CXCR4 AND P-GLYCOPROTEIN PROMOTE NEUROBLASTOMA METASTASIS

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 晚期神经母细胞瘤在很大程度上是无法治愈的使用目前的治疗方案。儿童死于转移性疾病，转移主要发生在骨内。因此，确定导致神经母细胞瘤转移到骨的因素可能会导致新的，更有效的靶向治疗选择。细胞表面蛋白的表达和修饰对于转移过程的调节至关重要。NBL中的基因表达研究表明，几种细胞表面蛋白，包括受体酪氨酸激酶A和B（trk A和trk B）、CD 44、CXCR 4和P-糖蛋白（Pgp）在晚期转移性肿瘤中高度表达。Trk A、Trk B和CD 44在神经母细胞瘤中已被广泛研究;然而，CXCR 4和Pgp尚未被研究。因此，在本提案中的实验将解决其余两种细胞表面蛋白CXCR 4和Pgp在NBL骨转移中的作用。我们的假设是，高度致瘤性，转移性NBL细胞将过度表达CXCR 4和Pgp在其细胞表面，有助于迁移和侵入骨。这将通过以下具体目标进行检验： 特定目的：CXCR 4和P-糖蛋白表达促进NBL迁移至和随后的 骨中的跨内皮迁移： a.高致瘤性NBL细胞表达高水平的CXCR 4和P-糖蛋白， B. CXCR 4活化与Pgp相互作用并促进NBL细胞与内皮细胞结合， C. CXCR 4和Pgp诱导NBL细胞跨内皮迁移， D. CXCR 4和Pgp聚糖在NBL转移和与骨相互作用期间发生改变 骨髓内皮 通过这项研究，我们将支持靶向CXCR 4和Pgp治疗转移性神经母细胞瘤。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Advanced stage neuroblastoma is largely incurable using current treatment protocols. Children die of metastatic disease, with metastases occurring primarily within bone. Therefore, identifying factors contributing to the metastasis of neuroblastoma to bone may lead to new, more effective targeted treatment options. The expression and modification of cell surface proteins is critical for the regulation of the metastatic process. Gene expression studies in NBL suggest that several cell surface proteins, including the receptor tyrosine kinases A and B (trk A and trk B), CD44, CXCR4, and P-glycoprotein (Pgp), are highly expressed in late-stage, metastatic tumors. Trk A, Trk B, and CD44 have been extensively studied in neuroblastoma; however, CXCR4 and Pgp have not. Therefore, experiments within the current proposal will address the role of the remaining two cell surface proteins, CXCR4 and Pgp, in NBL bone metastasis. Our hypothesis is that highly tumorigenic, metastatic NBL cells will over express both CXCR4 and Pgp on their cell surface, contributing to migration and invasion into bone. This will be tested through the following specific aims: SPECIFIC AIMS: CXCR4 and P-glycoprotein expression promotes NBL migration to and subsequent transendothelial migration in bone: a. Highly tumorigenic NBL cells express high levels of CXCR4 and P-glycoprotein, b. CXCR4 activation interacts with Pgp and promotes NBL cell binding to endothelial cells, c. CXCR4 and Pgp induce NBL cell transendothelial migration, d. and CXCR4 and Pgp glycans are altered during NBL metastasis and interaction with bone marrow endothelium. Through this study, we will support targeting CXCR4 and Pgp for treatment in metastatic neuroblastoma.