Chemokine Signals in Head and Neck Cancer Progression

趋化因子是由炎症部位的细胞分泌的小分子，其介导归巢， 通过G蛋白连接的受体募集免疫细胞。最近，肿瘤细胞已经被证明 表达趋化因子受体（CCR）7，可能促进淋巴结转移，我们已经表明， 头颈部转移性鳞状细胞癌（SCCHN）上功能性CCR 7的上调， 与非转移性肿瘤相比。我们的数据表明NF-κ B介导下游CCR 7诱导的细胞凋亡。 活性，以及自分泌环中CCR 7本身及其配体的表达。但 体内CCR 7上调的机制和功能重要性还没有很好地理解。我们的中央 假设是i）肿瘤微环境中的炎性信号导致上调， CCR 7被SCCHN细胞激活，和ii）CCR 7介导的信号促进肿瘤进展、存活和 转移为了验证这些假设，在AIM 1中，炎症自分泌/旁分泌细胞因子对 将在SCCHN细胞中分析CCR 7表达和NF-κ B的活化，并分析CCR 7表达和NF-κ B活化的预后价值。 将通过以下方法分析SCCHN标本中作为临床疾病状态生物标志物的CCR 7表达： 免疫组化目的2：阐明细胞内CCR 7介导的促进侵袭的信号， 转移性SCCHN细胞的存活和顺铂抗性。因为单一信号的抑制 由于该途径不太可能具有显著的临床益处，因此需要组合靶向策略。因此 将在体外评估CCR 7抑制的抗肿瘤作用，并结合另一种重要的信号传导 在SCCHN，EGFR的途径，以提高翻译治疗潜力。在AIM 3中， 将在临床前鼠SCCHN模型系统中测试CCR 7对体内肿瘤进展的活性。我们 已经观察到CCR 7过表达增加了转移性差的小鼠的迁移能力， SCCHN肿瘤细胞系。使用该模型，CCR 7抑制在调节肿瘤中的抗肿瘤功效被评估。 生长和转移将单独或与EGFR阻断剂组合测试。这些数据将 与缺乏CCR 7配体的pit/pit小鼠中的肿瘤形成相比。总体而言，这些研究 旨在鉴定EGFR非依赖性，CCR 7介导的与肿瘤侵袭和存活相关的通路。 SCCHN，并使用这些信息来促进CCR 7靶向治疗策略的发展。

Chemokines are small molecules secreted by cells at inflammatory sites that mediate homing and recruitment of immune cells, through G-protein linked receptors. Recently, tumor cells have been shown to express chemokine receptor (CCR)7 that may facilitate lymph node metastasis, and we have shown upregulation of functional CCR7 on metastatic squamous cell carcinoma of the head and neck (SCCHN), compared to nonmetastatic tumors. Our data suggest that NF-KB mediates downstream CCR7-induced activities, as well as the expression of CCR7, itself, and its ligands in an autocrine loop. However, the mechanism and functional importance of CCR7 upregulation in vivo are not well understood. Our central hypotheses are that i) inflammatory signals in the tumor microenvironment lead to upregulation and activation of CCR7 by SCCHN cells, and ii) CCR7-mediated signals promote tumor progression, survival and metastasis. To test these hypotheses, in AIM 1 the effect of inflammatory autocrine/paracrine cytokines on CCR7 expression and activation of NF-KB will be analyzed in SCCHN cells, and the prognostic value of CCR7 expression as a biomarker of clinical disease status in SCCHN specimens will be analyzed by immunohistochemistry. AIM 2, we will elucidate the intracellular CCR7-mediated signals promoting invasion, survival and cis-platinum resistance of metastatic SCCHN cells. Because inhibition of a single signaling pathway is unlikely to have significant clinical benefit, combination targeting strategies are needed. Thus, the antitumor effect of CCR7 inhibition will be evaluated in vitro, and combined with another important signaling pathway in SCCHN, EGFR, to enhance the translational therapeutic potential. In AIM 3, the importance CCR7 activity on tumor progression in vivo will be tested in preclinical murine SCCHN model systems. We have observed that CCR7 overexpression increased migratory capacity of a poorly metastatic murine SCCHN tumor cell line. Using this model, the antitumor efficacy of CCR7 inhibition, in modulating tumor growth and metastasis will be tested alone or in combination with EGFR blockade. These data will be compared to tumor formation in pit/pit mice, which are deficient in CCR7 ligands. Overall these studies are designed to identify the EGFR-independent, CCR7-mediated pathways relevant to invasion and survival of SCCHN and to use this information to facilitate the development of CCR7 targeted therapeutic strategies.