Matricelluar-mediated cell migration in tumor cells

肿瘤细胞中基质细胞介导的细胞迁移

基本信息

批准号：
8849682
负责人：
Cimona V Hinton
金额：
$ 1.86万
依托单位：
CLARK ATLANTA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-15 至 2017-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8849682
关键词：
AM 1241 Absence of pain sensation Adverse effects Affect Agonist Allergic Reaction Animals Apoptosis Attenuated Binding CXCL12 gene CXCR4 Receptors CXCR4 gene Cancer Control Cannabinoids Cell Culture Techniques Cell Proliferation Cells Complement Complex Congenital Heart Defects Coupled Data Development Dimerization Distal Fc Receptor Fluorescence Resonance Energy Transfer GTP-Binding Proteins Heterodimerization Homo Immune Implant In Vitro Individual Injection of therapeutic agent Lead Ligands Limb structure Luciferases Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of lung Mediating Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Metastatic to Modeling Molecular Movement Mus Neoplasm Metastasis Organ Organism Pathway interactions Prevention approach Primary Neoplasm Principal Investigator Prostate Prostatic Neoplasms Proteins Publishing Reporting Research Design Signal Pathway Signal Transduction Stromal Cell-Derived Factor 1 Testing Therapeutic Tissues base bone cancer cell cancer therapy cannabinoid receptor cell motility chemokine receptor delta opioid receptor desensitization dimer experience in vivo male mouse model neoplastic cell neutralizing antibody programs prostate cancer cell public health relevance receptor response simulation small hairpin RNA tumor tumor growth tumor progression

项目摘要

DESCRIPTION (provided by applicant): Upon activation by stromal cell derived factor 1 alpha (SDF1 alpha), the G-protein-coupled chemokine receptor, CXCR4, generates signals that eventually lead to the metastatic spread and survival of primary tumor cells in distal organs. Indeed, elevated expression of CXCR4 protein in prostate tissues correlates with metastasis and overall prediction of poor survival. CXCR4 can form homodimers or can heterodimerize with unrelated receptors, such as the delta opioid receptor (DOR). Simultaneous treatment with appropriate agonists for the individual receptors that are heterodimerizing, such as the CXCR4/DOR heterodimer, results in a dimer that is unable to signal, although each receptor can bind its respective ligand. Therefore, heterodimerization can cause decreased signaling through such receptor complexes, representing functional desensitization. In the context of cancer treatment, CXCR4 signaling and subsequent functions can be silenced by desensitization through heterodimeric association with other receptors, thereby inhibiting CXCR4-generated signals that would otherwise lead to metastasis. Thus, antagonizing the function of CXCR4 through heterodimerization could be a rational approach to the prevention and management of metastatic prostate cancer, and could be an effective alternative to current therapeutics involving neutralizing antibodies or antagonists against CXCR4, both of which have undesirable consequences. Studies reported that simultaneous treatment with CXCR4 and cannabinoid receptor 2 (CB2R) agonists caused a reduction in CB2R-induced analgesia, suggesting a functional desensitization of CB2R, although dimerization was not analyzed. Given this scenario, a heterodimer of CXCR4/CB2R could potentially attenuate responses triggered individually by CXCR4 or CB2R, without the side effects experienced with the use of receptor antibodies or antagonists, especially in situations where both receptors are expressed on the same tumor cells. We will demonstrate that receptor heterodimerization could form the molecular basis for decreasing CXCR4-mediated signaling, and therefore, metastasis. Hypothesis: CXCR4 function can be abrogated by simultaneous ligand-dependent heterodimerization of CXCR4 with CB2R, resulting in decreased CXCR4 signaling, cell metastasis and overall tumor development. Specific aims: (1): To determine whether CXCR4 and CB2R physically associate in vitro; (2): To determine which signaling pathways are modulated as a result of heterodimerization of CXCR4 with CB2R; and (3): To determine whether heterodimerization of CXCR4 with CB2R antagonizes CXCR4-mediated metastasis in intact animals. Research design: Our strategy will include: (i) confirming that CXCR4 and CB2R dimerize by FRET analysis; (ii) determining whether CB2R is required as a dimer partner to abrogate signaling and known functions of CXCR4 by shRNA for CB2R; and (iii) examining whether heterodimerization of CXCR4 with CB2R will inhibit tumor growth and metastasis of prostate cancer cells to the bone in vivo.

描述（由申请人提供）：通过基质细胞衍生因子1α（SDF1α）激活后，G蛋白偶联的趋化因子受体CXCR4会产生信号，最终导致远端器官中原代肿瘤细胞的转移扩散和存活。实际上，前列腺组织中CXCR4蛋白的表达升高与转移和整体预测生存率相关。 CXCR4可以形成同型二聚体，也可以与无关的受体（例如Delta阿片受体（DOR））异二聚体。同时使用适当的激动剂治疗异二聚体的单个受体，例如CXCR4/DOR异二聚体，导致二聚体无法发信号，尽管每个受体都可以结合其各自的配体。因此，异二聚化会通过这种受体复合物导致信号传导降低，代表功能脱敏。在癌症治疗的背景下，CXCR4信号传导和随后的功能可以通过与其他受体的异二聚体缔合来沉默，从而抑制CXCR4生成的信号，否则会导致转移。因此，通过异二聚化对CXCR4的功能进行拮抗可能是预防和管理转移性前列腺癌的一种合理方法，并且可以有效地替代涉及中和抗CXCR4的抗体或拮抗剂的当前疗法，这两者都有不良后果。研究报告说，用CXCR4和大麻素受体2（CB2R）激动剂同时治疗导致CB2R诱导的镇痛降低，表明CB2R的功能脱敏，尽管未分析二聚化。鉴于这种情况，CXCR4/CB2R的异二聚体可能会潜在地减弱由CXCR4或CB2R触发的反应，而没有受体抗体或拮抗剂的副作用，尤其是在同一肿瘤细胞上表达两种受体的情况下。我们将证明受体异二聚化可能构成降低CXCR4介导的信号传导的分子基础，因此可以转移。假设：CXCR4功能可以通过与CB2R的CXCR4同时依赖配体依赖性异二聚化来消除，从而导致CXCR4信号传导，细胞转移和整体肿瘤发育降低。具体目的：（1）：确定CXCR4和CB2R是否在体外与物理缔合；（2）：确定CXCR4与CB2R的异二聚化对哪些信号通路进行了调节；（3）：确定CB2R的CXCR4的异二聚化是否会拮抗完整动物中CXCR4介导的转移。研究设计：我们的策略将包括：（i）通过FRET分析确认CXCR4和CB2R二聚；（ii）确定是否需要CB2R作为二聚体伴侣，以消除SHRNA的CXCR4信号传导和CB2R的已知功能；（iii）检查使用CB2R的CXCR4异二二聚体是否会抑制肿瘤的生长和前列腺癌细胞转移到体内的骨骼。