Identification of CD114 Membrane Receptors as a Molecular Target in Medulloblastomas

Abstract

Medulloblastomas are the most common solid tumors in children, accounting for 8–30% of pediatric brain cancers. It is a high-grade tumor with aggressive behavior and a typically b poor prognosis. Its treatment includes surgery, chemotherapy, and radiotherapy, and presents high morbidity. Significant clinical, genetic, and prognostic differences exist between its four molecular subgroups: WNT, SHH, Group 3, and Group 4. Many studies seek to develop new chemotherapeutic agents for medulloblastomas through the identification of genes whose expressions are new molecular targets for drugs, such as membrane receptors associated with cell replication. This study aimed to assess the association of CD114 expression with mortality in patients with medulloblastoma. Databases from the Medulloblastoma Advanced Genomics International Consortium (MAGIC) were analyzed, focusing on the expression of the CD114 membrane receptor in different molecular types and its possible association with mortality. Our findings showed different CD114 expressions between Group 3 and other molecular groups, as well as between the molecular subtypes SHH γ and Group 3 α and Group 3 β. There was no statistically significant difference between the other groups and subtypes. Regarding mortality, this study did not find statistical significance in the association between low and high CD114 expressions and mortality. Medulloblastoma is a heterogeneous disease with many subtype variations of its genetic and intracellular signaling pathways. Similarly to this study, which could not demonstrate different CD114 membrane receptor expression patterns between groups, others who sought to associate CD114 expression with mortality in other types of cancer failed to establish a direct association. Since many indications point to the relation of this gene with cancer stem cells (CSCs), it may be part of a more extensive cellular signaling pathway with an eventual association with tumor recurrence. This study found no direct relationship between CD114 expression and mortality in patients with medulloblastoma. Further studies are needed on the intracellular signaling pathways associated with this receptor and its gene (the CSF3R).

Gene Expression of CSF3R/CD114 Is Associated with Poorer Patient Survival in Glioma

“…Recombinant human GCSF is clinically used to prevent neutropenia, due to its effects on neutrophil mobilization and maturation [ 32 ]. GCSF/CD114 signaling has also been investigated as a modulator of neuronal survival, synaptic plasticity [ 6 , 28 , 29 , 30 , 31 ], and cancer [ 7 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. Specifically, CD114 has been put forward as a marker to identify CSC subpopulations associated with tumorigenicity, metastasis, and resistance to treatment [ 7 , 9 , 10 ].…”

“…However, no association between the protein expression of CD114 and patient mortality was found [ 13 ]. Similarly, different levels of CSF3R transcripts occur among different tumor subgroups and subtypes of MB, but no significant association with patient survival was established [ 18 ]. A previous study in glioma analyzed the RNA and protein expression of GCSF and CD114 in a set of 22 human gliomas (WHO grade II, III, and IV) and cell cultures derived from these tumors.…”

“…CD114 has been proposed as a marker for CSCs in neural crest-derived tumors such as neuroblastoma (NB) and melanoma [ 7 , 9 , 10 ]. Expression of CD114 is found in solid tumors including brain, ovarian, cervical, bladder, and skin cancers [ 7 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ]. In addition, CSF3R mutations have been found in rare types of leukemia [ 19 , 20 ].…”

“…CD114+ cells show resistance against cytotoxic chemotherapy and are responsive to stimulation by GCSF [ 17 ]. In addition, transcript levels of the CSF3R gene have been identified across molecular subgroups of MB [ 18 ]. A previous study focusing on human gliomas described widespread RNA and protein expression of GCSF.…”

Theranostics in Neurooncology: Heading Toward New Horizons

“…They differ in many aspects from the disease in adults, both in site (pediatric brain tumors are more often infratentorial [#60% of cases]) and in histology (50), as has been recognized in the most recent WHO classification of CNS tumors (fifth edition, 2021), in which specific pediatric variants have been added (e.g., pediatric-type low-grade and highgrade diffuse gliomas) (51)(52)(53). Recent advances in molecular and genetic characterization have detected many peculiarities of pediatric CNS tumors, significantly impacting spreading, response to treatment, and survival (54,55).…”