Role of SDF1a pathway in prostate cancer relapse and metastasis post-radiotherapy

描述（由申请人提供）：越来越多的人接受某些细胞因子可以通过直接增加癌细胞存活和侵袭或通过募集促肿瘤炎性细胞来促进肿瘤生长和转移。局部照射与肿瘤中细胞因子产生增加和炎性细胞浸润有关。因此，这些机制可能与肿瘤逃避治疗更广泛相关。这一概念得到了放疗后肿瘤复发模型结果的有力支持，并且可能与局部照射后基质衍生因子1 α（SDF 11，也称为CXCL 12）的上调直接相关。在这里，我们建议研究SDF 11受体CXCR 4和CXCR 7在局部复发和转移的局部晚期前列腺癌放疗后复发模型中的作用。在具体目标1中，我们将检查（i）在照射后抑制PCa细胞中的CXCR 4或CXCR 7;和（ii）将照射的前列腺癌细胞与未照射的骨髓衍生细胞（BMDC）共培养对前列腺癌细胞活力和迁移的影响。在具体目标2中，我们将评估（i）体内照射后前列腺癌细胞中CXCR 4或CXCR 7抑制对肿瘤复发的影响;以及（ii）照射后SDF 11/CXCR 4通路在骨髓衍生细胞（BMDC）募集中的作用，以及放疗后BMDC对肿瘤血管系统的贡献。在具体目标3中，我们将在原位前列腺癌模型中测试靶向CXCR 4或SDF 11的药理学药物与放射疗法的疗效。该提案将通过揭示前列腺癌复发期间SDF 11通路和骨髓BMDC掺入的作用来揭示前列腺癌对标准治疗（放疗）的抗性机制。在建立了（i）相关的临床前方法学来模拟小鼠前列腺癌并测量拟议的参数，以及（ii）前列腺癌，BMDC和SDF 11生物学的必要专业知识之后，我们认为我们的团队有能力成功完成这些研究。此外，通过将CXCR 4抑制与临床可用的药剂（例如，plerixafor）与放射的组合方法。

DESCRIPTION (provided by applicant): It is increasingly accepted that certain cytokines may promote tumor growth and metastasis either by directly increasing cancer cell survival and invasion or by recruiting tumor-promoting inflammatory cells. Local irradiation is associated with increased cytokine production and with infiltration of inflammatory cells in tumors. Thus, these mechanisms may be more broadly relevant for tumor escape from therapy. This concept is strongly supported by results from models of tumor relapse after radiotherapy, and may be directly related to upregulation of stromal-derived factor 1 alpha (SDF11, also known as CXCL12) after local irradiation. Here, we propose to study the role of the SDF11 receptors CXCR4 and CXCR7 in local relapse and metastasis in a model of locally advanced prostate cancer recurrence after radiation therapy. In Specific Aim 1, we will examine the impact on prostate cancer cell viability and migration of (i) inhibiting CXCR4 or CXCR7 in PCa cells after irradiation; and (ii) co-culturing the irradiated prostate cancer cells with non-irradiated bone marrow-derived cells (BMDCs). In Specific Aim 2, we will evaluate (i) the impact of CXCR4 or CXCR7 inhibition in prostate cancer cells on tumor relapse after irradiation in vivo; and (ii) the role of SDF11/CXCR4 pathway in bone marrow-derived cell (BMDC) recruitment after irradiation, and the contribution of BMDCs to the vasculature of tumors after radiotherapy. In Specific Aim 3, we will test the efficacy of pharmacologic agents targeting CXCR4 or SDF11 with radiation therapy in orthotopic prostate cancer models. This proposal will uncover mechanisms of resistance to standard treatment (radiotherapy) in prostate cancer by revealing the role of SDF11 pathway and myeloid BMDC incorporation during prostate cancer relapse. Having established (i) relevant preclinical methodology to model prostate cancer in mice and measure the proposed parameters, and (ii) the necessary expertise on prostate cancer, BMDC and SDF11 biology, we think that our team is capable to successfully complete these studies. In addition, this work may be rapidly translated in the clinic by integrating CXCR4 inhibition with clinically available agents (e.g., plerixafor) with combinatorial approaches with radiation.