Medulloblastoma cancer stem cells: molecular signatures and therapeutic targets

Bahmad, Hisham F.; Poppiti, Robert

doi:10.1136/jclinpath-2019-206246

Cited by 33 publications

(22 citation statements)

References 149 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As discussed above, abnormal epigenetic programming in pediatric cancers may lock tumor cells in a stem cell-like, poorly differentiated state (Lawlor and Thiele, 2012;Marshall et al, 2014). Pediatric brain tumors often display upregulation of genes known as markers of neural stem cells, including CD133, Nestin, and Musashi, and deregulation of other genes that regulate stemness is frequently found (Bahmad and Poppiti, 2020).…”

Section: The Role Of Modulating Stemness and Differentiationmentioning

confidence: 99%

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Perla

Fratini

Cardoso

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Brain cancers are the leading cause of cancer-related deaths in children. Biological changes in these tumors likely include epigenetic deregulation during embryonal development of the nervous system. Histone acetylation is one of the most widely investigated epigenetic processes, and histone deacetylase inhibitors (HDACis) are increasingly important candidate treatments in many cancer types. Here, we review advances in our understanding of how HDACis display antitumor effects in experimental models of specific pediatric brain tumor types, i.e., medulloblastoma (MB), ependymoma (EPN), pediatric high-grade gliomas (HGGs), and rhabdoid and atypical teratoid/rhabdoid tumors (ATRTs). We also discuss clinical perspectives for the use of HDACis in the treatment of pediatric brain tumors.

show abstract

Section: The Role Of Modulating Stemness and Differentiationmentioning

confidence: 99%

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Perla

Fratini

Cardoso

et al. 2020

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

show abstract

“…4–7,29,30 MB recurrent tumors, either in the primary or metastatic site, derive from a subpopulation of cancer stem cells (MBSCs), which can evade current chemotherapeutics and radiation therapy. 48 MBSCs express stemness markers, such as CD133, CD15, and Sox2, and can possess an inordinate capability to form aggressive tumors with increased self-renewal ability, facilitating MB relapse and rapid demise. 49,50 In NFIB-silenced and miR-212-3p restored group 3 MB cells, we noted decreased expression of stemness markers, i.e.…”

Section: Discussionmentioning

confidence: 99%

MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting Nuclear Factor I/B (NFIB)

Perumal

Kanchan²,

Doss³

et al. 2021

Preprint

View full text Add to dashboard Cite

Background: Medulloblastoma (MB), the most frequent malignant pediatric brain tumor, is subdivided into four primary subgroups, wingless-type (WNT), sonic hedgehog (SHH), group 3, and group 4. Haploinsufficiency of chromosome 17p13.3 and c-Myc amplification distinguish high-risk group 3 tumors associated with rapid metastasis, recurrence and early mortality. We sought to identify the role of miR-212-3p, which resides on chromosome 17p13.3, in the pathophysiology of group 3 MB. Methods: We first determined miR-212-3p expression in group 3 MB using several publicly-available datasets with confirmatory studies in vitro. We then identified epigenetic regulation by studying methylation and HDAC modifications along the promoter region. We used two systems for expression restoration, i.e. transient transfection or stable induction, to delineate miR-212-3p tumor suppressive and biochemical properties via assays assessing cancer proliferation, migration, invasion, colony formation, along with cell cycle and apoptosis analyses. We then compared MB and miR target databases to isolate a putative target whose biochemical and oncogenic properties were similarly elucidated using either transient silencing of target expression or stable induction of miR-212-3p. Results: RNA expression analyses revealed dramatically reduced miR-212-3p levels in group 3 tumors and cell lines mainly through epigenetic silencing via histone modifications. Restoring miR-212-3p expression reduced in vitro cancer cell proliferation, migration, colony formation, and wound healing. Elevated miR-212-3p levels shifted c-Myc phosphorylation (from serine-62 to threonine-58), triggering destabilization and degradation; concurrently, its pro-apoptotic binding partners, i.e., Bin-1 and P19ARF, were upregulated with subsequent elevated apoptotic signals. Using a combination of transcriptomic data and dual luciferase assay, we isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors, with poor survival shown in high-expressing patients. Transient NFIB silencing in vitro reduced cancer cell proliferation, colony formation, migration, and invasion. Concurrently, in group 3 MB cells, reduced medullosphere formation along with decreased expression of stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. Conclusion: These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and provide a potential therapeutic oncogenic target implicated in metastasis and tumor recurrence.

show abstract

“…93 Like many other tumors as well as GB, highly aggressive MB cells have shown to upregulate CSC markers such as CD133 and Nestin. 240 Although the functional role of CD133 is not well delineated, overexpression of CD133 is associated with chemoresistance 246 and high tumor-initiating capacity. 247 Similarly, CD133 cell surface marker expression has been used to identify CSCs in NB cell lines which display more resistance to anticancer drugs.…”

Section: Targeting Cancer Stem Cells In the Treatment Of Pediatric Brain Tumorsmentioning

confidence: 99%

Repurposing of Anticancer Stem Cell Drugs in Brain Tumors

Bahmad

Daher

Aljamal

et al. 2021

J Histochem Cytochem.

View full text Add to dashboard Cite

Brain tumors in adults may be infrequent when compared with other cancer etiologies, but they remain one of the deadliest with bleak survival rates. Current treatment modalities encompass surgical resection, chemotherapy, and radiotherapy. However, increasing resistance rates are being witnessed, and this has been attributed, in part, to cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells that reside within the tumor bulk and have the capacity for self-renewal and can differentiate and proliferate into multiple cell lineages. Studying those CSCs enables an increasing understanding of carcinogenesis, and targeting CSCs may overcome existing treatment resistance. One approach to weaponize new drugs is to target these CSCs through drug repurposing which entails using drugs, which are Food and Drug Administration–approved and safe for one defined disease, for a new indication. This approach serves to save both time and money that would otherwise be spent in designing a totally new therapy. In this review, we will illustrate drug repurposing strategies that have been used in brain tumors and then further elaborate on how these approaches, specifically those that target the resident CSCs, can help take the field of drug repurposing to a new level.

show abstract

Medulloblastoma cancer stem cells: molecular signatures and therapeutic targets

Cited by 33 publications

References 149 publications

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting Nuclear Factor I/B (NFIB)

Repurposing of Anticancer Stem Cell Drugs in Brain Tumors

Contact Info

Product

Resources

About