Chemokine Signals in Head and Neck Cancer Progression

描述（由申请方提供）：趋化因子是由炎症部位的细胞分泌的小分子，通过G蛋白连接受体介导免疫细胞的归巢和募集。最近，肿瘤细胞已被证明表达趋化因子受体（CCR）7，可能有助于淋巴结转移，我们已经表明上调功能性CCR 7的转移性鳞状细胞癌的头部和颈部（SCCHN），相比非转移性肿瘤。我们的数据表明，NF-？B介导下游CCR 7诱导的活性，以及自分泌环中CCR 7本身及其配体的表达。然而，体内CCR 7上调的机制和功能重要性还没有很好地理解。我们的中心假设是i）肿瘤微环境中的炎症信号导致SCCHN细胞上调和激活CCR 7，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炎症自分泌/旁分泌细胞因子对CCR 7表达和NF-？将在SCCHN细胞中分析B，并将通过免疫组织化学分析CCR 7表达作为SCCHN标本中临床疾病状态的生物标志物的预后价值。目的2：阐明CCR 7介导的细胞内信号对转移性SCCHN细胞侵袭、存活和顺铂耐药的促进作用。由于抑制单一信号通路不太可能具有显著的临床益处，因此需要联合靶向策略。因此，将在体外评估CCR 7抑制的抗肿瘤作用，并与SCCHN中的另一个重要信号通路EGFR结合，以增强翻译治疗潜力。在AIM 3中，将在临床前鼠SCCHN模型系统中测试CCR 7活性对体内肿瘤进展的重要性。我们已经观察到CCR 7过表达增加了转移性差的鼠SCCHN肿瘤细胞系的迁移能力。使用该模型，将测试CCR 7抑制在调节肿瘤生长和转移中单独或与EGFR阻断组合的抗肿瘤功效。将这些数据与缺乏CCR 7配体的plt/plt小鼠中的肿瘤形成进行比较。总的来说，这些研究旨在确定EGFR非依赖性，CCR 7介导的途径相关的侵袭和生存的SCCHN，并使用这些信息，以促进CCR 7靶向治疗策略的发展。

DESCRIPTION (provided by applicant): 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-?B 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-?B 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 plt/plt 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.