All ETDs from UAB

Advisory Committee Chair

Karina J Yoon

Advisory Committee Members

Robert Cam Van Waardenburg

Charles N Falany

Christopher Klug

Elizabeth Beierle Chen

Document Type

Dissertation

Date of Award

2014

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Neuroblastoma (NB) is the most common extracranial solid tumor in childhood, accounting for 15% of all childhood cancer deaths. At the time of initial diagnosis, the majority of patients present with NB that has already metastasized. While initial remission is often achieved following treatment, roughly 50% of these patients will relapse and die from the development of intractable metastatic progression. Intercellular adhesion molecule-2 (ICAM-2) is a transmembrane glycoprotein, normally expressed only in endothelial cells and subsets of leukocytes. ICAM-2 expression in cancer cells had not been previously investigated, until our lab recently reported the novel finding of endogenous ICAM-2 expression in a subset of NB cell lines and primary NB tumor cells. Those NB cells that expressed ICAM-2 exhibited decreased motility in vitro and decreased metastatic potential in vivo. Furthermore, it was found that primary NB tumors found to express high levels of ICAM-2 correlated with favorable clinical features. The goal of this dissertation was to gain functional insight toward the mechanism in which ICAM-2 suppresses a metastatic phenotype. We approached this by synthesizing constructs encoding for structurally modified variants of ICAM-2, then expressing these constructs in NB cells. These modifications included altering the amino acid sequence of the cytoplasmic domain (CD), the extracellular domain, (ED) and the glycosylation status of the ICAM-2 protein. This is the first known attempt to comprehensively investigate the mechanism that ICAM-2 regulates in NB metastasis suppression. We compared the impact of ICAM-2 and each variant on NB cell adhesion, migration, anchorage-independent growth in soft agar, the formation localized and disseminated tumors in an in vivo metastasis model. The in vitro and in vivo phenotypes of cells expressing the ICAM-2 variants differed not only from cells expressing wild-type (WT) ICAM-2, but also no from cells expressing no detectable ICAM-2. Like the WT protein, ICAM-2 variants inhibited cell adhesion, migration and colony growth in vitro. However, unlike the WT protein, ICAM-2 variants did not completely suppress development of disseminated NB tumors in vivo. Furthermore, the data suggest that ICAM-2 may regulate the progression of NB metastasis through both alpha-actinin-dependent and alpha-actinin-independent pathways.

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