Transiently hypoxic tumour cell turnover and radiation sensitivity in human tumour xenografts

Wadsworth, Brennan J.; Lee, Che-Min; Bennewith, Kevin L.

doi:10.1038/s41416-021-01691-5

Cited by 9 publications

(9 citation statements)

References 75 publications

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“…Only NF-κB was upregulated in CAFs activated by TGFβ ( Supplementary Table S1 ). Tumors with high proportion of hypoxic cells have worse therapeutic outcome linked both to surgery and radiation, and patients with hypoxic tumors have increased risk for metastases and worse overall survival ( Wadsworth et al, 2022 ). Hypoxia has previously been linked to IL-1 induced iCAFs ( Biffi et al, 2019 ; Schwörer et al, 2023 ).…”

Section: Discussionmentioning

confidence: 99%

Extracellular vesicles promote activation of pro-inflammatory cancer-associated fibroblasts in oral cancer

Arebro,

Towle,

Lee

et al. 2023

Front. Cell Dev. Biol.

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Introduction: Oral squamous cell carcinoma (OSCC) is the most common form of head and neck cancer and has a survival rate of ∼50% over 5 years. New treatment strategies are sorely needed to improve survival rates—and a better understanding of the mechanisms underlying tumorigenesis is needed to develop these strategies. The role of the tumor microenvironment (TME) has increasingly been identified as crucial in tumor progression and metastasis. One of the main constituents of the TME, cancer-associated fibroblasts (CAFs), plays a key role in influencing the biological behavior of tumors. Multiple mechanisms contribute to CAF activation, such as TGFβ signaling, but the role of extracellular vesicles (EVs) in CAF activation in OSCC is poorly understood. Assessing the impact of oral cancer-derived EVs on CAF activation will help to better illuminate OSCC pathophysiology and may drive development of novel treatments options.Methods: EVs were isolated from OSCC cell lines (Cal 27, SCC-9, SCC-25) using differential centrifugation. Nanoparticle tracking analysis was used for EV characterization, and Western blot to confirm the presence of EV protein markers. Oral fibroblasts were co-cultured with enriched EVs, TGFβ, or PBS over 72 h to assess activation. Flow cytometry was used to evaluate CAF markers. RNA collected from fibroblasts was extracted and the transcriptome was sequenced. Conditioned media from the co-cultures was evaluated with cytokine array profiling.Results: OSCC-derived EVs can activate oral fibroblasts into CAFs that are different from those activated by TGFβ, suggesting different mechanisms of activation and different functional properties. Gene set enrichment analysis showed several upregulated inflammatory pathways in those CAFs exposed to OSCC-derived EVs. Marker genes for inflammatory CAF subtypes were also upregulated, but not in CAFs activated by TGFβ. Finally, cytokine array analysis on secreted proteins revealed elevated levels of several pro-inflammatory cytokines from EV-activated CAFs, for instance IL-8 and CXCL5.Discussion: Our results reveal the ability of OSCC-derived EVs to activate fibroblasts into CAFs. These CAFs seem to have unique properties, differing from TGFβ-activated CAFs. Gaining an understanding of the interplay between EVs and stromal cells such as CAFs could lead to further insights into OSCC tumorigenesis and potential novel therapeutics.

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Section: Discussionmentioning

confidence: 99%

Extracellular vesicles promote activation of pro-inflammatory cancer-associated fibroblasts in oral cancer

Arebro,

Towle,

Lee

et al. 2023

Front. Cell Dev. Biol.

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“…Chronic (diffusion-limited) hypoxia prevents oxygen from diffusing into cells that have been pushed too far away (>70–100 μm) from blood vessels due to the proliferation of tumor cells [ 24 ]. As these cells experience hypoxia, their ability to proliferate diminishes, and they start to localize in areas of necrosis [ 25 ]. Cycling or transient (perfusion-limited) hypoxia occurs when blood flow is suddenly halted for a varying degree of time [ 23 ].…”

Section: Cancer Angiogenesis and The Tmementioning

confidence: 99%

“…Cycling or transient (perfusion-limited) hypoxia occurs when blood flow is suddenly halted for a varying degree of time [ 23 ]. As transiently hypoxic tumor cells still undergo HIF-1-induced gene expression changes, including increases in migration-related genes, these cells are poised to move into the blood vessel at the moment when functional blood vessel perfusion occurs [ 25 , 26 ]. Thus, transient hypoxia in the tumor is of concern for tumor cell migration and metastasis, and normalizing TV is thought to prevent the development of transient hypoxia.…”

Section: Cancer Angiogenesis and The Tmementioning

confidence: 99%

Induced Vascular Normalization—Can One Force Tumors to Surrender to a Better Microenvironment?

