Morphological and molecular-biological features of glioblastoma progression in tolerant and susceptible to hypoxia Wistar rats

Abstract

Hypoxia is a major pathogenetic factor in many cancers. Individual resistance to suboptimal oxygen availability is subject to broad variation and its possible role in tumorigenesis remains underexplored. This study aimed at specific characterization of glioblastoma progression in male tolerant and susceptible to hypoxia Wistar rats. Hypoxia resistance was assessed by gasping time measurement in an 11,500 m altitude-equivalent hypobaric decompression chamber. Based on the outcome, the animals were assigned to three groups termed ‘tolerant to hypoxia’ (n = 13), ‘normal’, and ‘susceptible to hypoxia’ (n = 24). The ‘normal’ group was excluded from subsequent experiments. One month later, the animals underwent inoculation with rat glioblastoma 101.8 followed by monitoring of survival, body weight dynamics and neurological symptoms. The animals were sacrificed on post-inoculation days 11 (subgroup 1) and 15 (subgroup 2). Relative vessels number, necrosis areas and Ki-67 index were assessed microscopically; tumor volumes were determined by 3D reconstruction from histological images; serum levels of HIF-1α, IL-1β, and TNFα were determined by ELISA. None of the tolerant to hypoxia animals died of the disease during observation period, cf. 85% survival on day 11 and 55% survival on day 15 in the susceptible group. On day 11, proliferative activity of the tumors in the tolerant animals was higher compared with the susceptible group. On day 15, proliferative activity, necrosis area and volume of the tumors in the tolerant to hypoxia animals were higher compared with the susceptible group. ELISA revealed no dynamics in TNFα levels, elevated levels of IL-1β in the susceptible animals on day 15 in comparison with day 11 and tolerant ones. Moreover, there were elevated levels of HIF-1α in the tolerant animals on day 15 in comparison with day 11. Thus, the proliferative activity of glioblastoma cells and the content of HIF-1α were higher in tolerant to hypoxia rats, but the mortality associated with the tumor process and IL-1β level in them were lower than in susceptible animals. Specific features of glioblastoma 101.8 progression in tolerant and susceptible to hypoxia rats, including survival, tumor growth rates and IL-1β level, can become the basis of new personalized approaches for cancer diseases treatment in accordance to individual hypoxia resistance.

Morphological and Molecular Biological Characteristics of Experimental Rat Glioblastoma Tissue Strains Induced by Different Carcinogenic Chemicals

“…High levels of HIF-1α in GBMs have been associated with a poor prognosis and low overall survival [53]. In a recent study, our colleagues reported high mortality in Wistar rats susceptible to hypoxia due to the progression of GBM 101.8 and the larger size of tumors and necrosis areas in rats tolerant to hypoxia [14]. Although we did not observe an upregulation of Hif-1α in any of the three GBM 101.8, GBM 14-4-5, and GBM 11-9-2, the HIF-1α protein content was increased in GBM 101.8 according to WB data.…”

“…The GBM 101.8 strain was originally obtained by an intracranial placement of a bolus containing 1 mg of 7,12-Dimethylbenz[a]anthracene (DMBA). It is a particularly aggressive strain, which was used for investigation of chemotherapy for GBM and could be a potentially highly reliable model of human high-grade glioma [13][14][15]. Both GBM 14-4-5 and GBM 11-9-2 strains were obtained from the offspring of rats that were administered an intravenous injection of 75 µg of N-ethyl-N-nitrosourea (ENU) performed on the 20th day of pregnancy [11,12].…”

Speeding up Glioblastoma Cancer Research: Highlighting the Zebrafish Xenograft Model

“…In this way, the ECM displays ligands, such as integrins, binding tumor cells and performing mesenchymal migration [33]. Another peculiar feature of GBM is a highly hypoxic TME [34]. Indeed, hypoxia represents a hallmark of GBM, and it is associated with multiple aspects of its pathogenesis (Figure 1) [6,30].…”