that of NEC. Low-dose oncostatin M slightly enhanced proliferation of SCC, whereas that of NEC was suppressed (P = 0.016). This study identified significant alterations in signal transduction pathways engaged by cytokines and which are associated with loss of growth inhibition of HNSCC. Increased signal transducer and activator of transcription phosphorylation, along with constitutively phosphorylated extracellular signal-regulated kinase in HNSCC, suggest that these pathways as molecular markers are important in the malignant transformation process and are potential targets for treatment.