Accelerated tumor growth under intermittent hypoxia is associated with hypoxia-inducible factor-1-dependent adaptive responses to hypoxia

Yoon, Dae Wui; So, Daeho; Min, Sra; Kim, Jiyoung; Lee, Mingyu; Khalmuratova, Roza; Cho, Chung Hyun; Park, Jong-Wan; Shin, Hyun Woo

doi:10.18632/oncotarget.18644

Cited by 32 publications

(21 citation statements)

References 45 publications

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“…Hypoxia has been shown to be involved in the induction of EMT, drug resistance and metastasis [ 50 ]. Intermittent or cyclic hypoxia – believed to be the most commonly observed scenario in a tumor – has been shown to accelerate tumor growth through cellular adaptation driven by HIF-1α [ 51 ]. Hypoxia can push cells towards a partial EMT [ 52 , 53 ]; however, a better mapping of different extents of hypoxia in terms of duration and/or oxygen concentration with corresponding EMT phenotypes attained remains to be done.…”

Section: Introductionmentioning

confidence: 99%

Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis

Saxena

Jolly

Balamurugan

2020

Translational Oncology

141

112

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Epithelial-mesenchymal transition (EMT) is a cellular biological process involved in migration of primary cancer cells to secondary sites facilitating metastasis. Besides, EMT also confers properties such as stemness, drug resistance and immune evasion which can aid a successful colonization at the distant site. EMT is not a binary process; recent evidence suggests that cells in partial EMT or hybrid E/M phenotype(s) can have enhanced stemness and drug resistance as compared to those undergoing a complete EMT. Moreover, partial EMT enables collective migration of cells as clusters of circulating tumor cells or emboli, further endorsing that cells in hybrid E/M phenotypes may be the ‘fittest’ for metastasis. Here, we review mechanisms and implications of hybrid E/M phenotypes, including their reported association with hypoxia. Hypoxia-driven activation of HIF-1α can drive EMT. In addition, cyclic hypoxia, as compared to acute or chronic hypoxia, shows the highest levels of active HIF-1α and can augment cancer aggressiveness to a greater extent, including enriching for a partial EMT phenotype. We also discuss how metastasis is influenced by hypoxia, partial EMT and collective cell migration, and call for a better understanding of interconnections among these mechanisms. We discuss the known regulators of hypoxia, hybrid EMT and collective cell migration and highlight the gaps which needs to be filled for connecting these three axes which will increase our understanding of dynamics of metastasis and help control it more effectively.

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Section: Introductionmentioning

confidence: 99%

Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis

Saxena

Jolly

Balamurugan

2020

Translational Oncology

141

112

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“…Further study should be focused on the combined effects of endostatin plus chemotherapy or radiotherapy in OSA-mimicking animal or patients. Finally, as previous studies showed [14][15][16], the IH exposure time was relatively short in our current study (5 weeks); ongoing study is required to figure out the effect of long-term IH exposure on tumor mice.…”

Section: Discussionmentioning

confidence: 85%

“…As a novel pathophysiological feature of OSA, IH is closely correlated with tumor [11,12]. Both in vivo and in vitro studies confirmed that IH promotes various tumor growth, migration, invasiveness, and metastasis [13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 76%

“…Increasing attention has been paid to illustrating the exact relationship between IH and tumor [11,12]. Almendros et al [13] and Yoon et al [31] demonstrated that IH facilitates tumor growth. Meanwhile, the previous studies both in vivo and in vitro also prove that IH induces migration and metastasis in different types of tumor [15][16][17][18].…”

Section: Discussionmentioning

confidence: 99%

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Anti-tumor effect of endostatin in a sleep-apnea mouse model with tumor

et al. 2018

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Background Obstructive sleep apnea (OSA) is associated with cancer incidence and mortality. The underlying mechanism is unclear. This study aims to evaluate the influence of intermittent hypoxia (IH), a novel hallmark of OSA, on tumor and to access the anti-tumor effect of endostatin on a mouse model with OSA. Methods The C57BL/6 J mice were randomly classified into four groups: control (normoxia) (CTL), control plus endostatin (CTL + ED), IH, and IH plus endostatin (IH + ED). Mice in IH and IH + ED groups were subjected to IH 8 h per day in 5 weeks. Lewis lung cancer cells were injected into the flank of each mouse after 1 week of IH exposure. Endostatin was also intraperitoneally injected after tumor volume reached about 200 mm 3. The maximum standard uptake values (SUVmax) were detected by micro-positron emission tomography-computed tomography (micro-PET-CT) imaging prior and postendostatin administration. Microvessel density (MVD) and vascular endothelial growth factor (VEGF) were determined for evaluating the anti-tumor effect of endostatin among the normoxia and IH conditions. Results Mice had higher SUVmax in the IH group than the CTL group (p < 0.01). When compared with mice in the CTL group, those in the IH group had significantly greater MVD values (p < 0.001). The SUVmax can be attenuated by endostatin both in the CTL (p < 0.01) and IH conditions (p < 0.001). When compared with CTL group, mice in the IH group had increased MVD values (p < 0.001) and VEGF expression both at mRNA (p < 0.05) and protein levels (p < 0.001 in western blotting results). Treatment with endostatin attenuated serum and tissue VEGF levels, lowering the MVD values. As compared to normoxia condition, the endostatin-therapeutic effects were more significant under the IH condition (p < 0.05 in western blotting results). Conclusions Micro-PET-CT imaging is a promising non-invasive technique to evaluate the tumor metabolic characteristics under IH condition in vivo. The anti-tumor effect of endostatin under IH condition is superior to that of the normoxia condition.

