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Molecular and cellular heterogeneity of tumour stem cells in human glioblastoma

Final Report Summary - TUMOURSTEMCELLS (Molecular and cellular heterogeneity of tumour stem cells in human glioblastoma)

This project revolves around the investigation of the biological function and complexity of the so called "tumour stem cells" in the most devastating human brain cancer, i.e. glioblastoma (GBM). GBM is characterized by inter- and intra-tumour heterogeneity and resistance to therapy. As a consequence, tumour diversity results in different clinical phenotypes, whose common feature is the rapid emergence of treatment resistance as a result of environmental selection pressures generated by radiotherapy and chemotherapy that represent the standard care for GBM patients.
Little is known about the impact of intra-tumour heterogeneity on tumour growth and the consequences of such heterogeneity on the emergence of resistant disease. This is a relevant problem in brain tumour research, as median life expectancy in optimally managed patients is only 17-62 weeks with only 25% surviving 2 years. GBM patients die for recurrences that develop after 9-12 months from the initial surgery.
One explanation of this intra-tumour heterogeneity in GBM is that tumours might consist of a minority of the so called “tumour stem cells” (TSCs) that closely recapitulate the original disease and give rise to distinct populations of differentiated progeny resulting in molecular and cellular diversity coexisting in the same tumour.
In this project, analysis of the molecular and cellular properties of TSCs in human GBM has led to increase our understanding of the biology of the disease and to describe for the first time a previously unrecognized complexity of genomic, gene expression and phenotypic profiles in individual GBM patients.

In order to achieve this goal, this project has been divided in the following tasks:

1. Collection of necrotic, margin and core areas of 10 human tumour samples from adult patients diagnosed with primary GBM.
2. Characterization of the cellular phenotype of TSCs derived under stem cell conditions in defined medium from distinct compartments of individual GBMs.
3. Characterization of the molecular genetic profile of TSCs derived under stem cell conditions in defined medium from distinct compartments of individual GBMs.
4. Comparison of the molecular genetic profile of TSCs with the molecular sub-classes of GBM identified in The Cancer Genome Atlas (TCGA).

All together, our findings show an objective identification of the margin compartment of the disease and a molecular and phenotypic characterization of this area. Our data also describe extensive genetic intra-tumour heterogeneity in the tumour core in individual GBMs.
This has contributed to refine our understanding of the complex molecular landscape of GBM and if performed on a larger scale, this project has the potential to result in improved therapeutic strategies to bring hope to future patients.

The clinical need to improve patients’ outcome is acute and urgent. Each year in the United Kingdom (UK) around 4,300 new cases of brain or central nervous system cancers are diagnosed, around 7 per 100,000 of the UK population (http://www.cancerresearchuk.org/cancer-info/cancerstats/types/brain/incidence/). Although brain tumours account for less than 2% of all primary tumours they are responsible for 7% of the years of life lost from cancer before age 70. The high rates of mortality make these rare cancers the third leading cause of cancer-related death among economically active men between 15-54 years of age and the fourth leading cause of cancer-related death among economically active women between 15-34 years of age. If the burden of disease is considered in terms of the average years of life lost per patient brain tumours are one of the most lethal cancers with over 20 years of life lost.
Analysis of survival trends in the UK has confirmed “The absence of any improvement in survival from brain tumours in adults between 1986 and 1999, for either sex, represents a rare exception to the general trend in cancer survival in England and Wales during this period. For brain tumours, the overall trend is in fact towards a decline in survival in both sexes, which is statistically significant for 5-year survival among men (-3% every 5 years)”. The economic impact is significant in terms of direct healthcare costs and indirect costs (73% of indirect costs are related to premature mortality). Recent data puts the direct healthcare costs at €28,848 per patient with high-grade glioma. Thus improving the survival of brain cancer in the UK could save €1,702,032 (£1,457,219) in direct healthcare costs alone each year.