68 research outputs found
Data for: Cell quiescence correlates with enhanced glioblastoma cell invasion and cytotoxic resistance
No full textDifferentially expressed genes comparing Oregon Green positive (1% highest proliferating/brightest GBM cell subpopulation) versus Oregon Green negative (1% lowest proliferating/least bright GBM cell subpopulation). Data was derived from mRNA sequencing using the Illumina HiSeq 2500 platform
Collagen loss and impaired wound healing is associated with c-Myb deficiency.
No full textCollagen type I serves as an abundant structural and signalling component of skin. It is also an established target gene of the transcription factor, c-Myb. When c-myb−/− embryos were examined it was observed that their skin was markedly thinner than normal. Importantly, immunohistochemical investigation showed complete absence of collagen type I. Although these homozygous knock-out embryos fail to develop beyond day 15, fibroblasts established from these embryos (mouse embryonic fibroblasts [MEFs]) show defective proliferative
responses. Furthermore, in vitro scratch wound assays demonstrated that these c-myb−/− MEFs also exhibit slower closure than their wild-type counterparts. Embryonic lethality has meant that examination of the role of c-Myb in adult mouse skin has not been reported to date. However, in view of the abundance of collagen type I in normal skin, its role in skin integrity and the in vitro data showing proliferative and migration defects in c-myb−/− MEFs, we investigated the consequences of heterozygous c-myb loss in adult mice on the complex process of skin repair in response to injury. Our studies clearly demonstrate that heterozygous c-myb deficiency has a functional effect on wound repair, collagen type I levels and, in response to wounding, transforming growth factor-β1 (an important collagen stimulating factor) induction expression is aberrantly high. Manipulation of c-Myb may therefore provide new therapeutic opportunities for improving wound repair
while uncontrolled expression may underpin some fibrotic disorders
Collagen loss and impaired wound healing is associated with c-Myb deficiency
No full textData source: Supporting information, http://onlinelibrary.wiley.com.access.library.unisa.edu.au/doi/10.1002/path.2113/abstract#footer-support-infoCollagen type I serves as an abundant structural and signalling component of skin. It is also an established target gene of the transcription factor, c-Myb. When c-myb-/- embryos were examined it was observed that their skin was markedly thinner than normal. Importantly, immunohistochemical investigation showed complete absence of collagen type I. Although these homozygous knock-out embryos fail to develop beyond day 15, fibroblasts established from these embryos (mouse embryonic fibroblasts [MEFs]) show defective proliferative responses. Furthermore, in vitro scratch wound assays demonstrated that these c-myb-/- MEFs also exhibit slower closure than their wild-type counterparts. Embryonic lethality has meant that examination of the role of c-Myb in adult mouse skin has not been reported to date. However, in view of the abundance of collagen type I in normal skin, its role in skin integrity and the in vitro data showing proliferative and migration defects in c-myb-/- MEFs, we investigated the consequences of heterozygous c-myb loss in adult mice on the complex process of skin repair in response to injury. Our studies clearly demonstrate that heterozygous c-myb deficiency has a functional effect on wound repair, collagen type I levels and, in response to wounding, transforming growth factor-β1 (an important collagen stimulating factor) induction expression is aberrantly high. Manipulation of c-Myb may therefore provide new therapeutic opportunities for improving wound repair while uncontrolled expression may underpin some fibrotic disorders.Z Kopecki, MM Luchetti, DH Adams, X Strudwick, T Mantamadiotis, A Stoppacciaro, A Gabrielli, RG Ramsay, AJ Cowi
Towards targeting PI3K-dependent regulation of gene expression in brain cancer
No full textThe PI3K pathway is one of the most highly perturbed cell signaling pathways in human cancer, including the most common malignant brain tumors, gliomas, where either activating mutations of positive pathway effectors or loss/inactivation of pathway inhibitors occurs. Knowledge of the precise transcription factors modulated by PI3K in tumor cells remains elusive but there are numerous PI3K-responsive signaling factors, including kinases, which can activate many transcription factors. In the context of cancer, these transcription factors participate in the regulation of target genes expression networks to support cancer cell characteristics such as survival, proliferation, migration and differentiation. This review focuses on the role of PI3K signaling-regulated transcription in brain cancer cells from a series of recent investigations. A deeper understanding of this regulation is beginning to provide the hope of developing more sophisticated anti-cancer targeting approaches, where both upstream and downstream components of the PI3K pathway may be targeted by existing and novel drugs
Data for: Cell quiescence correlates with enhanced glioblastoma cell invasion and cytotoxic resistance
No full textDifferentially expressed genes comparing Oregon Green positive (1% highest proliferating/brightest GBM cell subpopulation) versus Oregon Green negative (1% lowest proliferating/least bright GBM cell subpopulation). Data was derived from mRNA sequencing using the Illumina HiSeq 2500 platform.THIS DATASET IS ARCHIVED AT DANS/EASY, BUT NOT ACCESSIBLE HERE. TO VIEW A LIST OF FILES AND ACCESS THE FILES IN THIS DATASET CLICK ON THE DOI-LINK ABOV
