Microenvironmental adaptation of experimental tumours to chronic vs acute hypoxia

Abstract

This study investigated long-term microenvironmental responses (oxygenation, perfusion, metabolic status, proliferation, vascular endothelial growth factor (VEGF) expression and vascularisation) to chronic hypoxia in experimental tumours. Experiments were performed using s.c.-implanted DS-sarcomas in rats. In order to induce more pronounced tumour hypoxia, one group of animals was housed in a hypoxic atmosphere (8% O 2 ) for the whole period of tumour growth (chronic hypoxia). A second group was acutely exposed to inspiratory hypoxia for only 20 min prior to the measurements (acute hypoxia), whereas animals housed under normal atmospheric conditions served as controls. Acute hypoxia reduced the median oxygen partial pressure (pO 2 ) dramatically (1 vs 10 mmHg in controls), whereas in chronically hypoxic tumours the pO 2 was significantly improved (median pO 2 ¼ 4 mmHg), however not reaching the control level. These findings reflect the changes in tumour perfusion where acutely hypoxic tumours show a dramatic reduction of perfused tumour vessels (maybe the result of a simultaneous reduction in arterial blood pressure). In animals under chronic inspiratory hypoxia, the number of perfused vessels increased (compared to acute hypoxia), although the perfusion pattern found in control tumours was not reached. In the chronically hypoxic animals, tumour cell proliferation and tumour growth were significantly reduced, whereas no differences in VEGF expression and vascular density between these groups were observed. These results suggest that long-term adaptation of tumours to chronic hypoxia in vivo, while not affecting vascularity, does influence the functional status of the microvessels in favour of a more homogeneous perfusion.

Tumors exposed to acute cyclic hypoxia show increased vessel density and delayed blood supply

“…Moreover, acute or chronic hypoxia did not induce angiogenesis in DS sarcomas (Thews et al, 2004). In these tumor models, the various hypoxia exposures decreased or did not alter the microvascular density, and the hypoxia exposures reduced tumor growth.…”

Morphological and functional evaluation of angiogenesis of a xenografted human sarcoma in nude mice

“…Only few data are available, despite the fact that the functional status of a vascular network may have major biological impact on the sensitivity of a tumour towards cytotoxic drugs or irradiation. Tumour angiogenesis shows several structural and functional abnormalities including irregular branching patterns, increased vascular permeability and high amounts of arterio-venous shunt formation which leads to an inadequate perfusion (Thews et al 2004).…”

A proof-of-principle study of epigenetic therapy with hydralazine and magnesium valproate plus doxorubicin cyclophosphamide as neoadjuvant therapy for locally advanced breast cancer

“…Many tumor models have demonstrated a close correlation between local oxygen deficiency and the production of HIF-1α and VEGF [21,22]. HIF-1α activity as well as VEGF secretion is tightly regulated by the oxygen-level, and in the well oxygenated state they are rapidly degraded [24].…”