Therapy targets in glioblastoma and cancer stem cells: lessons from haematopoietic neoplasms

Abstract

Despite intense efforts to identify cancer-initiating cells in malignant brain tumours, markers linked to the function of these cells have only very recently begun to be uncovered. The notion of cancer stem cell gained prominence, several molecules and signalling pathways becoming relevant for diagnosis and treatment. Whether a substantial fraction or only a tiny minority of cells in a tumor can initiate and perpetuate cancer, is still debated. The paradigm of cancer-initiating stem cells has initially been developed with respect to blood cancers where chronic conditions such as myeloproliferative neoplasms are due to mutations acquired in a haematopoietic stem cell (HSC), which maintains the normal hierarchy to neoplastic haematopoiesis. In contrast, acute leukaemia transformation of such blood neoplasms appears to derive not only from HSCs but also from committed progenitors that cannot differentiate. This review will focus on putative novel therapy targets represented by markers described to define cancer stem/initiating cells in malignant gliomas, which have been called 'leukaemia of the brain', given their rapid migration and evolution. Parallels are drawn with other cancers, especially haematopoietic, given the similar rampant proliferation and treatment resistance of glioblastoma multiforme and secondary acute leukaemias. Genes associated with the malignant conditions and especially expressed in glioma cancer stem cells are intensively searched. Although many such molecules might only coincidentally be expressed in cancer-initiating cells, some may function in the oncogenic process, and those would be the prime candidates for diagnostic and targeted therapy. For the latter, combination therapies are likely to be envisaged, given the robust and plastic signalling networks supporting malignant proliferation.

Keywords: cell surface markers; glioblastoma cancer stem cell; haematopoietic stem cells; leukaemia; signalling pathways.

Fig. 1

Schematic analogies between tumour initiation levels in neural and haematopoietic compartment. (A) Stem-cell compartment. Both neural stem cells (NSC) and haematopoietic stem cells (HSC) display Musashi protein alterations that may lead to tumour formation. Furthermore, NSC may express epidermal growth factor receptor mutations and/or Bmi-1 overexpression and HSC may acquire alterations in genes coding for different kinases, such as JAK2 (the V617F mutation) and ABL (the BCR-ABL translocation). (B) Precursor cell compartment. There are several tumour-initiating events, such as PDGFR mutations and transforming growth factor beta 1 and 2 up-regulation, that may lead to tumour formation in both neural precursor cell and haematopoietic precursor cells. It is postulated that such modified precursors acquire stem-cell properties, like self-renewal, and represent a tumour cell reservoir. (C) Differentiated cell compartment. Cancer stem cells can result from terminally differentiated cells, which acquire several genetic mutations in both glial and haematopoietic compartments, de-differentiate, become immortalized and perpetuate the malignant phenotype.

Fig. 2

Molecular mediators involved in adult stem-cell renewal within neural and haematopoietic stem-cell (HSC) niche. Both neural and HSCs communicate with their niches through similar signalling pathways, such as Notch. Some factors are responsible for homoeostasis of each particular niche, such as Tpo for the haematopoietic system, which is required for HSC's quiescence and maintenance of HSC reservoir and brain-derived nerve factor (BDNF) for neural stem cells (NSCs). It is not known whether certain mutations acquired by HSC or NSC are positively selected by defects in the niche, which apply a certain pressure of selection on stem and progenitor cells. Figure adapted from [68] and [75].