Cell cycle distribution of hypoxia and progression of hypoxic tumour cells in vivo

Abstract

Summary Hypoxia was assessed in three murine tumour models in vivo by measuring the incorporation of 7-(4'-(2-nitroimidazole-1-yl)-butyl)-theophylline (NITP), an immunologically identifiable hypoxia marker that binds bioreductively to cells under low-oxygen conditions. Proliferating cells were labelled in the same tumours by administering the thymidine analogue bromodeoxyuridine (BrdUrd). The relative hypoxia in each cell cycle phase of cells isolated from tumours was assessed by addition of propidium iodide with analysis by flow cytometry. There was no relationship between tumour volume and hypoxia in either the anaplastic sarcoma SaF or the poorly differentiated carcinoma CaNT and only a slight negative correlation in moderately well-differentiated carcinoma Rh. The G1/Go phase contained the greatest number of aneuploid hypoxic cells (aneuploid hypoxia ranging from less than 1% up to 40%, 38% and 71% in SaF, CaNT and Rh respectively), although there were significant amounts of hypoxia present in S-and G/M phases for all three tumours examined. However, the highest proportion of hypoxia occurred in the G/M phase, in which up to 60% of the cells were hypoxic. Simultaneous measurement of hypoxia, proliferation and DNA content using a novel triple-staining flow cytometry method showed that hypoxic cells could actively participate in the cell cycle. In addition, the cell cycle distribution of NITP and BrdUrd labelling showed that hypoxic cells could progress through the cell cycle, although their rate of progression was slower than that of better oxygenated cells.

Multi-biomarker pattern for tumor identification and prognosis

“…These binding reactions allow that the hypoxic status be isotopically and immunologically recognizable and also detected by single photon emission tomography (SPECT) or positron emission tomography (PET) ]. Interestingly, a clear correlation between the increase in 2-nitromidazole level and the proliferation marker BrdUrd in murine mammary carcinomas has been reported; although for other murine tumor types (SaF sarcoma) such correlation does not occur [Webster et al, 1998]. The improvement in the assessment of this important parameter should help us to better understand the interaction cancer-hypoxia and their influence in the clinical response of tumors.…”

Tumor microenvironment in head and neck squamous cell carcinomas: Predictive value and clinical relevance of hypoxic markers. A review

“…Hypoxia delays progression of the tumor cell through the cell cycle, which may allow rapid repopulation under better conditions. 15 Cells that retain proliferative capacity under hypoxic conditions may therefore represent an important clonogenic subpopulation of tumor cells responsible for treatment failure.…”

Reactive Oxygen Species-independent Oxidation of Thioredoxin in Hypoxia

“…In addition, cells in G 2 /M phases have been reported to be insensitive to hypoxia (19), progressing through mitosis to G 1 , where arrest may occur. In contrast, recent in vivo studies have shown that although the greatest number of hypoxic cells reside in G 1 /G 0 phases (20), the phase of the cell cycle with the highest proportion of hypoxia was G 2 /M (20).…”