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的存活和侵袭或通过招募促肿瘤炎症细胞来促进肿瘤的生长和转移。局部照射与细胞因子的产生增加和炎性细胞在肿瘤中的渗透有关。因此，这些机制可能更广泛地与肿瘤逃脱治疗有关。这一概念得到了放疗后肿瘤复发模型的有力支持，并可能与局部照射后基质衍生因子1α(SDF11，也称为CXCL12)的上调直接相关。在这里，我们建议研究SDF11受体CXCR4和CXCR7在局部晚期前列腺癌放射治疗后局部复发和转移中的作用。在具体目标1中，我们将研究(I)照射后抑制前列腺癌细胞中的CXCR4或CXCR7；以及(Ii)照射后的前列腺癌细胞与非照射的骨髓来源的细胞(BMDCs)共培养对前列腺癌细胞活力和迁移的影响。在特定的目标2中，我们将评估(I)抑制前列腺癌CXCR4或CXCR7对体内照射后肿瘤复发的影响；(Ii)SDF11/CXCR4通路在照射后骨髓来源细胞(BMDC)募集中的作用，以及BMDCs在放射治疗后对肿瘤血管的作用。在具体目标3中，我们将测试针对CXCR4或SDF11的药物与放射治疗在原位前列腺癌模型中的疗效。这项建议将通过揭示SDF11途径和髓系BMDC掺入在前列腺癌复发中的作用来揭示前列腺癌对标准治疗(放射治疗)耐药的机制。在建立了(I)建立小鼠前列腺癌模型并测量建议参数的相关临床前方法学，以及(Ii)前列腺癌、BMDC和SDF11生物学方面的必要专业知识后，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CXCR4抑制与临床上可用的药物(例如，plerixafor)与放射治疗的组合方法相结合，这项工作可能会迅速转化为临床。 公共卫生相关性：在局部晚期前列腺癌模型中，我们将检查间质衍生因子11途径在逃避标准放射治疗中的影响。我们已经建立了相关的临床前方法学来测量前列腺癌的拟议参数，并获得了关于这种疾病的必要专业知识。我们的研究可能会产生这种可怕疾病迫切需要的新方法。

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. PUBLIC HEALTH RELEVANCE: We will examine the impact of stromal-derived factor 11pathway in escape from standard radiation therapy in locally advanced prostate carcinoma models. We have established relevant preclinical methodology to measure the proposed parameters in prostate carcinoma and acquired the necessary expertise on this disease. Our research may generate new approaches that are desperately needed for this dreadful disease.