Lung involvement in neuroblastoma: Incidence and characteristics

Cowie, Fiona; Corbett, Robin; Pinkerton, CR

doi:10.1002/(sici)1096-911x(199706)28:6<429::aid-mpo7>3.0.co;2-i

Cited by 46 publications

(26 citation statements)

References 3 publications

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“…1,37 NB pulmonary metastases are rare at diagnosis and represent a terminal stage. [37][38][39][40] Accordingly, lung metastasis indicates the presence of biologically more aggressive cells and portends a poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

Gene‐expression‐based analysis of local and metastatic neuroblastoma variants reveals a set of genes associated with tumor progression in neuroblastoma patients

Nevo

Oberthuer

Botzer

et al. 2010

Intl Journal of Cancer

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Metastasis is the primary cause of mortality in Neuroblastoma (NB) patients, but the metastatic process in NB is poorly understood. Metastsis is a multistep process that requires the coordinated action of many genes. The identification of genes that promote or suppress tumor metastasis can advance our understanding of this process. In the present study, we utilized a human NB xenograft model comprising local and metastatic NB variants, which was recently developed in our laboratory. We set out to identify molecular correlates of NB metastasis and to determine the clinical relevance of these molecules. We first performed genome-wide expression profiles of metastatic and nonmetastatic NB variants that have an identical genetic background. We found that some of the proteins highly expressed in the metastatic NB variants are localized in the cytoplasm and endoplasmic reticulum. Other proteins are linked to metabolic processes and signaling pathways, thereby supporting the invasive and metastatic state of the cells. Subsequently, we intersected the differentially expressed genes in the human xenografted variants with genes differentially expressed in Stage 1 and Stage 4 primary tumors of NB patients. By using the same gene-expression platform, molecular correlates associated with metastatic progression in primary NB tumors were identified. The resulting smaller gene set was clinically relevant as it discriminated between high-and low-risk NB patients.Neuroblastoma (NB) is the most commonly occurring extracranial tumor in childhood. These tumors originate in embryonic neural crest precursor cells of the sympathetic nervous system. NB accounts for $8% of all malignancies in patients younger than 15 years, and occurs most frequently in the adrenal gland. 1 The tumors can regress spontaneously, particularly in infants. However, children older than 1 year of age, with a widespread metastatic disease or with a large, aggressive, localized tumor, have a poor long-term survival rate of $30%. 2,3 Metastasis is the primary cause of mortality in cancer patients, but despite of that it is one of the most poorly understood processes in cancer biology. This is a multistep process that requires the coordinated action of many genes. [4][5][6] A systematic identification of genes that promote or suppress tumor invasion and metastasis can advance the understanding of this process.We recently described the generation and characterization of novel local and metastatic human NB variants. 7 Lungmetastasizing MHH-NB-11 cells were isolated from mice bearing orthotopically inoculated adrenal tumors. ''Local'' variants were isolated from the adrenal tumors. ''Lung metastatic'' variants were generated by repeated cycles of in vivo passages. These cells displayed an aggressive and metastatic phenotype in vivo, portend a poor prognosis and exhibited unique properties in vitro. 7 Oberthuer et al. recently described a robust, gene-expression-based classifier, which reliably predicts NB tumor behavior and can aid physicians in choosing the most app...

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Section: Discussionmentioning

confidence: 99%

Gene‐expression‐based analysis of local and metastatic neuroblastoma variants reveals a set of genes associated with tumor progression in neuroblastoma patients

Nevo

Oberthuer

Botzer

et al. 2010

Intl Journal of Cancer

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“…The fact that in neuroblastoma patients, lung metastasis is a relatively late event 42,43 may be explained by the possibility that lung-residing dormant micrometastatic neuroblastoma cells are initially suppressed by viability-inhibitory factors in the lungs. One or both of the above scenarios may account for the late emergence of metastasis in this organ site.…”

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

Maman¹,

Edry-Botzer

Sagi‐Assif

et al. 2013

Intl Journal of Cancer

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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...

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“…4 Lung metastases are considered a terminal event representing a widely disseminated metastatic disease. [5][6] Approximately 50% of children with high-risk NB that complete consolidation therapy develop early or late relapse, often from minimal residual disease in the form of circulating NB cells or micrometastases. 7 Most of the children with NB present metastatic disease at diagnosis with poor outcome, despite intensive treatment protocols.…”

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confidence: 99%

Lung-Residing Metastatic and Dormant Neuroblastoma Cells

Botzer

Maman

Sagi‐Assif

et al. 2011

The American Journal of Pathology

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The mechanism by which dormant tumor cells can begin growing after long periods of inactivity and accelerate disease recurrence is poorly understood. The present study characterizes dormant neuroblastoma (NB) cells, as well as metastatic cells, which reside in the same organ microenvironment. A xenograft model of human NB consisting of variants that generate nonmetastatic local tumors in the orthotopic inoculation site and variants that generate lung metastatic NB (MetNB) cells was developed in our laboratory. The present study shows that lungs of mice inoculated with nonmetastatic NB variants contain disseminated neuroblastoma (DisNB) human cells. Both DisNB and MetNB variants expressed a similar tumorigenicty phenotype in vivo, whereas the MetNB variants produced a heavy metastatic load and the DisNB variants produced no or little metastasis. A comparative in vitro characterization of MetNB and DisNB cells revealed similarities and differences. DisNB, but not MetNB cells, expressed the minimal residual disease markers PHOX2B and TH. MetNB cells demonstrated higher migratory capacity, an elevated matrix metalloproteinase (MMP) secretion, and a higher constitutive phosphorylation of extracellular signalregulated kinase (ERK) than DisNB cells. We suggest that characteristics common to both MetNB and DisNB cells were acquired relatively early in the metastatic process and the characteristics that differ between these variants were acquired later. We hypothesize that the DisNB cells are metastasis precursors, which may progress toward metastasis under certain microenvironmental conditions. Neuroblastoma (NB) is the most common extracranial solid tumor in children comprising 8% to 10% of all childhood cancers. More than half of these patients have a metastatic disease at diagnosis. 1-3 NB cells disseminate either by hematogenous spread, producing metastasis most frequently in bone marrow, bone, liver, and skin, or by lymphatic spread to regional and distant lymph nodes. 4 Lung metastases are considered a terminal event representing a widely disseminated metastatic disease. [5][6] Approximately 50% of children with high-risk NB that complete consolidation therapy develop early or late relapse, often from minimal residual disease in the form of circulating NB cells or micrometastases. 7 Most of the children with NB present metastatic disease at diagnosis with poor outcome, despite intensive treatment protocols. 8 The presence of circulating NB cells and/or NB micrometastasis may indicate a significant high-risk disease. 9 However, the question whether NB micrometastases develop into metastatic disease is yet to be answered.Previous studies from our laboratory were aimed to identify molecular pathways that are involved in NB metastasis. We focus on the cross talk between metastatic NB cells and components of their microenvironment, and on the downstream effects of such interactions.We suggested that NB cells might use chemokinechemokine receptor axes in their progression to metastasis. For example the CXCR4 -CXCL12 10 ...

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Lung involvement in neuroblastoma: Incidence and characteristics

Cited by 46 publications

References 3 publications

Gene‐expression‐based analysis of local and metastatic neuroblastoma variants reveals a set of genes associated with tumor progression in neuroblastoma patients

Gene‐expression‐based analysis of local and metastatic neuroblastoma variants reveals a set of genes associated with tumor progression in neuroblastoma patients

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

Lung-Residing Metastatic and Dormant Neuroblastoma Cells

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