DIFFERENTIAL SIGNALING OF CCR7 THROUGH ITS 2 ENDOGENOUS LIGANDS, CCL19 & CCL21

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 C-C趋化因子受体7(CCR7)在T细胞发育和T细胞进入和定位到淋巴结内的过程中调节原始胸腺细胞的运输。为了开发一个体内模型来了解CCR7控制细胞迁移的信号，我们开发了一个转移模型。CCR7通常在乳腺上皮细胞中低水平表达，在某些乳腺癌中表达上调，然而，这种上调在肿瘤发生/转移中的作用尚不清楚。为了明确CCR7在肿瘤转移中的作用，我们建立了两种小鼠模型。为了了解CCR7在肿瘤发展过程中的早期表达是否可以阻断肿瘤的转移，我们构建了一个四环素可调控的CCR7表达载体，并在N端与myc融合。将该载体用于与C57/BL6小鼠同基因的两个细胞系：高转移的4T07细胞系和非转移的67NR细胞系。为了确定CCR7是否可以改变具有可预测转移行为的细胞系的迁移效率或靶向，我们在据报道仅迁移到肺部的PyVMT细胞中过表达了结构性激活的CCR7。PYVMT细胞与FVB小鼠同源。应我们LAR机构的要求，在注射肿瘤之前，所有小鼠都接受了阿司匹林的预治疗，作为预防疼痛的措施。尽管小鼠被注射了5x105肿瘤细胞，这些小鼠模型的特征是在28天内发生肿瘤，但在137只注射的小鼠中，只有8只在一年的时间里在注射部位出现了肿瘤。肿瘤的发展与CCR7的表达无关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The C-C chemokine receptor 7 (CCR7) regulates trafficking of na¿ve thymocytes during T cell development and during localization of T cells to and within lymph nodes. To develop an in vivo model to understand the signaling of CCR7 that controls migration of cells, we developed a metasis model. CCR7, which is also normally expressed at low levels in breast epithelia is up-regulated in certain breast cancers, however, the role of this up-regulation in tumor development/metastasis remains unclear. To define the role for CCR7 in metastasis we worked to develop two mouse models. To understand whether early expression of CCR7 during tumor development could block tumor metastasis, we generated a tetracycline regulatable CCR7 expression vector that was fused at the N-terminus to myc. This vector was to be used in two cell lines that are syngeneic with C57/Bl6 mice; the highly metastatic 4T07 and as a the non-metastatic 67NR cell lines. To determine if CCR7 could change the migration efficiency or targeting of a line that had a predictable metastatic behavior, we overexpressed constitutively activated CCR7 in the the PyVMT cells that reportedly migrate only to the lungs. PyVMT cells are syngeneic with FVB mice. Following a request by our LAR facility, all mice were pre-treated with aspirin, as a prophylactic measure for pain, prior to tumor injections. Although the mice were injected with 5 x105 tumor cells, and these mouse models characteristically develop tumors within 28 days only 8 of the 137 injected mice developed tumors at the injection site over a one year period. The development of tumors did not correlate with expression of CCR7.