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“…Other studies have demonstrated that CIH is associated with accelerated tumor growth, migration and metastasis in different types of malignancies including malignant melanoma, breast cancer and prostate cancer [25][26][27][28][29] . Our results were consistent with those studies.…”

Section: Discussionmentioning

confidence: 98%

Intermittent hypoxia exacerbates tumor progression in a mouse model of lung cancer

Kang

Kwon

Kim

et al. 2020

Sci Rep

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the purpose of this study was to evaluate whether obstructive sleep apnea (oSA)-related chronic intermittent hypoxia (CIH) influences lung cancer progression and to elucidate the associated mechanisms in a mouse model of lung cancer. C57/BL6 mice in a CIH group were exposed to intermittent hypoxia for two weeks after tumor induction and compared with control mice (room air). Hypoxia inducible factor 1α (HIF-1α), vascular endothelial growth factor (VeGf) and metastasis-related matrix metalloproteinases (MMp) were measured. the expression levels of several hypoxia-related pathway proteins including HIF-1α, Wnt/ß-catenin, the nuclear factor erythroid 2-related factor 2 (Nrf2) and mammalian target of rapamycin-eRK were measured by western blot. the number (p < 0.01) and volume (p < 0.05) of tumors were increased in the CIH group. The activity of MMP-2 was enhanced after CIH treatment. The level of VEGF was increased significantly in the CIH group (p < 0.05). ß-catenin and Nrf2 were translocated to the nucleus and the levels of downstream effectors of Wnt/ß-catenin signaling increased after iH exposure. ciH enhanced proliferative and migratory properties of tumors in a mouse model of lung cancer. ß-catenin and Nrf2 appeared to be crucial mediators of tumor growth. Obstructive sleep apnea (OSA) is characterized by recurrent occlusion of the upper airway during sleep leading to chronic intermittent hypoxia (CIH). OSA is a highly prevalent sleep disorder affecting at least 3% to 7% of the adult population 1. OSA has been shown to be associated with morbidities including metabolic syndrome, systemic hypertension, pulmonary vascular disease, ischemic heart disease and congestive heart failure 2. In addition, OSA-related CIH has been suggested to affect tumor development and progression 3. OSA has been implicated in the increasing incidence of certain types of solid malignancies. In a Spanish cohort, increased overnight hypoxia as a surrogate of OSA severity was associated with increased cancer incidence in selected populations 4-6. Also, OSA was associated with increased cancer mortality in a community-based sample 7. The association between OSA and lung cancer has been evaluated. OSA-related CIH induced resistance to apoptosis and increased metastasis in lung cancer cells, in a manner related to hypoxia inducible factor 1α (HIF-1α) 8. The role of immune cells has been suggested as a potential mechanism linking OSA and cancer. Almendros et al. demonstrated that CIH induced changes in host immune responses are related to adverse cancer outcomes. CIH increases the mobilization of tumor-associated macrophages (TAMs) into tumors, and induces macrophages to transform from an anti-tumor phenotype (M1) to a tumor-promoting phenotype (M2) 9. Cyclooxygenase-2 inhibited IH-induced M2 polarization of TAMs and prevented IH-induced adverse tumor outcomes in a mouse model of sleep apnea 10. OSA-related CIH altered CD8 + T-cells in combination with changes in the tumor microenvironment that enhanced malignant tumor properties 11. Studies...

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Accelerated tumor growth under intermittent hypoxia is associated with hypoxia-inducible factor-1-dependent adaptive responses to hypoxia

Cited by 32 publications

References 45 publications

Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis

Hypoxia, partial EMT and collective migration: Emerging culprits in metastasis

Anti-tumor effect of endostatin in a sleep-apnea mouse model with tumor

Intermittent hypoxia exacerbates tumor progression in a mouse model of lung cancer

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