Lung-Residing Metastatic and Dormant Neuroblastoma Cells

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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...

Section: Orthotopic Inoculation Of Tumor Cellsmentioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

Section: Cell Culturementioning

confidence: 99%

“…21 Therefore, it was tentatively concluded that these micrometastatic cells do not form overt lung metastasis since they are in a state of dormancy in the lungs.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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

Maman¹,

Edry-Botzer

Sagi‐Assif

et al. 2013

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The metastatic microenvironment: Brain‐residing melanoma metastasis and dormant micrometastasis

Izraely

Sagi‐Assif

Klein

et al. 2011

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126

Brain metastasis occurs frequently in melanoma patients with advanced disease whereby the prognosis is dismal. The underlying mechanisms of melanoma brain metastasis development are not well understood. We generated a reproducible melanoma brain metastasis model, consisting of brain-metastasizing variants and local, subdermal variants that originate from the same melanomas thus sharing a common genetic background. The brain-metastasizing variants were obtained by intracardiac inoculation. Brain metastasis variants when inoculated subdermally yielded spontaneous brain dormant micrometastasis. Cultured cells from the spontaneous brain micrometastasis grew very well in vitro and generated subdermal tumors after an orthotopic inoculation. Expression analysis assays indicated that the brain metastasis and micrometastasis cells expressed higher levels of angiopoietinlike 4, prostaglandin-synthesizing enzyme cyclooxygenase-2, matrix metalloproteinase-1 and preferentially expressed antigen in melanoma and lower levels of claudin-1 and cysteine-rich protein 61 than the corresponding cutaneous variants. The reproducible models of human melanoma metastasizing experimentally and spontaneously to the brain will facilitate the identification of novel biomarkers and targets for therapy and contribute to the deciphering of mechanisms underlying melanoma metastasis.Brain metastasis represents a significant cause of death in melanoma patients, and its frequency is increasing, 1 possibly as a result of new therapies prolonging patient survival. 2 Of all human solid tumors, malignant cutaneous melanoma has one of the highest risks to develop brain metastasis. More than 40% of advance stage melanoma patients are treated for complications due to brain metastasis. 1,3 Treatment options for melanoma patients with cerebral brain metastasis are limited and not effective to date. 4 Tumor cells with the potential to metastasize and colonize the brain may express distinctive molecular determinants that promote metastasis formation in this organ. They may also be able to respond to brain-derived growth factors or to deliver signals that alter the brain microenvironment, making it more supportive to metastasis development. 3 Prevention strategies for brain metastasis could be used if cells expressing such molecules could be identified in the primary melanoma. Currently, such molecular biomarkers are unknown.Human to mouse melanoma xenograft models that recapitulate the phenotypes seen in the clinic provide a valuable resource of cells for translational research and can accelerate drug discovery processes for this disease. 5 Current human melanoma brain metastasis models consist of xenografted cells inoculated into immune-deficient mice mainly by intracarotid or intracardiac administration. 6 Although these types of injections bypass the initial steps of brain metastasis

Site‐specific metastasis: A cooperation between cancer cells and the metastatic microenvironment

Izraely

2020

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The conclusion derived from the information provided in this review is that disseminating tumor cells (DTC) collaborate with the microenvironment of a future metastatic organ site in the establishment of organ‐specific metastasis. We review the basic principles of site‐specific metastasis and the contribution of the cross talk between DTC and the microenvironment of metastatic sites (metastatic microenvironment [MME]) to the establishment of the organ‐specific premetastatic niche; the targeted migration of DTC to the endothelium of the future organ‐specific metastasis; the transmigration of DTC to this site and the seeding and colonization of DTC in their future MME. We also discuss the role played by DTC‐MME interactions on tumor dormancy and on the differential response of tumor cells residing in different MMEs to antitumor therapy. Finally, we summarize some studies dealing with the effects of the MME on a unique site‐specific metastasis—brain metastasis.