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Stimulation of medulloblastoma stem cells differentiation by a peptidomimetic targeting neuropilin-1.

ABSTRACT: Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains important. The neuropilin-1 (NRP-1) receptor has recently been implicated in tumor progression of MB, which seems to play an important role in the phenotype of cancer stem cells. Targeting this receptor appears as an interesting strategy to promote MB stem cells differentiation. Cancer stem-like cells of 3 MB cell lines (DAOY, D283-Med and D341-Med), classified in the more pejorative molecular subgroups, were obtained by in vitro enrichment. These models were characterized by an increase of NRP-1 and cancer stem cell markers (CD15, CD133 and Sox2), meanwhile a decrease of the differentiated cell marker Neurofilament-M (NF-M) was observed. Our previous work investigated potential innovative peptidomimetics that specifically target NRP-1 and showed that MR438 had a good affinity for NRP-1. This small molecule decreased the self-renewal capacity of MB stem cells for the 3 cell lines and reduced the invasive ability of DAOY and D283 stem cells while NRP-1 expression and cancer stem cell markers decreased at the same time. Possible molecular mechanisms were explored and showed that the activation of PI3K/AKT and MAPK pathways significantly decreased for DAOY cells after treatment. Finally, our results highlighted that targeting NRP-1 with MR438 could be a potential new strategy to differentiate MB stem cells and could limit medulloblastoma progression.

SUBMITTER: Gong C

PROVIDER: S-EPMC5880606 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Stimulation of medulloblastoma stem cells differentiation by a peptidomimetic targeting neuropilin-1.

Gong Caifeng C Valduga Julie J Chateau Alicia A Richard Mylène M Pellegrini-Moïse Nadia N Barberi-Heyob Muriel M Chastagner Pascal P Boura Cédric C

Oncotarget 20180216 20

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Despite the progress of new treatments, the risk of recurrence, morbidity, and death remains important. The neuropilin-1 (NRP-1) receptor has recently been implicated in tumor progression of MB, which seems to play an important role in the phenotype of cancer stem cells. Targeting this receptor appears as an interesting strategy to promote MB stem cells differentiation. Cancer stem-like cells of 3 MB cell lines (DAOY, D283- ...[more]

PMID: 29632646

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Project description:Pluripotent stem cell-derived endothelial cells (ECs) have great potential to be used in vascular therapy or tissue engineering. It is also much desired to obtain arterial or venous ECs for specific applications. Factors that are critical for the proper arterial or venous differentiation from pluripotent stem cells still need to be understood. Here, we aim at investigating this problem deeper by examining neuropilin-1 (Nrp1), an early arterial marker that may be critical for arterial cell fate commitment. Using murine embryonic stem cells as the model system, this study investigates the neuropilin-1 (Nrp1) expression during the differentiation of pluripotent stem cells toward a vascular progenitor population. We hypothesize that Nrp1, an early arterial marker present in a developing embryo, may be more responsive when further induced in vitro toward an arterial fate. We developed a two-step differentiation approach that yielded a large percentage of Nrp1+ vascular progenitor cells (VPCs) and investigated their potential to become arterial ECs. We have defined the culture parameters that contribute greatly to the emergence of Nrp1+ VPCs: certain soluble factors, especially Wnt and BMP4, early cell-cell contact, and hypoxia. Subsequent isolation of this population demonstrated a highly proliferative and network-forming behavior. The Nrp1+ VPCs exhibited increased gene expression of several Notch pathway-related arterial markers compared with Nrp1- VPCs. Most importantly, Nrp1+ VPCs demonstrated a dramatically greater response to hemodynamic stimuli by upregulating many arterial markers whereas Nrp1- VPCs have very little response. Surprisingly, these differences between Nrp1+ and Nrp1- VPCs are not evident with vascular endothelial growth factor (VEGF) treatment. Our data suggest that Nrp1+ VPCs may serve as the arterial progenitor by enhanced response to hemodynamic flow but not to VEGF, whereas Nrp1- VPCs lack the plasticity to become arterial ECs. The findings of this research indicate that Nrp1+ VPCs in the murine model act as an important step in the arterial differentiation process.

Dataset Information

Stimulation of medulloblastoma stem cells differentiation by a peptidomimetic targeting neuropilin-1.

Publications

Stimulation of medulloblastoma stem cells differentiation by a peptidomimetic targeting neuropilin-1.

Similar Datasets

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