Metabolic regulation of glioma stem-like cells in the tumor micro-environment

Abstract

Cancer metabolism has emerged as one of the most interesting old ideas being revisited from a new perspective. In the early 20th century Otto Warburg declared metabolism the prime cause in a disease of many secondary causes, and this statement seems more prescient in view of modern expositions into the true nature of tumor evolution. As the complexity of tumor heterogeneity becomes more clear from a genetic perspective, it is important to consider the inevitably heterogeneous metabolic components of the tumor and the tumor microenvironment. High grade gliomas remain one of the most difficult to treat solid tumors, due in part to the highly vascularized nature of the tumor and the maintenance of more resistant stem-like subpopulations within the tumor. Maintenance of glioma stem cells (GSCs) requires specific alterations within the cells and the greater tumor microenvironment with regards to signaling and metabolism. Specific niches within gliomas help foster the survival of stem-like sub-populations of cells with high tumorigenicity and high metabolic plasticity. Understanding these maintenance pathways and the metabolic dependencies within the niche may highlight potential avenues of addressing tumor resistance and recurrence in glioma patients.

The complement system in glioblastoma multiforme

“…Factors that are involved in GSC maintenance comprise of metabolic, genetic and epigenetic regulatory mechanisms [ 90 ]. Although the mechanisms underlying GSC plasticity are largely unknown, several intrinsic regulatory mechanisms are known to be involved in reprogramming differentiated GBM cells into stem-like cells.…”

Targeting of replicating CD133 and OCT4/SOX2 expressing glioma stem cells selects a cell population that reinitiates tumors upon release of therapeutic pressure

“…At the histological level, GBMs show a cellular hierarchy dominated by stem-like cells 3,4 . Glioblastoma stem cells (GSCs), at the apex of this hierarchy, are functionally defined as having the capacity for self-renewal, multipotent differentiation and recapitulation of the original tumor phenotype, upon implantation in immunodeficient mice 5,6 .…”

CEST‐MRI for glioma pH quantification in mouse model: Validation by immunohistochemistry

“…The study was focused on glioma, an aggressive cerebral tumor characterized by a typical poor prognosis. In glioma acidic pHe is well known to regulate proliferation, angiogenesis, immunosuppression, invasion and chemoresistance, pathophysiological processes that are at the basis of its high heterogeneity. Therefore, a robust imaging method that would allow the quantification of the glioma pHe is of great interest.…”

“…Despite optimal treatment consisting of maximal resection followed by radiation and chemotherapy, virtually all tumors quickly recur . A feature commonly present in GBM, as in many other tumors, is the onset of a highly glycolytic metabolism with the presence of an acid extracellular microenvironment . The chaotic and irregular vasculature occurring in the tumor region leads to an unbalanced blood supply with a consequent transient or chronic hypoxia .…”

“…2 A feature commonly present in GBM, as in many other tumors, is the onset of a highly glycolytic metabolism with the presence of an acid extracellular microenvironment. 3,4 The chaotic and irregular vasculature occurring in the tumor region leads to an unbalanced blood supply with a consequent transient or chronic hypoxia. 5,6 This, in addition to the rapid glucose uptake and high metabolic rate is at the basis of the acidic extracellular/extravascular pH (pHe) of GBM.…”