CXCR4 AND P-GLYCOPROTEIN PROMOTE NEUROBLASTOMA METASTASIS

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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.