<i>In vitro</i>model of leukemia cell migration across the blood–cerebrospinal fluid barrier

Naumann, Jordan A.; Gordon, Peter M.

doi:10.1080/10428194.2016.1254778

Cited by 12 publications

(11 citation statements)

References 10 publications

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“…CNS leukaemia is considered to be primarily a leptomeningeal disease [12,21,22] and the BCSFB, formed by the epithelial lining of the CP, has been pointed out by several authors to play a key role in ALL cell dissemination to the leptomeninges [23][24][25]. However, the pathway by which leukaemic blasts could reach the BCSFB has not been defined yet.…”

Section: Discussionmentioning

confidence: 99%

The choroid plexus stroma constitutes a sanctuary for paediatric B‐cell precursor acute lymphoblastic leukaemia in the central nervous system

Fernández-Sevilla

Valencia

Flores‐Villalobos

et al. 2020

The Journal of Pathology

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Despite current central nervous system‐directed therapies for childhood B‐cell precursor acute lymphoblastic leukaemia, relapse at this anatomical site still remains a challenging issue. Few reports have addressed the study of the specific cellular microenvironments which can promote the survival, quiescence, and therefore chemoresistance of B‐cell precursor acute lymphoblastic leukaemia cells in the central nervous system. Herein, we showed by immunofluorescence and electron microscopy that in xenotransplanted mice, leukaemic cells infiltrate the connective tissue stroma of the choroid plexus, the brain structure responsible for the production of cerebrospinal fluid. The ultrastructural study also showed that leukaemia cells are able to migrate through blood vessels located in the choroid plexus stroma. In short‐term co‐cultures, leukaemic cells established strong interactions with human choroid plexus fibroblasts, mediated by an increased expression of ITGA4 (VLA‐4)/ITGAL (LFA‐1) and their ligands VCAM1/ICAM1. Upon contact with leukaemia cells, human choroid plexus fibroblasts acquired a cancer‐associated fibroblast phenotype, with an increased expression of α‐SMA and vimentin as well as pro‐inflammatory factors. Human choroid plexus fibroblasts also have the capacity to reduce the proliferative index of leukaemic blasts and promote their survival and chemoresistance to methotrexate and cytarabine. The inhibition of VLA‐4/VCAM‐1 interactions using anti‐VLA‐4 antibodies, and the blockade of Notch signalling pathway by using a γ‐secretase inhibitor partially restored chemotherapy sensitivity of leukaemia cells. We propose that the choroid plexus stroma constitutes a sanctuary for B‐cell precursor acute lymphoblastic leukaemia cells in the central nervous system. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

The choroid plexus stroma constitutes a sanctuary for paediatric B‐cell precursor acute lymphoblastic leukaemia in the central nervous system

Fernández-Sevilla

Valencia

Flores‐Villalobos

et al. 2020

The Journal of Pathology

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“…When the predilection of CNS involvement in T-ALL hijacks these pathways [18], the BCSFB within the choroid plexus might well represent a significant gate into the CNS. Several studies have addressed this potential entry site [7,20,21], but so far, have described only limited lymphoblast transmigration across the BCSFB [3,49]. However, pediatric ALL presents with only subtle symptoms in most patients, and time to diagnosis is often prolonged.…”

Section: Translational Implicationsmentioning

confidence: 99%

“…However, despite the rarity of parenchymal metastases during initial stages, most in vitro studies applied models of the BBB. Despite its central role on immune cells traveling into the CNS [19], the BCSFB within the choroid plexus is yet under-recognized concerning the CNS infiltration by leukemic blasts [20]. Therefore, we investigated the relevance of leukemia-derived exosomes on ALL cell transmigration across the blood-cerebrospinal fluid barrier (BCSFB).…”

Section: Introductionmentioning

confidence: 99%

The Impact of Small Extracellular Vesicles on Lymphoblast Trafficking across the Blood-Cerebrospinal Fluid Barrier In Vitro

