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

描述（由申请人提供）：越来越多的人认为某些细胞因子可能通过直接增加癌细胞的存活和侵袭或通过募集促瘤炎性细胞来促进肿瘤的生长和转移。局部照射与肿瘤中细胞因子产生增加和炎症细胞浸润有关。因此，这些机制可能与肿瘤逃避治疗有更广泛的关系。放疗后肿瘤复发模型的结果有力地支持了这一概念，并可能与局部照射后基质衍生因子1 α （SDF11，也称为CXCL12）的上调直接相关。本研究拟在局部晚期前列腺癌放疗后复发模型中研究SDF11受体CXCR4和CXCR7在局部复发和转移中的作用。在Specific Aim 1中，我们将研究(i)在照射后抑制前列腺癌细胞中的CXCR4或CXCR7对前列腺癌细胞活力和迁移的影响；（ii）将辐照后的前列腺癌细胞与未辐照的骨髓源性细胞（bmdc）共培养。在Specific Aim 2中，我们将评估(i)体内照射后前列腺癌细胞中CXCR4或CXCR7抑制对肿瘤复发的影响；（ii） SDF11/CXCR4通路在放疗后骨髓源性细胞（BMDC）募集中的作用，以及BMDC在放疗后肿瘤血管中的作用。在Specific Aim 3中，我们将在原位前列腺癌模型中测试靶向CXCR4或SDF11的药物与放射治疗的疗效。本研究将通过揭示SDF11通路和骨髓BMDC掺入在前列腺癌复发中的作用，揭示前列腺癌对标准治疗（放疗）的耐药机制。我们已经建立了(i)相关的临床前方法来模拟小鼠前列腺癌并测量所提出的参数，以及（ii）前列腺癌、BMDC和SDF11生物学方面的必要专业知识，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CXCR4抑制与临床可用的药物（如plerixafor）结合放射治疗，这项工作可能会在临床中迅速转化。

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.