Circulating Endothelial Progenitor Cell Subsets

对于患有高风险恶性实体瘤的儿科患者，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而具有显著的发病率和死亡率。需要基于不同的生物学特征和对治疗的反应的新型生物标志物来开发个体化治疗和反应评估。 血管生成标记物已成为成人试验中有前途的候选物。然而，儿科研究很少。我们的长期目标是确定儿童新的血管生成生物标志物，以促进个体化化疗和促进新疗法的开发。血管生成通过复杂的遗传和细胞机制协调。血管内皮生长因子A（VEGFA）是一种调节血管生成的主要生长因子，由高度多态性的基因编码。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组分是循环内皮祖细胞（EPCs）。EPCs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， 增加血管疾病的风险。尽管标记了EPCs，但它们是来自骨髓而不是内皮的造血祖细胞。因此，骨髓毒性疗法将影响EPCs，随后影响正常和病理性血管生成。流式细胞术的最新进展允许使用适于在儿科研究中实施的血容量来计数血管生成（循环祖细胞，CPC）和非血管生成（非CPC）祖细胞。我们的总体假设是，化疗后循环EPC亚群的个体间差异将作为化疗疗效的生物标志物。 恶性实体瘤治疗以及预测HSCT后的毒性。在这个建议中，我们将研究儿童化疗反应和血管生成标志物的个体间差异。我们建议评估新的血管生成标志物，包括EPC亚群，VEGF遗传异质性和微血管密度。

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.