Chemokine Signals in Head and Neck Cancer Progression

描述(申请人提供)：趋化因子是由炎症部位的细胞分泌的小分子，通过G蛋白连接的受体调节免疫细胞的归巢和招募。最近，肿瘤细胞表达趋化因子受体(CCR)7，与非转移性肿瘤相比，我们发现功能性CCR7在转移性头颈部鳞状细胞癌(SCCHN)中表达上调。我们的数据表明，核因子-βB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。我们的中心假设是：1)肿瘤微环境中的炎症信号导致SCCHN细胞上调和激活CCR7；2)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AIM 1中，将分析炎性自分泌/旁分泌细胞因子对SCCHN细胞CCR7表达和NF-βB激活的影响，并通过免疫组织化学方法分析CCR7表达作为SCCHN临床疾病状态生物标志物的预后价值。目的2，我们将阐明细胞内CCR7介导的信号促进转移性SCCHN细胞的侵袭、存活和顺铂耐药。由于抑制单一信号通路不太可能有显著的临床益处，因此需要联合靶向策略。因此，我们将在体外评估抑制CCR7的抗肿瘤作用，并与SCCHN中另一个重要的信号通路EGFR联合使用，以增强翻译治疗的潜力。在AIM 3中，CCR7活性在体内肿瘤进展中的重要性将在临床前小鼠SCCHN模型系统中进行测试。我们观察到CCR7过表达增加了低转移的小鼠SCCHN肿瘤细胞系的迁移能力。利用这一模型，CCR7抑制在调节肿瘤生长和转移方面的抗肿瘤效果将被单独或与EGFR阻断联合测试。这些数据将与缺乏CCR7配体的PLT/PLT小鼠的肿瘤形成进行比较。总体而言，这些研究旨在确定与SCCHN的侵袭和生存相关的EGFR非依赖的、CCR7介导的通路，并利用这些信息促进CCR7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.