Gene knockout of the master regulator of mitochondrial fission, Drp1, prevents neoplastic transformation. Also, mitochondrial fission and its opposing process of mitochondrial fusion are emerging as ...crucial regulators of stemness. Intriguingly, stem/progenitor cells maintaining repressed mitochondrial fission are primed for self-renewal and proliferation. Using our newly derived carcinogen transformed human cell model, we demonstrate that fine-tuned Drp1 repression primes a slow cycling 'stem/progenitor-like state', which is characterized by small networks of fused mitochondria and a gene-expression profile with elevated functional stem/progenitor markers (Krt15, Sox2 etc) and their regulators (Cyclin E). Fine tuning Drp1 protein by reducing its activating phosphorylation sustains the neoplastic stem/progenitor cell markers. Whereas, fine-tuned reduction of Drp1 protein maintains the characteristic mitochondrial shape and gene-expression of the primed 'stem/progenitor-like state' to accelerate neoplastic transformation, and more complete reduction of Drp1 protein prevents it. Therefore, our data highlights a 'goldilocks' level of Drp1 repression supporting stem/progenitor state dependent neoplastic transformation.
Stem cells reside in niches that regulate the balance between self-renewal and differentiation. The identity of a stem cell is linked with the ability to interact with its niche through adhesion ...mechanisms. To identify targets that disrupt cancer stem cell (CSC) adhesion, we performed a flow cytometry screen on patient derived glioblastoma (GBM) cells and identified junctional adhesion molecule-A (JAM-A) as a CSC adhesion mechanism essential for self-renewal and tumor growth. JAM-A was dispensable for normal neural stem/progenitor cell (NPC) function and JAM-A expression was reduced in normal brain versus GBM. Targeting JAM-A compromises the self-renewal of CSCs. JAM-A expression negatively correlated to GBM patient prognosis. Our results demonstrate that novel GBM targeting strategies can be identified through screening adhesion receptors and JAM-A represents a novel mechanism for niche driven CSC maintenance.
Casein kinase 2 (CK2) is an ubiquitously expressed serine/threonine kinase composed of two catalytic subunits ( alpha and/or alpha ') and two regulatory ( beta ) subunits. The expression and kinase ...activity of protein kinase CK2 are elevated in many different cancers, including glioblastoma (GBM). Brain tumor initiating cells (BTICs) are a subset of cells that are tumorigenic and are considered to promote the resistance of GBM to current therapies. Previously our lab has reported that CK2 activity promotes prosurvival signaling in GBM; however, the role of CK2 in BTICs has not been examined. In this study, we found that the expression of CK2 alpha was increased in CD133+ BTICs compared to CD133- cells from GBM xenografts. We found that GBM cells are sensitive to cell death caused by CX-4945, an ATP-competitive inhibitor of CK2. Inhibition of CK2 also reduced the frequency of CD133+ BTICs over the course of 7 days, indicating a role for CK2 in BTIC persistence and survival. Additionally, using an in vitro limiting dilution assay, we found that CX-4945 reduced neurosphere formation in bulk cells from GBM xenografts. On the other hand, inhibition of CK2 had no effect on the proliferation or neurosphere formation of normal murine neural precursor cells. We are currently investigating the mechanism of cell death and reduced neurosphere formation and have found a reduction in the constitutive activation of signal transduction pathways dysregulated in GBM including NF-kB and MAPK pathways. Due to the integration of CK2 in multiple signaling pathways important for BTIC survival, protein kinase CK2 is a promising target in GBM.
The failure of current therapies to control brain tumor growth and invasion accounts for the poor survival of glioma patients. For example, a patient diagnosed with glioblastoma (WHO grade IV) will ...probably live for less than 1 yr past the initial diagnosis. To combat this deadly cancer, novel therapies are being designed to target specific signal transduction pathways, including TGF-β, implicated in glioma development and progression. This chapter defines the effects of TGF-β on glioma proliferation, migration, invasion, angiogenesis, and immunosuppression, to explore the molecular mechanisms through which targeting TGF-β signaling could be beneficial for patient therapy. Recent promising results from preclinical and clinical trials of therapies developed towards TGF-β ligand or receptor will also be summarized to demonstrate the potential benefit of targeting TGF-β signaling for glioma therapy.
The Cancer Stem Cell Paradigm Eyler, Christine E.; Heddleston, John M.; Hitomi, Masahiro ...
Adult Stem Cells
Book Chapter
Following the discovery that leukemic cells exhibit properties of hematopoietic stem cells, the prospective isolation of stem-like cells with high tumorigenicity has been reported for a variety of ...tumors. These “cancer stem cells” (CSCs) are so named because they exhibit the capacity for sustained self-renewal and possess the ability to regenerate transplanted tumor masses resembling the primary tumor in immunodeficient mice. However, the existence of CSCs remains contentious in the field of cancer biology, in part because of the application of inconsistent and inaccurate definitions and disputes over terminology. Herein, we review the discovery of CSCs, examine in detail their physical and functional characteristics, the mechanisms that lead to their formation, and how their contribution to solid tumor formation impacts cancer therapies.
PDF
