Morphological Characteristic of Melanoma B16 Progression in C57BL/6 Mice with High and Low Resistance to Hypoxia

Fridman, I A; Ponomarenko, E A; Makarova, Olga; Postovalova, Ekaterina; Золотова, Н.А.; Мхитаров, В А; Цветков, И.С.; Косырева, А. М.

doi:10.1007/s10517-020-04716-w

Cited by 9 publications

(5 citation statements)

References 11 publications

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“…To recapitulate the gradual onset and near anoxic tumor microenvironments, we developed a long-term hypoxia (LTHY) incubation protocol, where cells endure increasingly severe hypoxia after days of acclimatization ( Fig.1C ). These kinetics mimic the overall time course of tumor progression in the B16 mouse melanoma model and oxygen levels previously described in melanoma (16–18). Flow cytometry analyses of B16-HG cells during LTHY adaptation revealed partial stabilization of HIF1α-GFP at physoxia (5% O 2 ), and reached maximum stabilization at 1% O 2 and below ( Fig.1D ) (19).…”

Section: Resultssupporting

confidence: 68%

Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform

Quenneville,

Feghaly,

Tual

et al. 2023

Preprint

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The majority of cancer deaths are caused by solid tumors, where the four most prevalent cancers (breast, lung, colorectal and prostate) account for more than 60% of all cases (1). Tumor cell heterogeneity driven by variable cancer microenvironments, such as hypoxia, is a key determinant of therapeutic outcome. We developed a novel culture protocol, termed the Long-Term Hypoxia (LTHY) time course, to recapitulate the gradual development of severe hypoxia seenin vivo, to mimic conditions observed in primary tumors. Cells subjected to LTHY underwent a non-canonical epithelial to mesenchymal transition (EMT) based on miRNA and mRNA signatures as well as displayed EMT-like morphological changes. Concomitant to this, we report production of a novel truncated isoform of WT1 transcription factor (tWt1), a non-canonical EMT driver, with expression driven by a yet undescribed intronic promoter through hypoxia-responsive elements (HREs). We further demonstrated that tWt1 initiates translation from an intron-derived start codon, retains proper subcellular localization, DNA binding, and its human ortholog negatively predicts long-term patient survival. Our study demonstrates the importance of culture conditions that better mimic those observed in cancers, especially with regards to hypoxia, and identifies a novel isoform of WT1 which correlates with poor long-term survival in ovarian cancer.

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Section: Resultssupporting

confidence: 68%

Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform

Quenneville,

Feghaly,

Tual

et al. 2023

Preprint

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“…HIF-1α is activated in cancer cells by the loss of function of tumor suppressors (e.g., VHL or PTEN) and/or oncogene gain of function (constitutive growth factor /receptor activation [122][123][124]. Rapidly proliferating tumor cells experience chronic hypoxia and reduced O 2 availability that, in turn, induce HIF-1α, which regulates the transcription of a plethora of gene encoding proteins involved in every aspect of cancer biology including carcinogenesis, cell transformation; cell proliferation, genome instability/DNA mutation, inflammation, glucose and energy metabolism, angiogenesis, autocrine growth factor signaling, invasion, metastasis, immune evasion, stemness, and resistance to chemoand radiation therapy [105,122,[125][126][127][128][129][130][131][132][133].…”

Section: Hypoxia-inducible Factor-1 (Hif-1)mentioning

confidence: 99%

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

Ghoneum

Abdulfattah

Warren

et al. 2020

IJMS

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Reactive Oxygen Species or “ROS” encompass several molecules derived from oxygen that can oxidize other molecules and subsequently transition rapidly between species. The key roles of ROS in biological processes are cell signaling, biosynthetic processes, and host defense. In cancer cells, increased ROS production and oxidative stress are instigated by carcinogens, oncogenic mutations, and importantly, metabolic reprograming of the rapidly proliferating cancer cells. Increased ROS production activates myriad downstream survival pathways that further cancer progression and metastasis. In this review, we highlight the relation between ROS, the metabolic programing of cancer, and stromal and immune cells with emphasis on and the transcription machinery involved in redox homeostasis, metabolic programing and malignant phenotype. We also shed light on the therapeutic targeting of metabolic pathways generating ROS as we investigate: Orlistat, Biguandes, AICAR, 2 Deoxyglucose, CPI-613, and Etomoxir.

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“…Individual hypoxia resistance is not taken into account in experimental investigations. B16 melanoma progression was previously demonstrated as more pronounced in susceptible to hypoxia mice 51 . Nevertheless, since each type of tumor has its own characteristics and depends differently on the lack of oxygen, our findings indicate that tumor progression patterns in GBM, including tumor volume, systemic inflammatory response and survival, depend on individual resistance of the body to environmentally inflicted hypoxia.…”

Section: Discussionmentioning

confidence: 90%

“…However, hypoxia contributes to mutations and heterogeneity of tumors and therefore it can also play an important role in the tumor development processes 3 . Experimental models reveal some hypoxia-related patterns, notably higher rates of melanoma B16 progression in susceptible to hypoxia mice 51 , but there is no data referring brain tumors. According to the literature, the brain and internal organs differ in their resistance to lack of oxygen.…”

Section: Introductionmentioning

confidence: 99%

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

Джалилова

Золотова

Мхитаров

et al. 2023

Sci Rep

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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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Morphological Characteristic of Melanoma B16 Progression in C57BL/6 Mice with High and Low Resistance to Hypoxia

Cited by 9 publications

References 11 publications

Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform

Long-term severe hypoxia adaptation induces non-canonical EMT and a novel Wilms Tumor 1 (WT1) isoform

Redox Homeostasis and Metabolism in Cancer: A Complex Mechanism and Potential Targeted Therapeutics

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

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