Advances in CAR T cell immunotherapy for paediatric brain tumours
No full textBrain tumours are the most common solid tumour in children and the leading cause of cancer related death in children. Current treatments include surgery, chemotherapy and radiotherapy. The need for aggressive treatment means many survivors are left with permanent severe disability, physical, intellectual and social. Recent progress in immunotherapy, including genetically engineered T cells with chimeric antigen receptors (CARs) for treating cancer, may provide new avenues to improved outcomes for patients with paediatric brain cancer. In this review we discuss advances in CAR T cell immunotherapy, the major CAR T cell targets that are in clinical and pre-clinical development with a focus on paediatric brain tumours, the paediatric brain tumour microenvironment and strategies used to improve CAR T cell therapy for paediatric tumours
Viruses exploit growth factor mechanisms to achieve augmented pathogenicity and promote tumorigenesis
No full textCellular homeostasis is regulated by growth factors (GFs) which orchestrate various cellular processes including proliferation, survival, differentiation, motility, inflammation and angiogenesis. Dysregulation of GFs in microbial infections and malignancies have been reported previously. Viral pathogens exemplify the exploitation of host cell GFs and their signalling pathways contributing to viral entry, virulence, and evasion of anti-viral immune responses. Viruses can also perturb cellular metabolism and the cell cycle by manipulation of GF signaling. In some cases, this disturbance may promote oncogenesis. Viral pathogens can encode viral GF homologues and induce the endogenous biosynthesis of GFs and their corresponding receptors or manipulate their activity to infect the host cells. Close investigation of how viral strategies exploit and regulate GFs, a will shed light on how to improve anti-viral therapy and cancer treatment. In this review, we discuss and provide insights on how various viral pathogens exploit different GFs to promote viral survival and oncogenic transformation, and how this knowledge can be leveraged toward the design of more efficient therapeutics or novel drug delivery systems in the treatment of both viral infections and malignancies
Sensitivity of GBM cells to cAMP agonist-mediated apoptosis correlates with CD44 expression and agonist resistance with MAPK signaling
No full textIn some cell types, activation of the second messenger cAMP leads to increased expression of proapoptotic Bim and subsequent cell death. We demonstrate that suppression of the cAMP pathway is a common event across many cancers and that pharmacological activation of cAMP in glioblastoma (GBM) cells leads to enhanced BIM expression and apoptosis in specific GBM cell types. We identified the MAPK signaling axis as the determinant of cAMP agonist sensitivity in GBM cells, with high MAPK activity corresponding to cAMP resistance and low activity corresponding to sensitization to cAMP-induced apoptosis. Sensitive cells were efficiently killed by cAMP agonists alone, while targeting both the cAMP and MAPK pathways in resistant GBM cells resulted in efficient apoptosis. We also show that CD44 is differentially expressed in cAMP agonist-sensitive and -resistant cells. We thus propose that CD44 may be a useful biomarker for distinguishing tumors that may be sensitive to cAMP agonists alone or cAMP agonists in combination with other pathway inhibitors. This suggests that using existing chemotherapeutic compounds in combination with existing FDA-approved cAMP agonists may fast track trials toward improved therapies for difficult-to-treat cancers, such as GBM
Coexpression analysis of CD133 and CD44 identifies proneural and mesenchymal subtypes of glioblastoma multiforme
No full textAccumulating evidence suggests that the stem cell markers CD133 and CD44 indicate molecular subtype in Glioblastoma Multiforme (GBM). Gene coexpression analysis of The Cancer Genome Atlas GBM dataset was undertaken to compare markers of the Glioblastoma Stem-Progenitor Cell (GSPC) phenotype. Pearson correlation identified genes coexpressed with stem cell markers, which were then used to build a gene signature that classifies patients based on a CD133 coexpression module signature (CD133-M) or CD44-M subtype. CD133-M tumors were enriched for the Proneural (PN) GBM subtype compared to Mesenchymal (MES) subtype for CD44-M tumors. Gene set enrichment identified DNA replication/cell cycle genes in the CD133-M and invasion/migration in CD44-M, while functional experiments showed enhanced cellular growth in CD133 expressing cells and enhanced invasion in cells expressing CD44. As with the 4 major molecular subtypes of GBM, there was no long-term survival difference between CD44-M and CD133-M patients, although CD44-M patients responded better to temozolomide while CD133-M patients benefited from radiotherapy. The use of a targeted coexpression approach to predict functional properties of surface marker expressing cells is novel, and in the context of GBM, supports accumulating evidence that CD133 and CD44 protein marker expression correlates with molecular subtype.status: Publishe
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