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

Abstract

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. 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.Tumor cells disseminating from primary sites to various organ sites have several possible fates: death, progression toward metastasis or formation of dormant micrometastasis that, either due to a balance between proliferation and apoptosis or due to cell cycle arrest, remain as solitary cells or as small, steady-state cell clusters.1,2 Dormant micrometastasis could progress to an actively growing macrometastatic lesion and cause a late metastatic relapse.3,4 The ability of dormant tumor cells to "be activated" and subsequently generate a secondary frank metastatic lesion is, to a large extent, a function of their interaction with the microenvironment at the secondary site. 1,4-6 As the critical role of the microenvironment in tumor growth and progression is increasingly appreciated, [7][8][9][10][11][12] it has become clear that in order to eliminate metastasis, the full impact of interactions between tumor cells and the microenvironment has to be elucidated. Neuroblastoma, the most common extracranial solid tumor in children, accounts for approximately 15% of all childhood cancer deaths. 13,14 Despite intensive treatment regimens, 60 to 70% of children with high-risk disease will ultimately experience relapse due to neuroblastoma micrometastases. 15,16 Because of their scarcity and the absence of detection methods, dormant cells are dif...

Tumor Macroenvironment and Metabolism

“…In children with high-risk NB, pulmonary metastases are crucial for the long-term outcome. In an orthotopic mouse model for human neuroblastoma metastases (Mhh-NB11 and SH-SY5Y), Maman et al 131 showed that lung-derived factors significantly reduced the viability of micro-NB cells by upregulating the expression of pro-apoptotic genes, inducing cell cycle arrest and decreasing ERK and FAK phosphorylation. The authors concluded that further insights into distant organ environment could reveal therapeutic options against NB metastases.…”

Biological resonance for cancer metastasis, a new hypothesis based on comparisons between primary cancers and metastases

“…More importantly, they found common genes combined specific genes were required for successful metastasis to each site while a single molecule hardly exerted effect, which suggested that inhibition of both common genes and specific genes decrease metastasis and offered a new direction for target different metastasis from a same disease. Witz's group also identified common genes and different genes for site-specific metastasis using the cell lines with an identical genetic background [160,161]. These studies give us an clue that searching for common molecules playing key roles in different metastases from a same cancer or the same organ metastasis from various cancers is a direction of simplicity to treat cancer metastasis.…”

“…The different genes may be regulated by site-specific microenvironment, which have been testified in experiment studies. For example, Massague's group and Witz's group isolated of different site specific metastatic cells from the same tumors through selection in targeted organs [124,[158][159][160][161]. There were common mediators to contribute to pulmonary and brain metastases.…”

In Vitro Modeling of Tissue-Specific 3D Microenvironments and Possibile Application to Pediatric Cancer Research

“…Dormant micrometastasis could progress to an actively growing macrometastatic lesion and cause a late metastatic relapse in the high risk group of NBL patients [283]. Thus, specific microenvironment factors involved in the progression of micrometastasis or in the attraction of human neuroblastoma cells in the site of metastasis have been studied in several organs, such as lung [284], bone [285,286] or BM [287].…”