Sun

Nosrati²,

Ko³

et al. 2023

Pharmaceutics

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Immunotherapy has changed the way many cancers are being treated. Researchers in the field of immunotherapy and tumor immunology are investigating similar questions: How can the positive benefits achieved with immunotherapies be enhanced? Can this be achieved through combinations with other agents and if so, which ones? In our view, there is an urgent need to improve immunotherapy to make further gains in the overall survival for those patients that should benefit from immunotherapy. While numerous different approaches are being considered, our team believes that drug delivery methods along with appropriately selected small-molecule drugs and drug candidates could help reach the goal of doubling the overall survival rate that is seen in some patients that are given immunotherapeutics. This review article is prepared to address how immunotherapies should be combined with a second treatment using an approach that could realize therapeutic gains 10 years from now. For context, an overview of immunotherapy and cancer angiogenesis is provided. The major targets in angiogenesis that have modulatory effects on the tumor microenvironment and immune cells are highlighted. A combination approach that, for us, has the greatest potential for success involves treatments that will normalize the tumor’s blood vessel structure and alter the immune microenvironment to support the action of immunotherapeutics. So, this is reviewed as well. Our focus is to provide an insight into some strategies that will engender vascular normalization that may be better than previously described approaches. The potential for drug delivery systems to promote tumor blood vessel normalization is considered.

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“…It takes time for 2-nitroimidazoles to bind in hypoxic cells in sufficient quantities to elicit an increase in antibody binding intensity and for HIF-regulated proteins to be transcribed and translated in hypoxic cells. Furthermore, 2-nitroimidazole drug adducts that form in hypoxic cells can be quite stable over time in the absence of proliferation (31,32), and the lifetime of hypoxia-induced proteins such as CA9 can be on the order of days (33,34). Biological hypoxia markers therefore do not provide real-time indications of hypoxia in vitro or in vivo and instead reflect the hypoxic history of cells.…”

Section: Biological Readouts Of Oxygen Levelmentioning

confidence: 99%

Oxygen Measurement in Microdevices

Grist

Bennewith²,

Cheung

2022

Annual Rev. Anal. Chem.

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Oxygen plays a fundamental role in respiration and metabolism, and quantifying oxygen levels is essential in many environmental, industrial, and research settings. Microdevices facilitate the study of dynamic, oxygen-dependent effects in real time. This review is organized around the key needs for oxygen measurement in microdevices, including integrability into microfabricated systems; sensor dynamic range and sensitivity; spatially resolved measurements to map oxygen over two- or three-dimensional regions of interest; and compatibility with multimodal and multianalyte measurements. After a brief overview of biological readouts of oxygen, followed by oxygen sensor types that have been implemented in microscale devices and sensing mechanisms, this review presents select recent applications in organs-on-chip in vitro models and new sensor capabilities enabling oxygen microscopy, bioprocess manufacturing, and pharmaceutical industries. With the advancement of multiplexed, interconnected sensors and instruments and integration with industry workflows, intelligent microdevice-sensor systems including oxygen sensors will have further impact in environmental science, manufacturing, and medicine.

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Transiently hypoxic tumour cell turnover and radiation sensitivity in human tumour xenografts

Cited by 9 publications

References 75 publications

Extracellular vesicles promote activation of pro-inflammatory cancer-associated fibroblasts in oral cancer

Extracellular vesicles promote activation of pro-inflammatory cancer-associated fibroblasts in oral cancer

Induced Vascular Normalization—Can One Force Tumors to Surrender to a Better Microenvironment?

Oxygen Measurement in Microdevices

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