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

SDF1a通路在前列腺癌放疗后复发和转移中的作用

• 批准号: 8493794
• 负责人: Dan Gabriel Duda
• 金额: $ 30.54万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-19 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8493794
• 关键词: AMD3100; Apoptosis; Biology; Blood Vessels; Bone Marrow; Bone Marrow Transplantation; CXCL12 gene; CXCR4 Receptors; CXCR4 gene; Cancer Relapse; Cell Survival; Cells; Chalcone; Clinic; Coculture Techniques; Disease; Distant; Distant Metastasis; Dose; Excision; Genetic; Genetic Models; Growth; Human; Imaging Techniques; Immunohistochemistry; Implant; In Vitro; Infiltration; Inflammatory; Label; Luciferases; Malignant neoplasm of prostate; Measures; Mediating; Methodology; Modeling; Mus; Myelogenous; Myeloid Cells; Neoplasm Metastasis; Operative Surgical Procedures; PC3 cell line; Pathway interactions; Primary Neoplasm; Production; Prostate carcinoma; Radiation; Radiation therapy; Reagent; Recruitment Activity; Relapse; Research; Resistance; Role; System; Testing; Transgenic Mice; Translating; Tumor Escape; Up-Regulation; Work; bioluminescence imaging; cancer cell; cancer recurrence; cell motility; chemokine; combinatorial; cytokine; density; efficacy testing; improved; in vivo; inhibitor/antagonist; irradiation; migration; mouse model; new growth; novel strategies; pre-clinical; prostate cancer cell; prostate cancer model; research study; resistance mechanism; small hairpin RNA; standard care; tumor; tumor growth

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.

描述（由申请人提供）：越来越接受的是，某些细胞因子可以通过直接增加癌细胞存活和侵袭或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的产生增加和炎性细胞浸润有关。因此，这些机制可能与肿瘤摆脱治疗更为广泛。放疗后肿瘤复发模型的结果得到了强烈支持，并且可能与局部照射后基质来源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在放射治疗后局部晚期前列腺癌复发模型中局部复发和转移的作用。在特定目标1中，我们将检查对PROSTATE癌细胞活力的影响以及（i）抑制PCA细胞中CXCR4或CXCR7的迁移； （ii）将辐照的前列腺癌细胞与未辐照的骨髓衍生细胞（BMDC）共同培养。在特定目标2中，我们将评估（i）CXCR4或CXCR7在体内辐射后抑制前列腺癌细胞对肿瘤复发的影响； （ii）辐照后SDF11/CXCR4途径在骨髓衍生的细胞（BMDC）募集中的作用，以及放射治疗后BMDC对肿瘤的脉管系统的贡献。在特定目标3中，我们将测试针对原位前列腺癌模型中靶向CXCR4或SDF11的药理学剂的功效。该建议将通过揭示前列腺癌和髓样BMDC在前列腺癌复发期间的作用，从而发现前列腺癌中标准治疗（放射疗法）的耐药性机制。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生物学的必要专业知识，我们认为我们的团队能够成功完成这些研究。此外，这项工作可以通过将CXCR4抑制与临床上可用的药物（例如Plerixafor）与辐射的组合方法相结合，从而在诊所中迅速翻译。