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，介导归巢和 免疫细胞的招募，通过G蛋白连接的受体。最近，肿瘤细胞被证明是 表达趋化因子受体(CCR)7可能促进淋巴转移，我们已经证明 功能性CCR7在转移性头颈部鳞状细胞癌中的上调 与非转移性肿瘤相比。我们的数据表明，核因子-KB介导了CCR7诱导的下游 活性，以及CCR7本身及其配体在自分泌环中的表达。然而， CCR7在体内上调的机制和功能重要性还不是很清楚。我们的中央 假设：1)肿瘤微环境中的炎症信号导致上调和 CCR7由SCCHN细胞激活，以及II)CCR7介导的信号促进肿瘤的进展、生存和 转移。为了验证这些假说，在目标1中，炎性自分泌/旁分泌细胞因子对 将分析CCR7在SCCHN细胞中的表达和NF-KB的激活情况，以及CCR7在SCCHN细胞中的预后价值。 CCR7作为临床疾病状态的生物标志物在SCCHN标本中的表达将通过以下方式进行分析 免疫组织化学。目的2，我们将阐明细胞内CCR7介导的促进侵袭的信号， 转移性SCCHN细胞的存活和顺铂耐药。因为单一信号的抑制 途径不太可能有显著的临床益处，需要联合靶向策略。因此， CCR7抑制的抗肿瘤作用将在体外进行评估，并与另一个重要的信号转导相结合 在SCCHN，EGFR途径，以增强翻译治疗潜力。在AIM 3中，重要性 CCR7对体内肿瘤进展的活性将在临床前小鼠SCCHN模型系统中进行测试。我们 已经观察到CCR7过表达增加了低转移小鼠的迁移能力 SCCHN肿瘤细胞株。利用这一模型，CCR7抑制在调节肿瘤中的抗肿瘤效果 生长和转移将单独测试或与EGFR阻断联合测试。这些数据将是 与缺乏CCR7配体的PIT/PIT小鼠的肿瘤形成相比。总的来说，这些研究是 旨在识别EGFR非依赖的、CCR7介导的与肿瘤的侵袭和生存相关的途径 并利用这些信息促进CCR7靶向治疗策略的制定。

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.