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


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-1alpha 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-1alpha 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.
Mayer
Arnulf
A
Department of Radiooncology and Radiotherapy, University Medical Center, Mainz, Germany.
Steimel
Michaela
M
Wree
Alexander
A
Kelleher
Debra
D
Vaupel
Peter
P
D000818:Animals; D045744:Cell Line, Tumor; D051272:Glucose Transporter Type 1 / Q000378:metabolism; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D009389:Neovascularization, Pathologic; D010100:Oxygen / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012513:Sarcoma, Experimental / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology*
D051272:Glucose Transporter Type 1; C497444:Hif1a protein, rat; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019394:Ki-67 Antigen; C495679:Slc2a1 protein, rat; D010100:Oxygen