Molecular Imaging of Chemokine Receptor Signaling

摘要 趋化因子受体信号传导是原发性肿瘤生长的关键决定因素， 许多常见癌症的器官特异性转移。特别是，我们的实验室和 其他人已经表明趋化因子受体CXCR 4和CXCR 7被上调， 乳腺癌和肺癌中的恶性细胞。CXCR 4和CXCR 7信号显著 增加原发性肿瘤负荷并增强转移性肿瘤的存活和增殖 癌细胞，所有这些都对患者的生活质量和存活率产生不利影响。 肿瘤微环境中的趋化因子受体信号由基质细胞启动 分泌趋化因子配体。这些配体与肿瘤细胞上的同源受体结合， 从而激活控制肿瘤进展和转移的下游效应物。 了解趋化因子受体CXCR 4和CXCR 7的整合功能是 对于解剖原发性和转移性癌症的分子调控至关重要， 有效地靶向这些受体以改善癌症治疗。我们假设 可以开发分子成像报告物以检测和定量细胞内的多个步骤， CXCR 4和CXCR 7信号在基于细胞的测定和乳腺癌小鼠模型中的作用 这些成像报告建立在我们的专业知识成像蛋白质-蛋白质相互作用 在信号通路中。在aim 1中，我们将开发一种荧光素酶互补报告基因 分析趋化因子配体与乳腺癌细胞上CXCR 4和CXCR 7的细胞外结合， 癌细胞在目标2中，我们将构建一个成像报告系统， 细胞上的趋化因子受体复合物以及这些复合物在 信号最后，aim 3将开发一种用于细胞内激活 CXCR 4和CXCR 7基于支架蛋白抑制蛋白的募集。这 研究将建立新的成像技术，以调查综合功能， 乳腺癌中的CXCR 4和CXCR 7，并建立这些的治疗靶向 趋化因子受体在完整的细胞和活的小鼠。除了目前的研究， 这些报告技术有望作为一种通用的方法来研究 趋化因子和趋化因子受体的整个家族，扩展了这些 除了癌症之外，成像技术还可以用于许多疾病。这项研究的意义在于它将发展新的成像技术， 乳腺细胞间和细胞内信号网络以及广泛的其他 常见的癌症这些成像报告者将推进我们对细胞信号传导的认识 在癌症起始和进展为转移性疾病的临床前模型中。使用 这些成像技术还将大大提高我们测试和验证新的 治疗药物，我们预计这将导致改善患者的治疗 癌

Abstract Chemokine receptor signaling is a critical determinant of primary tumor growth and organ-specific metastases in many common cancers. In particular, our laboratory and others have shown that chemokine receptors CXCR4 and CXCR7 are upregulated on malignant cells in breast and lung cancer. CXCR4 and CXCR7 signaling significantly increases primary tumor burden and enhances survival and proliferation of metastatic cancer cells, all of which adversely affect quality of life and survival for patients. Chemokine receptor signaling in the tumor microenvironment is initiated by stromal cells that secrete chemokine ligands. These ligands bind to cognate receptors on tumor cells, thereby activating downstream effectors that control tumor progression and metastasis. Understanding integrated functions of chemokine receptors CXCR4 and CXCR7 is essential for dissecting molecular regulation of primary and metastatic cancer and effectively targeting these receptors to improve cancer therapy. We hypothesize that molecular imaging reporters can be developed to detect and quantify multiple steps in CXCR4 and CXCR7 signaling in cell-based assays and mouse models of breast cancer. These imaging reporters build upon our expertise in imaging protein-protein interactions in signaling pathways. In aim 1, we will develop a luciferase complementation reporter to analyze extracellular binding of chemokine ligands to CXCR4 and CXCR7 on breast cancer cells. In aim 2, we will construct an imaging reporter system to quantify chemokine receptor complexes on cells and changes in these complexes during signaling. Finally, aim 3 will develop an imaging reporter for intracellular activation of CXCR4 and CXCR7 based on recruitment of the scaffolding protein ¿-arrestin. This research will establish new imaging technologies to investigate integrated functions of CXCR4 and CXCR7 in breast cancer and establish therapeutic targeting of these chemokine receptors in intact cells and living mice. Beyond the current research, each of these reporter technologies is expected to serve as a general method to study the entire family of chemokines and chemokine receptors, extending applications of these imaging techniques to many diseases besides cancer. The significance of this research is that it will develop new techniques to image intercellular and intracellular signaling networks in breast and a wide range of other common cancers. These imaging reporters will advance our knowledge of cell signaling in pre-clinical models of cancer initiation and progression to metastatic disease. Using these imaging technologies also will greatly improve our ability to test and validate new therapeutic agents, which we anticipate will lead to improved treatments for patients with cancer.