Recent data suggest that the mechanisms determining whether a tumor cell reaching a secondary organ will enter a dormant state, progress toward metastasis or go through apoptosis are regulated by the microenvironment of the distant organ. In neuroblastoma, 60 -70% of children with high-risk disease will ultimately experience relapse due to the presence of micrometastases.
The main goal of this study is to evaluate the role of the lung microenvironment in determining the fate of neuroblastoma lung metastases and micrometastases. Utilizing an orthotopic mouse model for human neuroblastoma metastasis, we were able to generate two neuroblastoma cell populations – lung micrometastatic (MicroNB) cells and lung macrometastatic (MacroNB) cells. These two types of cells share the same genetic background, invade the same distant organ, but differ in their ability to create metastasis in the lungs. We hypothesize that factors present in the lung microenvironment inhibit the propagation of MicroNB cells preventing them from forming overt lung metastasis. This study indeed shows that lung-derived factors significantly reduce the viability of MicroNB cells by up regulating the expression of pro-apoptotic genes, inducing cell cycle arrest and decreasing ERK and FAK phosphorylation. Lung-derived factors affected various additional progression-linked cellular characteristics of neuroblastoma cells, such as the expression of stem cell markers, morphology and migratory capacity.
Present work focuses on identifying the factor restraining the viability of neuroblastoma micrometastases. Since to date, there are no effective treatment regimens that eliminate micrometastasis in neuroblastoma, identifying and purifying a factor that restrains the viability of these cells and elucidating its mechanism of action may lead to a discovery of a novel anti neuroblastoma drug that eradicates micrometastasis and/or prevents its progression to metastatic lesions.
