Role of BMDCs in Solid Tumor Growth and Relapse

描述（由申请人提供）：我们的初步数据和最近的报告已经确定骨髓源性细胞（bmdc）是实体瘤的关键成分。与浸润肿瘤组织的其他BMDCs相比，髓系细胞占主导地位，它们的浸润被认为是对肿瘤产生的血管生成生长因子的反应。然而，髓系BMDC亚群向肿瘤募集的动力学及其在细胞毒性治疗后肿瘤复发中的作用在很大程度上是未知的。拟议的研究旨在填补这一空白。我们的研究计划以三个主要假设为指导。首先，我们假设髓系BMDCs浸润促进肿瘤生长和血管生成。我们的目标是确定髓系BMDC亚群（髓系前体细胞/壁细胞、单核细胞/巨噬细胞和粒细胞/中性粒细胞）的组织分布及其在肿瘤血管生成和生长中的作用（目的1）。其次，我们假设骨髓细胞被动员到血液循环中，并被募集到肿瘤组织中，至少部分是由肿瘤产生的两种血管生成因子：VEGF和SDF-1的共同作用。我们将量化骨髓细胞向肿瘤募集的动力学，并评估VEGF和/或SDF-1阻断在这一过程中的作用（目的2）。最后，超过一半的癌症患者接受了放疗，但在许多情况下肿瘤复发。我们假设髓系BMDCs在放疗后肿瘤复发中起关键作用。我们将确定放疗后复发时骨髓性BMDC亚群的组织分布、表型和功能；随后，我们将测试一种临床相关的治疗策略，以抑制它们在治疗后参与肿瘤复发（目的3）。利用最先进的荧光显微镜和其他互补方法，我们建议表征肿瘤中髓系BMDCs的动力学，表型和功能。拟议的研究将明确阐明髓系BMDCs在肿瘤血管生成和生长中的作用，这在使用抗血管生成治疗癌症的临床前和临床方案中经常被忽视。此外，我们的研究结果将通过靶向对血管生成和骨髓BMDC募集至关重要的分子途径，提供抑制放疗后肿瘤复发的策略。

DESCRIPTION (provided by applicant): Our preliminary data and recent reports have established that bone marrow-derived cells (BMDCs) are key constituents of solid tumors. Cells of myeloid lineage predominate compared to other BMDCs that infiltrate tumor tissues, and their infiltration is thought to be in response to angiogenic growth factors produced by the tumors. However, the kinetics of the recruitment of myeloid BMDC subsets to tumors and their role in tumor relapse after cytotoxic therapy are largely unknown. The proposed research aims to fill this gap. Our research plan is guided by three principal hypotheses. First, we hypothesize that myeloid BMDCs infiltration facilitates tumor growth and angiogenesis. We aim to determine the tissue distribution of myeloid BMDC subsets (myeloid precursor cells/mural cells, monocytes/macrophages and granulocytes/neutrophils) and their role in tumor angiogenesis and growth (Aim 1). Second, we hypothesize that the myeloid cells are mobilized into blood circulation and recruited to tumor tissue, at least in part, by the combined effect of two angiogenic factors produced by the tumor: VEGF and SDF-1. We will quantify the kinetics of myeloid cells' recruitment to tumors, and evaluate the effect of VEGF and/or SDF-1 blockade in this process (Aim 2). Finally, more than half of the cancer patients are treated by radiotherapy, but in many cases tumors relapse. We hypothesize that myeloid BMDCs contribute in a critical manner to tumor relapse after radiotherapy. We will determine the tissue distribution, phenotype, and establish the function of the myeloid BMDC subsets during relapse after radiotherapy; subsequently, we will test a clinically relevant treatment strategy to inhibit their participation in tumor relapse after treatment (Aim 3). Using state-of-the-art fluorescence microscopy and other complementary approaches, we propose to characterize the kinetics, phenotype and function of myeloid BMDCs in tumors. The proposed studies will unambiguously elucidate the role of myeloid BMDCs in tumor angiogenesis and growth, often overlooked in preclinical and clinical protocols using antiangiogenic therapies for cancer. Furthermore, our results will offer strategies for the inhibition of tumor relapse after radiotherapy by targeting molecular pathways that are critical for both angiogenesis and myeloid BMDC recruitment.