Evidence for hypoxia increasing the tempo of evolution in glioblastoma.
Br J Cancer
; 123(10): 1562-1569, 2020 11.
Article
em En
| MEDLINE
| ID: mdl-32848201
ABSTRACT
BACKGROUND:
Tumour hypoxia is associated with metastatic disease, and while there have been many mechanisms proposed for why tumour hypoxia is associated with metastatic disease, it remains unclear whether one precise mechanism is the key reason or several in concert. Somatic evolution drives cancer progression and treatment resistance, fuelled not only by genetic and epigenetic mutation but also by selection from interactions between tumour cells, normal cells and physical micro-environment. Ecological habitats influence evolutionary dynamics, but the impact on tempo of evolution is less clear.METHODS:
We explored this complex dialogue with a combined clinical-theoretical approach by simulating a proliferative hierarchy under heterogeneous oxygen availability with an agent-based model. Predictions were compared against histology samples taken from glioblastoma patients, stained to elucidate areas of necrosis and TP53 expression heterogeneity.RESULTS:
Results indicate that cell division in hypoxic environments is effectively upregulated, with low-oxygen niches providing avenues for tumour cells to spread. Analysis of human data indicates that cell division is not decreased under hypoxia, consistent with our results.CONCLUSIONS:
Our results suggest that hypoxia could be a crucible that effectively warps evolutionary velocity, making key mutations more likely. Thus, key tumour ecological niches such as hypoxic regions may alter the evolutionary tempo, driving mutations fuelling tumour heterogeneity.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Encefálicas
/
Glioblastoma
/
Evolução Clonal
/
Hipóxia Tumoral
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Br J Cancer
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Irlanda