Abstract
The aim of this study was to evaluate hypoxia level at various tumor developmental stages and to compare various methods of hypoxia evaluation in pre-clinical CT26 tumor model.Using three methods of hypoxia determination, we evaluated hypoxia levels during CT26 tumor development in BALB/c mice from day 4 till day 19, in 2–3 days intervals. Molecular method was based on the analysis of selected genes expression related to hypoxia (HIF1A, ANGPTL4, TGFB1, VEGFA, ERBB3, CA9) or specific for inflammation in hypoxic sites (CCL2, CCL5) at various time points after CT26 cancer cells inoculation. Imaging methods of hypoxia evaluation included: positron-emission tomography (PET) imaging using [18F]fluoromisonidazole ([18F]FMISO) and a fluorescence microscope imaging of pimonidazole (PIMO)-positive tumor areas at various time points.Our results showed that tumor hypoxia at molecular level was relatively high at early stage of tumor development as reflected by initially high HIF1A and VEGFA expression levels and their subsequent decrease. However, imaging methods (both PET and fluorescence microscopy) showed that hypoxia increased till day 14 of tumor development. Additionally, necrotic regions dominated the tumor tissue at later stages of development, decreasing the number of hypoxic areas and completely eliminating normoxic regions (observed by PET).These results showed that molecular methods of hypoxia determination are more sensitive to show changes undergoing at cellular level, however in order to measure and visualize hypoxia in the whole organ, especially at later stages of tumor development, PET is the preferred tool. Furthermore we concluded, that during development of tumor, two peaks of hypoxia occur.
Highlights
Cells become hypoxic when the oxygen demand exceeds the oxygen supply
Necrotic regions dominated the tumor tissue at later stages of development, decreasing the number of hypoxic areas and completely eliminating normoxic regions. These results showed that molecular methods of hypoxia determination are more sensitive to show changes undergoing at cellular level, in order to measure and visualize hypoxia in the whole organ, especially at later stages of tumor development, positron-emission tomography (PET) is the preferred tool
Low oxygen levels inside the tumor, or sometimes lactic acid synthesized as by-product of anaerobic glycolysis of tumor cells, stimulate expression of hypoxia-inducible factor 1α (HIF1A) transcription factor, which induce vascular endothelial growth factor (VEGFA) production, which in turn gives rise to tumor-derived angiogenesis [1,2]
Summary
Cells become hypoxic when the oxygen demand exceeds the oxygen supply. Hypoxia arises in solid tumors due to various factors. Tumor growth depends upon the host tissue-derived blood vessels; these blood vessels normally support only selected parts of the tumor tissue and for a relatively short time. Tumor blood vessels are distinct from that in normal tissue and tumor blood supply is compromised as those vessels are often elongated, dilated and twisted [1]. Low oxygen levels inside the tumor, or sometimes lactic acid synthesized as by-product of anaerobic glycolysis of tumor cells, stimulate expression of hypoxia-inducible factor 1α (HIF1A) transcription factor, which induce vascular endothelial growth factor (VEGFA) production, which in turn gives rise to tumor-derived angiogenesis [1,2]
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