Mechanisms of invasion and metastasis in human neuroblastoma Tasnim Ara & Yves A. DeClerck Published online: 12 December 2006 # Springer Science + Business Media, LLC 2006 Abstract Neuroblastoma is the second most common solid tumor in children that is metastatic in 70% of patients at the time of diagnosis. The ability of neuroblastoma cells to colonize distant organs like the bone marrow and the bone is the result of close interactions between tumor cells and the microenvironment. Significant progress has been recently made in our understanding of the mechanisms that promote the colonization and invasion of the bone by neuroblastoma cells and these mechanisms are reviewed in this article. How this understanding is now allowing us to test new therapeutic agents specifically targeted at interfer- ing with neuroblastoma metastasis is then discussed. Keywords Neuroblastoma . Bone metastasis . Tumor invasion 1 Introduction Neuroblastoma is a biologically heterogeneous tumor derived from the neural crest. It is characterized by unexpected clinical behaviors, such as spontaneous regres- sion, maturation or aggressive progression [1]. Studies on neuroblastoma over the past decades have identified numerous factors that contribute to tumor progression and correlate to overall outcome including patient’ s age, stage, histology, molecular marker and genetic abnormalities. Despite a significant improvement in our understanding of the heterogeneous nature of primary neuroblastoma, metas- tasis which is the leading cause of death in this cancer has remained less well understood [2]. Researchers have been studying the processes of metastasis for more than 100 years. In 1889 Stephen Paget proposed the “seed and soil” theory which suggested that metastasis depends on a close interaction between selected tumor cells (the seed) and the microenvironment of a specific organ (the soil). Under this theory, metastasis can only develop when the seed and the soil are compatible [3]. With the discovery of specific genes responsible for metastasis and specific growth factors and chemokines expressed by organs colonized by tumor cells, this theory has proven to be correct. Metastasis is a highly complex and organized process that consists of multiple but interrelated steps, during which tumor cells leave the primary tumor, gain access to the circulatory system, are carried to a distant site, eventually exit the circulation and grow in a different microenvironment. The first step of metastasis is local invasion, which requires that malignant cells lose cell–cell adhesions and become motile, a process that enables them to invade surrounding tissues. During the second step, intravasation, tumor cells penetrate the endothelium of blood or lymphatic vessels and enter the vascular or lymphatic circulation. Few circulating tumor cells are however able to survive and form tumor aggregates or emboli with circulating leukocytes and platelets and arrest at distant sites. When arrested, some tumor cells will be able to extravasate blood and lymphatic vessels and colonize the metastatic site. Under the influence of a complex number of environmental factors tumor cells will undergo additional genetic and epigenetic changes that will allow them to proliferate and generate an angiogenic response necessary for the formation of a large metastatic tumor. Recently, microarray gene expression analysis has Cancer Metastasis Rev (2006) 25:645–657 DOI 10.1007/s10555-006-9028-9 T. Ara : Y. A. DeClerck (*) Division of Hematology–Oncology, Departments of Pediatrics and Biochemistry and Molecular Biology, USC Keck School of Medicine and The Saban Research Institute of Children’ s Hospital Los Angeles, Los Angeles, CA 90027, USA e-mail: declerck@usc.edu