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. 2023 Aug 4;13(1):12694.
doi: 10.1038/s41598-023-39914-9.

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

D Sh Dzhalilova  1 , N A Zolotova  2 , V A Mkhitarov  2 , A M Kosyreva  2   3 , I S Tsvetkov  2 , A S Khalansky  2 , A I Alekseeva  2 , T H Fatkhudinov  2   3 , O V Makarova  2
Affiliations

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

D Sh Dzhalilova et al. Sci Rep. .

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.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Survival curves for tolerant and susceptible to hypoxia rats, inoculated with GBM 101.8 on day 0.
Figure 2
Figure 2
Morphological characterization of GBM 101.8 brain tumors in tolerant (a, c) and susceptible (b, d) to hypoxia rats on post-inoculation days 11 and 15. (a) tumor with atypical cell morphology sprouting the lateral ventricle wall; and hemorrhage foci; (b, c) tumors with palisade arrangement of atypical cells and massive necrosis; (d) tumor with atypical cell morphology and hemorrhage. The inserts show tumor cell polymorphism and atypia. Staining—H&E.
Figure 3
Figure 3
Representative 3D models (a) and estimated volume (b) of GBM 101.8 brain tumors in tolerant and susceptible to hypoxia rats on post-inoculation days 11 and 15. Me (IQR); p—statistically significant differences, Kruskal–Wallis method with Dunn's post-hoc test and Mann–Whitney test for tolerant and susceptible to hypoxia animals comparison. In all groups there were minimum 5 observations.
Figure 4
Figure 4
Proliferative activity of the tumors in tolerant and susceptible to hypoxia rats on post-inoculation days 11 and 15. (a) Ki-67 index boxplot; p—statistically significant differences, Kruskal–Wallis method with Dunn's post-hoc test and Mann–Whitney test for tolerant and susceptible to hypoxia animals comparison, %—Ki-67 + from total cells number. (b) representative immunostaining for Ki-67 (green) on post-inoculation day 11, cell nuclei counterstained with DAPI (blue). In all groups there were minimum 5 observations.
Figure 5
Figure 5
Serum levels of IL-1β in tolerant and susceptible to hypoxia rats on post-inoculation days 11 and 15; p—statistically significant differences, Kruskal–Wallis method with Dunn’s post-hoc test and Mann–Whitney test for tolerant and susceptible to hypoxia animals comparison. In all groups there were minimum 5 observations.
Figure 6
Figure 6
Serum levels of HIF-1α in tolerant and susceptible to hypoxia rats on post-inoculation days 11 and 15; p—statistically significant differences, Kruskal–Wallis method with Dunn’s post-hoc test and Mann–Whitney test for tolerant and susceptible to hypoxia animals comparison. In all groups there were minimum 5 observations.
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