Circulating Endothelial Progenitor Cell Subsets

小儿高危恶性实体瘤的预后仍然严峻。恶性肿瘤儿童和接受造血干细胞移植（HSCT）的儿童由于化疗引起的毒性有显著的发病率和死亡率。需要基于独特的生物学特征和治疗反应的新型生物标志物来开发个性化治疗和反应评估。血管生成标记物在成人试验中已成为有希望的候选物。然而，儿科研究很少。我们的长期目标是确定新的儿童血管生成生物标志物，以促进个体化化疗和促进新疗法的发展。血管生成是通过复杂的遗传和细胞机制来协调的。血管内皮生长因子A （VEGFA）是调节血管生成的主要生长因子，由一个高度多态性基因编码。多项研究表明VEGFA基因型与血管生成改变的疾病之间存在相关性。调节血管生成的主要细胞成分是循环内皮祖细胞（EPCs）。内皮祖细胞促进内皮修复和血管重塑。EPCs减少与内皮功能障碍的临床指标相关

Prognosis remains grim for pediatric patients with high-risk, malignant solid tumors. Children with malignant tumors and children undergoing hematopoietic stem cell transplantation (HSCT) have significant morbidity and mortality due to chemotherapy-induced toxicities. Novel biomarkers based on a distinct biologic profile and on response to therapy are needed to develop individualized therapies and response assessments. Angiogenesis markers have emerged as promising candidates in adult trials. However, pediatric studies are scarce. Our long-term objectives are to identify novel angiogenesis biomarkers in children to promote individualized chemotherapy and to facilitate development of novel therapies. Angiogenesis is coordinated via complex genetic and cellular mechanisms. Vascular endothelial growth factor A (VEGFA), a major growth factor regulating angiogenesis, is encoded by a highly polymorphic gene. Multiple studies demonstrate a correlation between VEGFA genotype and diseases with altered angiogenesis. A major cellular component regulating angiogenesis is circulating endothelial progenitor cells (EPCs). EPCs facilitate endothelial repair and vascular remodeling. Reduced EPCs correlate with clinical indices of endothelial dysfunction and increased risk of vascular disease. Though labeled EPCs, these are hematopoietic progenitors that originate from the bone marrow, not endothelium. Thus, myelotoxic therapies will impact EPCs with subsequent implications for normal and pathologic angiogenesis. Recent advances in flow cytometry allow for enumeration of angiogenic (circulating progenitor cells, CPCs) and non-angiogenic (non-CPCs) progenitors, using blood volumes amenable for implementation in pediatric studies. Our overall hypothesis is that interindividual variability in circulating EPC subsets after chemotherapy will serve as a biomarker for efficacy of malignant solid tumor therapy as well as to predict toxicity after HSCT. In this proposal, we will examine inter-individual variability in chemotherapy response and angiogenesis markers in children. We propose to assess novel angiogenesis markers that include EPC subsets, VEGF genetic heterogeneity, and microvessel density.