Migration of vascular endothelial cells in monolayers under hypoxic exposure

Tabata, Yasuhiko; Yoshino, Daisuke; Funamoto, Kiyoe; Koens, Rei; Kamm, Roger D.; Funamoto, Kenichi

doi:10.1093/intbio/zyz002

“…HIF-1α was shown to facilitate ameboid dissemination from collective invasion strands with reduced E-cadherin levels [ 16 ]. Enhanced migration of endothelial cells under hypoxia as compared to normoxia in a microfluidic experimental setup has shown to be associated with loosening of intercellular junction resulting from reduced expression of VE-cadherin [ 256 ], consistent with reports of hypoxia involved in directed collective migration of border cells in developmental scenarios [ 257 ]. In prostate cancer cells, hypoxia induces the expression of SLUG – often associated with a partial EMT [ 34 ] – but does not lead to a complete loss of E-cadherin [ 258 ], thus possibly endorsing the hypoxia-partial EMT connection.…”

Section: Hif-1α Mediated Regulation Of Partial Emt and Collective Migsupporting

confidence: 77%

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

Saxena

¹

,

Jolly

²

,

Balamurugan

³

2020

Translational Oncology

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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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“…HIF-1α was shown to facilitate ameboid dissemination from collective invasion strands with reduced E-cadherin levels [218]. Enhanced migration of endothelial cells under hypoxia as compared to normoxia in a microfluidic experimental setup has shown to be associated with loosening of intercellular junction resulting from reduced expression of VEcadherin [220], consistent with reports of hypoxia involved in directed collective migration of border cells in developmental scenarios [221]. In prostate cancer cells, hypoxia induces the expression of SLUG -often associated with a partial EMT [17] -but does not lead to a complete loss of E-cadherin [222], thus possibly endorsing the hypoxia-partial EMT connection.…”

Section: Hif-1α Mediated Regulation Of Partial Emt and Collective Migrationmentioning

confidence: 99%

Hypoxia, Partial EMT and Collective Migration: Emerging Culprits in Metastasis

Saxena

¹

,

Jolly

²

,

Balamurugan

³

2020

Preprint

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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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“…Rodents exposed to 10% oxygen for 4 weeks but injected with melatonin showed elevated cardioprotection against myocardial injury under hypoxia by preserving sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) expression, thus improving SR Ca 2+ handling and calcium homeostasis (255). Hypoxia can increase HIF-1ɑ-mediated migration speed of endothelial cells by 1.4-fold (256). Melatonin downregulates HIF-1ɑ signaling pathways (ERK/Rac1), suppressing HIF-1ɑ expression and stabilization to prevent endothelial cell migration under hypoxic conditions (257,258).…”

Section: Melatonin Preserves Endothelial Cells Calcium Homeostasis During Hypoxiamentioning

confidence: 99%

The potential of melatonin in the prevention and attenuation of oxidative hemolysis and myocardial injury from cd147 SARS-CoV-2 spike protein receptor binding

Loh¹

2020

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The rapid escalation of pandemic health threats associated with the novel, pathogenic SARS-CoV-2 coronavirus poses unprecedented challenges as proven effective vaccines and drugs have yet to be produced. Refractory hypoxemia and myocardial injury have been observed as two of the major causes of fatality in COVID-19 patients. SARS-CoV-2 spike (S) protein binding to broadly expressed CD147 receptors on erythrocytes causes oxidative hemolysis that may result in refractory hypoxemia and myocardial injury. Both of these life-threatening conditions are further exacerbated by imbalance in ACE2 from spike (S) protein receptor binding. Dysregulation in the CD147-cyclophilin A signaling pathway, together with altered calcium signaling from SARS-CoV-2 ion channel activities, may contribute to hypercoagulation, thrombosis, and cardiac remodeling resulting in heart failure. Melatonin is an ancient pleiotropic molecule with recognized antioxidant properties that is essential for the protection of erythrocytes from oxidative hemolysis. Found in erythrocytes, melatonin can reverse hemolytic anemia, normalize heme synthesis, restore lymphocytes and platelet counts, and reduce vessel permeability during an acute hemolytic crisis by maintaining intracellular calcium homeostasis and reduction of oxidative stress. In acute hypoxic conditions, melatonin is cardioprotective via blunting of cardiopulmonary response to hypoxia and suppressing hypoxia pathways. Melatonin normalizes endothelial-dependent nitric oxide production to prevent multiple organ damage from hypercoagulability, thrombosis, and hypertension associated with oxidative hemolysis and ACE2 deficiency, protecting cardiomyocytes from hypertrophy. This review discusses the full potential of melatonin as a safe and effective therapeutic intervention for the prevention and attenuation of hemoglobinopathies, refractory hypoxemia and myocardial injury during critical COVID-19 infections.

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Migration of vascular endothelial cells in monolayers under hypoxic exposure

Cited by 23 publications

References 48 publications

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

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

Hypoxia, Partial EMT and Collective Migration: Emerging Culprits in Metastasis

The potential of melatonin in the prevention and attenuation of oxidative hemolysis and myocardial injury from cd147 SARS-CoV-2 spike protein receptor binding

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