Novel Inflammatory Mediators in Neuroblastoma Tumorigenesis

Abstract

<p>The tumor microenvironment is a dynamic, constantly evolving interplay between tumor cells, immune cells, endothelial and other stromal cells, and the extracellular matrix. Inflammation is an essential part of the immune system’s response against malignant growth but also a powerful pro-tumorigenic factor as cancer cells can hijack inflammatory mediators to support tumor growth. Neuroblastoma is a malignancy of early childhood with 90% of cases being diagnosed by the age of five. Tumor-promoting functions of several inflammatory mediators have already been described in neuroblastoma. The aim of this thesis is to identify novel inflammatory mediators in neuroblastoma and extend the knowledge on neuroblastoma biology, a prerequisite for the development of novel therapeutic approaches and the improvement of existing therapies. <p>Chemerin is multifunctional chemoattractant protein and this work demonstrates a functional chemerin/CMKLR1 axis in neuroblastoma that supports pro-tumorigenic cell signaling pathways. Furthermore, inhibition of CMKLR1 impaired neuroblastoma clonogenicity <i>in vitro</i> and tumor growth <i>in vivo</i>. Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase with diverse functions in immunity but also inflammatory diseases and cancer. This work demonstrates the presence of SYK and phosphorylated SYK in neuroblastoma tissues and to a lesser extent neuroblastoma cell lines. SYK downregulation or inhibition reduced the cell viability of SYK-positive neuroblastoma cells. Furthermore, the SYK inhibitor BAY 61-3606 potentiated the effect of common chemotherapeutic drugs on neuroblastoma cells. The IL-17 family of cytokines and their receptors demonstrate versatile functions in host defense, immunity, inflammatory diseases, and cancer. This work describes the presence of the IL-17 receptors RA, RB, and RC in neuroblastoma cell lines and tissues. Recombinant IL-17 proteins modulate hepatocyte growth factor and Dickkopf-related protein 1 secretion, promote neuroblastoma cell migration but only modestly affect cell viability. Furthermore, the p19 subunit of the functionally related IL-23 was detected in neuroblastoma cell lines and tumor tissue.