The Science

GlioStem is a novel molecular probe for live stem cell visualization and detection.

The Science

GlioStem

GlioStem is a new conductive polymer (luminescent conductive oligothiophene, LCO) that illuminates in and thereby specifically detects neural stem cells and stem cell-like cells in gliomas by conventional fluorescent microscopy and fluorescence-assisted cell sorting (FACS). Certain polymers, especially poly- and oligothiophenes, have been shown to be able to cross cell membranes without additional reagents and to illuminate when interacting with certain structures. For example, it has been shown that certain polythiophenes can cross cell membranes of neurons and illuminate when interacting with amyloid structures from a diversity of proteins, including amyloid-ß and prion. Such polythiophenes are currently under development for early detection of Alzheimer’s disease among other clinical issues.

Our goal is to develop similar molecules that based on chemical and structural characteristics can detect and thus be used as markers for various types of stem cells with the possibility of using such markers for visualizing and targeting the detected cells. After testing numerous poly- and oligothiophenes of different lengths, structures, and general characteristics, GlioStem, was identified to specifically detect neural stem cells in vitro and in vivo, and stem cell-like cells from gliomas in cultured cells and tumor tissue from patients.

The structure of GlioStem with its imidazole rings mimics a histidine/histamine molecule. We have further found that GlioStem detects neural and glioma-derived progenitors in a more specific and sensitive manner than current methods and does not cross-react with any other cell type investigated. The cell types tested include differentiated neural cells (neurons of different phenotype, astrocytes, oligodendrocytes), various fibroblasts, embryonic stem (ES) cells, multipotent stromal cells (also referred to as mesenchymal stem cells), a large number of tumor cell lines of different origin etc.

The disease

Glioma is the most common primary malignant brain tumor and arises throughout the central nervous system. Classification of gliomas by the World Health Organization (WHO) distinguishes malignancy by grade (I-IV). Based on histological appearance, gliomas of most grades and types are found in children and adults. Gliomas show profound cellular heterogeneity and influences from the tumor microenvironment; with treatment-resistant tumor cells displaying a high degree of stemness. Glioblastoma (GBM) is the most malignant primary brain tumor (grade IV glioma) with an annual incidence of around 3 in 100 000. The tumors are often found in a late stage of the disease and untreated patients have a median survival of only 3 months. Current state-of-the-art treatment includes maximal surgical resection, followed by concomitant radio-chemotherapy. However, despite state-of-the-art treatment the prognosis remains dismal with median survival of less than two years. At recurrence, further treatment (including surgery, radio- and chemotherapy or bevacizumab) offers only very limited prolonged survival.

Emerging research suggests that failure to target glioma stem cells (GSCs) rather than the inability to remove tumors through surgery, radiation, or chemotherapy, explains the poor survival of GBM patients. It is convincingly demonstrated that GSCs possess tumor initiating abilities. GSCs also seem to escape conventional therapy due to their slow metabolism, and they can be in quiescent states for long times. GSCs can extend into the healthy tissue from the actual tumor, which is challenging for the surgeon as the healthy cells and the GSCs cannot be distinguished in real-time by 5- aminolaevulinic acid (5-ALA) fluorescence guided resection or by other proven methods. Being able to detect and eliminate GSCs during tumor resection would mean a crucial step towards increased patient survival. Hence, there is a need for better methods for precise removal of GSCs with minimum damage to healthy tissue to improve GBM prognosis and quality of life of operated patients.

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