Poster Presentation 14th International Biennial Conference on Metastasis Research 2012

CXCR4 chemokine signalling in neuroblastoma bone marrow metastasis (#214)

Benjamin R Wilkinson 1 , Zillan Neiron 1 , Amanda Tivnan 1 , Toby N Trahair 1 , Jamie I Fletcher 1
  1. Children's Cancer Institute Australia, Lowy Cancer Research Centre, University of New South Wales, NSW, Australia

Background: Neuroblastoma is the most common cancer diagnosed during the first year of life, and accounts for 15% of all paediatric oncology deaths. Almost half of all patients have metastatic disease at diagnosis and metastases most frequently occur in the bone marrow, which is also the most common site of relapse. While expression of the chemokine receptor CXCR4 in primary neuroblastoma correlates with the presence of bone marrow disease, a causative role for CXCR4 in neuroblastoma metastasis has not been clearly demonstrated. It is also unknown whether inhibition of CXCR4 can slow metastatic growth or sensitize neuroblastoma cells to chemotherapy.

Methods & Results: We have used in vivo selection techniques to generate human neuroblastoma cell lines variants with differing tropism for bone marrow in immunodeficient mice. Comparative gene expression studies using these variants indicate that higher CXCR4 expression correlates with a preference for bone marrow colonization. In transwell migration assays, these neuroblastoma cells migrate toward the CXCR4 ligand SDF-1 and chemotaxis can be inhibited by the highly specific small molecule CXCR4 inhibitor AMD3100. We are currently generating neuroblastoma cell lines with specific down-regulation of CXCR4 to determine whether there is a causative link between CXCR4 expression and bone marrow metastasis and whether inhibition of CXCR4 can sensitize neuroblastoma cells to cytotoxic drugs or reduce their growth in the bone marrow.

Conclusions: CXCR4 is likely to be involved in metastasis of neuroblastoma to bone marrow in mouse xenograft models and further preclinical studies of CXCR4 inhibition are warranted.