Tumors exposed to acute cyclic hypoxia show increased vessel density and delayed blood supply

Gaustad, Jon Vidar; Simonsen, Trude G.; Roa, A.M. Acosta; Rofstad, Einar K.

doi:10.1016/j.mvr.2012.11.002

Cited by 21 publications

(14 citation statements)

References 28 publications

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“…The vascular morphology was observed by transillumination and the blood flow was assessed thanks to the intravenous injection of isothiocyanate-labeled dextran. Results showed that cycling hypoxia treatment increased the vessel density notably by increasing the number of small vessels as well as decreased the interstitial distances, but paradoxically cycling hypoxia delayed blood supply, compared to control tumors [70]. These findings thus evidenced that cycling hypoxia favors angiogenesis that aggravates the poor functionality of the tumor blood network and hence contributes to a vicious cycle of chronic and cycling hypoxia occurrence.…”

Section: Cycling Hypoxia and Angiogenesismentioning

confidence: 86%

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Cycling hypoxia: A key feature of the tumor microenvironment

Michiels

Tellier

Feron

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

183

179

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Section: Cycling Hypoxia and Angiogenesismentioning

confidence: 86%

“…More recently, Gaustad et al [70] investigated the effects of cycling hypoxia on tumor vasculature in A-07 human melanoma xenografts using dorsal window chambers. Cycling hypoxia treatment was 12 cycles/day of 10 min 8 % O 2 breathing followed by 10 min air applied daily along tumor growth (9 days).…”

Section: Cycling Hypoxia and Angiogenesismentioning

confidence: 99%

Cycling hypoxia: A key feature of the tumor microenvironment

Michiels

Tellier

Feron

2016

Biochimica et Biophysica Acta (BBA) - Reviews on Cancer

183

179

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“…For this reason, it is reasonable to assume that sunitinib, as a type I TKI, has a greater number of off-target effects compared to some of the more specific TKIs categorized as type II, such as sorafenib and imatinib. This may help explain some contrasting effects observed in different cell lines following TKI therapy [ 33 , 47 , 51 – 53 ].…”

Section: Discussionmentioning

confidence: 99%

Detecting functional changes with [18F]FAZA in a renal cell carcinoma mouse model following sunitinib therapy

Chapman

Jans

et al. 2014

EJNMMI Res

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BackgroundThe multitargeting tyrosine kinase inhibitor (TKI) sunitinib is currently the first-line drug therapy for metastasizing renal cell carcinoma (RCC). TKIs have profound effects on tumor angiogenesis, leading to modifications of the tumor microenvironment. The goal of this study was to determine whether these treatment-induced changes can be detected with [18F]FAZA.MethodsThe present study utilized positron emission tomography (PET) to analyze tumor oxygenation status during and after sunitinib therapy in the murine Caki-1 RCC tumor model. Dynamic and static scans were performed, as well as ex vivo biodistributions at 3 h post injection (p.i.). Immunohistochemical analysis of tumor tissue was carried out for the quantification of pimonidazole binding and the hypoxia-associated factors CD-31, Ki-67, and Von Willebrand factor (VWF). In addition, in vitro cellular uptake studies were done to analyze the direct effects of sunitinib on the Caki-1 cells.ResultsDuring therapy with sunitinib (40 mg/kg/day), uptake of [18F]FAZA into Caki-1 mice decreased by 46 ± 5% (n = 4; 5 days) at 3 h post injection (p.i.) during the first study and 22 ± 5% (n = 8; 9 days) during the long-term study, indicating a decrease in the tumor's hypoxia level. However, when drug therapy was stopped, this effect was reversed completely, and the tumor [18F]FAZA uptake increased to 126 ± 6% (n = 6) of the control tumor uptake, indicative of an even higher level of tumor hypoxia compared to the therapy starting point. Sunitinib had no direct effect on [18F]FAZA uptake into Caki-1 cells in vitro.Conclusion[18F]FAZA PET could be used to monitor drug response during sunitinib therapy in RCC and may guide combination therapies based on the tumor's hypoxia status.

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“…For example, under IH, cancer cells have shown to display greater metastasis in mouse models of human cancers, as compared to chronic hypoxia [ [203] , [204] , [205] ]. IH has been shown to increase angiogenesis [ [206] , [207] , [208] , [209] ] and the survival of endothelial cells under proapoptotic stimuli with enhanced migration and tubulogenesis in a HIF-1α-dependent manner [ 206 , 207 ]. Similarly, IH has been shown to increase stem-like properties in breast cancer and neuroblastoma cells [ 210 , 211 ].…”

Section: Hypoxiamentioning

confidence: 99%

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

Saxena

Jolly

Balamurugan

2020

Translational Oncology

153

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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Tumors exposed to acute cyclic hypoxia show increased vessel density and delayed blood supply

Cited by 21 publications

References 28 publications

Cycling hypoxia: A key feature of the tumor microenvironment

Cycling hypoxia: A key feature of the tumor microenvironment

Detecting functional changes with [18F]FAZA in a renal cell carcinoma mouse model following sunitinib therapy

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

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