Solid tumours arising from differently pre-oxygenated cells: Comparable growth rates despite dissimilar tissue oxygenation

Abstract

Purpose: The hypoxia-inducible factor (HIF)-dependent transcriptional response is often very pronounced in hypoxic microregions of solid malignant tumours, leading to secretion of pro-angiogenic factors and activation of a hypoxia-tolerant, glycolytic metabolism. Here, the influence of the microenvironment of tumour-initiating cells as a factor determining intertumoural variations in the relative contributions of both processes has been examined.

Material and methods: The oxygenation status was assessed in rat DS-sarcomas using polarographic needle electrodes. Tumours were generated by allografting cells from either normoxic cell culture or severely hypoxic/anoxic ascites. HIF-related marker expression and intercapillary distances were analysed using immunohistochemistry.

Results: Cells preconditioned in hypoxic ascites form poorly vascularised, hypoxic tumours in rats, showing strong activation of HIF-1α and glucose transporter (GLUT)- 1. Conversely, tumour-initiating DS-cells derived from normoxic cell culture form highly angiogenic, normoxic tumours with a significantly lower expression of HIF-1α and GLUT-1. Growth rates and the fraction of Ki-67 positive cells for both tumour groups were comparable.

Conclusions: The intensity of angiogenesis in this model is primarily determined by the state of metabolic adaptation of tumour-initiating cells, rather than being a function of HIF-activation during solid tumour growth, a finding which is highly relevant for the design of treatment regimens targeting the tumour vasculature.

Keywords:

• tumour hypoxia
• angiogenesis
• tumour-initiating cells
• microenvironment
• intercapillary distance

Acknowledgement

This study has been supported by grant # 106758 from the Deutsche Krebshilfe.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.