Developmental Biology - Glioblastoma|
Discovering the Achilles' Heel of Glioblastoma
Could antihistamine be a potential aid in defeating cancerous cells?...
Glioblastoma is the most prevalent and most lethal type of brain tumour in adults, with no curative treatment currently available. Glioblastomas cannot be surgically completely excised, as the tumour cells are adept at invading tissues and spreading around the brain. In addition, glioblastoma cells are extremely resistant to existing drug therapies.
For a long time, researchers have been looking for a weakness in glioblastoma cells which could target them for effective therapies. Research headed by Professor Pirjo Laakkonen, University of Helsinki, Finland, had previously found expression of a small fatty acid-binding protein MDGI (or FABP3) in glioblastoma cells, increases those cells ability to invade tissue — and is linked to a poorer prognosis for the patient.
"Our new research reveals that glioblastoma cells depend on the expression of a gene which produces MDGI protein. Inhibiting the function of this gene resulted in the death of tumour cells."
Pirjo Laakkonen PhD, Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki. Laboratory Animal Centre, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Finland.
The absence of MDGI caused instability in lysosome membranes, cleaning organelles found inside tumour cells, which, in turn, results in leakage of acidic and proteolytic enzymes from within the lysosomes into the cytoplasm, initiating cell death.
Further investigations revealed that silencing MDGI causes change in the phospholipid composition of lysosomes in glioblastoma cells. The transport of linoleic acid from outside to inside cells — a substance found in food and essential to humans — was disturbed. This results in a significant change in the fatty acid composition of the lysosomal membrane apparently by increasing the permeability of the membrane.
"Our research demonstrates that MDGI is a key factor regulating and maintaining the structure of the lysosomal membrane. This is the first gene found to regulate the stability of that membrane," says Laakkonen.
What makes this finding particularly interesting is that cell death caused by leakage in the lysosomes of glioblastoma cells can be activated using drugs that cross the blood-brain barrier. In their study, Laakkonen's group used an antihistamine known as clemastine.
In cell cultures, clemastine resulted in lysosome-mediated cell death in glioblastoma cells at concentrations which had no significant effect on healthy cells of different types. In mouse models, clemastine was very effective in reducing the spread of brain tumours and improving the survival rate of the animals. In the case of the most invasive brain tumour model, the administration of clemastine resulted in the disappearance of the entire tumour.
"Our findings demonstrate that antihistamines and other drugs that increase the permeability of the lysosomal membrane can be considered as an enhancing therapy for patients with glioblastoma alongside established treatments," says Laakkonen.
The study was published in the distinguished journal EMBO Molecular Medicine.
The current clinical care of glioblastomas leaves behind invasive, radio- and chemo-resistant cells. We recently identified mammary-derived growth inhibitor (MDGI/FABP3) as a biomarker for invasive gliomas. Here, we demonstrate a novel function for MDGI in the maintenance of lysosomal membrane integrity, thus rendering invasive glioma cells unexpectedly vulnerable to lysosomal membrane destabilization. MDGI silencing impaired trafficking of polyunsaturated fatty acids into cells resulting in significant alterations in the lipid composition of lysosomal membranes, and subsequent death of the patient-derived glioma cells via lysosomal membrane permeabilization (LMP). In a preclinical model, treatment of glioma-bearing mice with an antihistaminergic LMP-inducing drug efficiently eradicated invasive glioma cells and secondary tumours within the brain. This unexpected fragility of the aggressive infiltrating cells to LMP provides new opportunities for clinical interventions, such as re-positioning of an established antihistamine drug, to eradicate the inoperable, invasive, and chemo-resistant glioma cells from sustaining disease progression and recurrence.
Vadim Le Joncour, Pauliina Filppu, Maija Hyvönen, Minna Holopainen, S Pauliina Turunen, Harri Sihto, Isabel Burghardt, Heikki Joensuu, Olli Tynninen, Juha Jääskeläinen, Michael Weller, Kaisa Lehti, Reijo Käkelä and Pirjo Laakkonen.
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Image of a patient-derived glioblastoma in murine brain treated with saline (LEFT) or clemastine (RIGHT). Glioblastoma cells (RED) are known to invade the brain (BLUE), and are impossible to remove by surgery. They are highly resistant to chemotherapies. However, clemastine-treatment destroyed the invasive cells leading to clear tumor/brain borders.
CREDIT Laakkonen Lab, University of Helsinki, Finland.