The metastatic microenvironment: Lung-derived factors control the viability of neuroblastoma lung metastasis

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 populationslung 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. An insight into the microenvironmental effects governing neuroblastoma recurrence and progression would be of pivotal importance as they could have a therapeutic potential for the treatment of neuroblastoma residual disease. What's new? Factors in the microenvironment of distant organs are key suspects in the process of cancer progression, possibly determining whether circulating tumor cells that arrive to secondary organs become dormant or give rise to metastatic lesions. This report sheds new light on the role of the secondary organ microenvironment, specifically concerning the fate of metastatic neuroblastoma cells. Its central finding, that in mice factors derived from the lungs restrain neuroblastoma cells, particularly micrometastatic neuroblastoma cells, could facilitate the identification of novel anticancer therapies that aim to eradicate micrometastasis and/or prevent its progression to metastatic lesions.