Chemoresistance in High-Grade Gliomas: Relevance of Adenosine Signalling in Stem-Like Cells of Glioblastoma Multiforme

Abstract

Glioblastoma multiforme (GBM) is the most common glial cell-derived brain tumour, with one of the worst prognoses among all cancers. GBM cells are infiltrative and extremely resistant to radio- and chemotherapy, which inevitably leads to recurrence after surgical resection. These inherent GBM properties are the reasons that patient treatment has not seen major improvements in decades. Studies have consistently shown that glioblastoma stem-like cells (GSCs) are responsible for the tumourigenic properties in the GBM population. In fact, their self-renewal and proliferative potential are required for tumour growth, and their extreme chemoresistance leads to early recurrence of this tumour. Among those mechanisms associated with chemoresistance and having the greatest clinical impact in cancer treatment, are the activities of plasma membrane transporters that extrude antitumour drugs from the cell, thus notably decreasing the pharmacological efficiency of these drugs. The multiple drug resistance associated protein-1 (Mrp1) transporter has been shown to be particularly important in GBM, as inhibition of Mrp1 activity notably chemosensitises cells to antiproliferative drugs. As current therapeutic options for GBM offer only a poor improvement in overall survival rate, alternative strategies for overcoming tumour resistance are urgently sought after. To this end, it is of major clinical relevance to know more about the endogenous modulators that control Mrp1 expression within the pathological environment of the tumour. This review describes the particular properties of glioblastoma cells that overcome multimodal therapy and relapse, with an emphasis on the microenvironmental tumour properties that influence the chemoresistance phenotype to antiproliferative drugs. We also discuss alternative methods of reversal of Mrp1-mediated chemoresistance in these cells by targeting extracellular adenosine production or signalling through particular plasma membrane receptors.

ABC Transporters in Cancer Stem Cells: Beyond Chemoresistance

“…While it is known that hypoxia promotes chemoresistance, the mechanisms are not yet fully understood. It has been shown that nucleoside adenosine, which is elevated in the tumour microenvironment, plays a prominent role in mediating resistance mechanisms [ 148 ]. Therefore, hypoxic conditions may be a functional component of the stem cell niche, which highlights the close relationship between the maintenance of stem cell phenotype and chemoresistance.…”

Inhibition of glioma growth by flavokawain B is mediated through endoplasmic reticulum stress induced autophagy

“…Although cancers, such as GBM, may be intrinsically resistant to therapy, the ability to engage survival mechanisms in response to treatment potentially further reduces efficacy of any promising agent [3][4][5] Autophagy is one such conserved cellular pathway. The process removes dysfunctional or damaged organelles through lysosomal degradation and recycles the products for cellular metabolic needs [6].…”

BRM270 targets cancer stem cells and augments chemo‑sensitivity in cancer (Review)

“…This resistance also leads to the recurrence of glioblastoma following standard cancer therapy. Accumulating evidence suggests that glioblastoma stem cells are the major cause of chemo- and radio-resistance and are largely responsible for tumor recurrence ( 46 – 49 ). Therefore, the glioblastoma stem cell population is an important target for the successful clinical management of progressive and recurrent malignant glioblastoma.…”