Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Smolle, E.
Expression of gluconeogenesis and glycolysis markers in non-small cell lung cancer
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medical University Graz; 2021. pp. 83
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Haybäck Johannes
- Leithner Katharina
- Olschewski Horst
- Altmetrics:
- Abstract:
- Purpose. Glycolysis and gluconeogenesis feed anabolic metabolism of tumor cells from carbohydrate and non-carbohydrate precursors, respectively. Their interplay in solid tumors is still poorly understood. Experimental Design. Protein abundance of GLUT1, the prime glucose transporter, and of the gluconeogenesis enzymes PCK1 and PCK2 was analyzed in 450 samples of non-small cell lung cancer (NSCLC) and in 54 NSCLC metastases using tissue microarrays (TMAs) and whole tumor slides. Spatial distribution was assessed by automated data analysis. Additionally, glycolytic and gluconeogenic gene expression was assessed by means of data from ‘The Cancer Genome Atlas’ (TCGA) cohorts. Results. PCK2 was predominantly expressed in lung adenocarcinoma (69% positive cases), while GLUT1 expression was higher in squamous cell carcinoma (94%) compared to adenocarcinoma (41%). A mixed phenotype harboring both, glycolytic and gluconeogenic cancer cells was found in more than 40% of all cases. Gluconeogenic adenocarcinomas were associated with improved overall survival compared to glycolytic or mixed tumors, however gluconeogenesis gene expression was enhanced in metastases compared to primary tumors. PCK2 expression was reduced in KRAS mutant tumors, indicating that metabolic phenotype is influenced by particular mutations. Tumor microenvironment and the 3-dimensional context play an important role in modulating both pathways, as suggested by preferential PCK2 expression at the tumor margin and by a differential impact of hypoxia on glycolysis and gluconeogenesis in NSCLC cells in vitro. Conclusion. This study reveals a complex metabolic landscape in NSCLC with heterogenous activation of glycolysis and gluconeogenesis, considerable histology-related differences, inter-patient variability and correlation with outcome.