Erb

Hikel

Meyer

et al. 2020

IJMS

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Central nervous System (CNS) disease in pediatric acute lymphoblastic leukemia (ALL) is a major concern, but still, cellular mechanisms of CNS infiltration are elusive. The choroid plexus (CP) is a potential entry site, and, to some extent, invasion resembles CNS homing of lymphocytes during healthy state. Given exosomes may precondition target tissue, the present work aims to investigate if leukemia-derived exosomes contribute to a permissive phenotype of the blood-cerebrospinal fluid barrier (BCSFB). Leukemia-derived exosomes were isolated by ultracentrifugation from the cell lines SD-1, Nalm-6, and P12-Ichikawa (P12). Adhesion and uptake to CP epithelial cells and the significance on subsequent ALL transmigration across the barrier was studied in a human BCSFB in vitro model based on the HiBCPP cell line. The various cell lines markedly differed regarding exosome uptake to HiBCPP and biological significance. SD-1-derived exosomes associated to target cells unspecifically without detectable cellular effects. Whereas Nalm-6 and P12-derived exosomes incorporated by dynamin-dependent endocytosis, uptake in the latter could be diminished by integrin blocking. In addition, only P12-derived exosomes led to facilitated transmigration of the parental leukemia cells. In conclusion, we provide evidence that, to a varying extent, leukemia-derived exosomes may facilitate CNS invasion of ALL across the BCSFB without destruction of the barrier integrity.

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“…In vitro co-culture of leukemia cells with CNS-derived cells can be used to examine the effect of both direct cell–cell interactions as well as soluble factors on leukemia biology (35–37). Similarly, in vitro transwell assays that assess the migration of leukemia cells across endothelial or choroid plexus (CP) cells can be used to model the process of leukemia migration across the blood–brain or blood–cerebral spinal fluid (CSF) barriers, respectively (38–41). Cerebral organoids, three-dimensional in vitro cultures that model brain organogenesis, represent a new and powerful model system that could also potentially be exploited for expanding our understanding of CNS leukemia (42).…”

Section: Approaches For Studying Cns Leukemiamentioning

confidence: 99%

“…Using a pre-B ALL murine leukemia model, Wigton et al showed that myosin-IIA depletion or inhibition with either shRNA or blebbistatin, respectively, significantly decreased leukemia infiltration into the CNS as a result of impaired trans-endothelial extravasation (55). Similarly, known inhibitors of T-cell leukemia migration diminished the ability of leukemia cells to cross CP epithelial cells in a transwell assay designed to mimic the blood–CSF barrier (38). Using similar in vitro co-culture and transwell assays, with brain-derived endothelial cells rather than CP cells, Akers et al showed VE-cadherin expression by leukemia cells enhanced adhesion to endothelial cells while PECAM-1 expression enhanced adhesion to, and migration through, endothelial cells (39).…”

Section: Trafficking Of Leukemia Cells To the Cnsmentioning

confidence: 99%

The Role of the Central Nervous System Microenvironment in Pediatric Acute Lymphoblastic Leukemia

Gossai

Gordon

2017

Front. Pediatr.

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Acute lymphoblastic leukemia (ALL) is the most common cancer in children. While survival rates for ALL have improved, central nervous system (CNS) relapse remains a significant cause of treatment failure and treatment-related morbidity. Accordingly, there is a need to identify more efficacious and less toxic CNS-directed leukemia therapies. Extensive research has demonstrated a critical role of the bone marrow (BM) microenvironment in leukemia development, maintenance, and chemoresistance. Moreover, therapies to disrupt mechanisms of BM microenvironment-mediated leukemia survival and chemoresistance represent new, promising approaches to cancer therapy. However, in direct contrast to the extensive knowledge of the BM microenvironment, the unique attributes of the CNS microenvironment that serve to make it a leukemia reservoir are not yet elucidated. Recent work has begun to define both the mechanisms by which leukemia cells migrate into the CNS and how components of the CNS influence leukemia biology to enhance survival, chemoresistance, and ultimately relapse. In addition to providing new insight into CNS relapse and leukemia biology, this area of investigation will potentially identify targetable mechanisms of leukemia chemoresistance and self-renewal unique to the CNS environment that will enhance both the durability and quality of the cure for ALL patients.

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In vitromodel of leukemia cell migration across the blood–cerebrospinal fluid barrier

Cited by 12 publications

References 10 publications

The choroid plexus stroma constitutes a sanctuary for paediatric B‐cell precursor acute lymphoblastic leukaemia in the central nervous system

The choroid plexus stroma constitutes a sanctuary for paediatric B‐cell precursor acute lymphoblastic leukaemia in the central nervous system

The Impact of Small Extracellular Vesicles on Lymphoblast Trafficking across the Blood-Cerebrospinal Fluid Barrier In Vitro

The Role of the Central Nervous System Microenvironment in Pediatric Acute Lymphoblastic Leukemia

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