Pulsation-limited oxygen diffusion in the tumour microenvironment

Milotti, E.; Stella, Sabrina; Chignola, Roberto

doi:10.1038/srep39762

Cited by 26 publications

(18 citation statements)

References 44 publications

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“…[6][7][8] . This has already allowed us to characterize new biophysical properties of tumors and of their microenvironment [34][35][36][37] , but the program still contains an excindingly simplified description of how cells control their intracellular pH. The program has an incremental structure, and we add new parts as soon as they are independently validated.…”

Section: Discussionmentioning

confidence: 99%

The control of acidity in tumor cells: a biophysical model

Piasentin

Milotti

Chignola

2020

Sci Rep

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Acidosis of the tumor microenvironment leads to cancer invasion, progression and resistance to therapies. We present a biophysical model that describes how tumor cells regulate intracellular and extracellular acidity while they grow in a microenvironment characterized by increasing acidity and hypoxia. the model takes into account the dynamic interplay between glucose and O 2 consumption with lactate and CO 2 production and connects these processes to H + and HCO − 3 fluxes inside and outside cells. We have validated the model with independent experimental data and used it to investigate how and to which extent tumor cells can survive in adverse micro-environments characterized by acidity and hypoxia. the simulations show a dominance of the H + exchanges in well-oxygenated regions, and of HCO − 3 exchanges in the inner hypoxic regions where tumor cells are known to acquire malignant phenotypes. the model also includes the activity of the enzyme carbonic Anhydrase 9 (CA9), a known marker of tumor aggressiveness, and the simulations demonstrate that CA9 acts as a nonlinear pH i equalizer at any O 2 level in cells that grow in acidic extracellular environments.

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Section: Discussionmentioning

confidence: 99%

The control of acidity in tumor cells: a biophysical model

Piasentin

Milotti

Chignola

2020

Sci Rep

Self Cite

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“…An adaptive, key hallmark of cancer is the tumor's capacity to accommodate to changeable states of oxygen deprivation. As oxygen content regulation is essential to maintaining cell homeostasis, small deviations in oxygen level in the TME can result in major changes in tumor cell functionality (34,(58)(59)(60). Physiological oxygen levels in solid tumors are very heterogeneous ranging from 0.5 -4% oxygen saturation compared to 4 -14% in healthy tissues (59,(61)(62)(63).…”

Section: Discussionmentioning

confidence: 99%

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Bhattacharya

Calar

Evans

et al. 2019

Preprint

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Oxygen deprivation within tumors is one of the most prevalent causes of resilient cancer cell survival and increased immune evasion in breast cancer (BCa). Current in vitro models do not adequately mimic physiological oxygen levels relevant to breast tissue and its tumor-immune interactions. Here, we propose an approach to engineer a three-dimensional (3D) model (named 3D engineered oxygen, 3D-O) that supports growth of BCa cells and generates physio-and pathophysiological oxygen levels. Low oxygen-induced changes within the 3D-O model supported known tumor hypoxia characteristics such as reduced BCa cell proliferation, increased extracellular matrix protein expression, increased extracellular vesicle secretion and enhanced immune surface marker expression on BCa cells. We further demonstrated that low oxygeninduced changes mimicked tumor-immune interactions leading to immune evasion mechanisms. CD8+ T cell infiltration was significantly impaired under pathophysiological oxygen levels andwe were able to establish that hypoxia inhibition re-sensitize BCa cells to cytotoxic CD8+ T cells.Therefore, our novel 3D-O model could serve as a promising platform for the evaluation of immunological events and as a drug-screening platform tool to overcome hypoxia-driven immune evasion.

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“…In our study, the human hypoxia status was effectively improved by inhaling oxygen continuously. This method may successfully increase the oxygen supply to the tumor and its surrounding microenvironment 24 , 25 . The SpO2 decline of most volunteers during rest may be explained by the changes in blood SpO2 that could delay the actual physiological level of the normal tissues because of the oxygen and carbon dioxide diffusion times.…”

Section: Discussionmentioning

confidence: 99%

Study of an Oxygen Supply and Oxygen Saturation Monitoring System for Radiation Therapy Associated with the Active Breathing Coordinator

Gong

Guo

Sun

et al. 2018

Sci Rep

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In this study, we designed an oxygen supply and oxygen saturation monitoring (OSOSM) system. This OSOSM system can provide a continuous supply of oxygen and monitor the peripheral capillary oxygen saturation (SpO2) of patients who accept radiotherapy and use an active breathing coordinator (ABC). A clinical test with 27 volunteers was conducted. The volunteers were divided into two groups based on the tendency of SpO2 decline in breath-holding without the OSOSM system: group A (12 cases) showed a decline in SpO2 of less than 2%, whereas the decline in SpO2 in group B (15 cases) was greater than 2% and reached up to 6% in some cases. The SpO2 of most volunteers declined during rest. The breath-holding time of group A without the OSOSM system was significantly longer than that of group B (p < 0.05) and was extended with the OSOSM system by 26.6% and 27.85% in groups A and B, respectively. The SpO2 recovery time was reduced by 36.1%, and the total rest time was reduced by 27.6% for all volunteers using the OSOSM system. In summary, SpO2 declines during breath-holding and rest time cannot be ignored while applying an ABC. This OSOSM system offers a simple and effective way to monitor SpO2 variation and overcome SpO2 decline, thereby lengthening breathholding time and shortening rest time.Breathing motion is a critical factor that affects the accuracy of radiotherapy for thoracic and abdominal cancers; it can induce errors in tumor localization, treatment planning design, patient setup and dose delivery 1 . These errors can result in uncertain doses of radiation to the target tumor volume and organs at risk (OARs), which increases the risks of treatment failure and of radiation injury to OARs. Thus, it is important to solve problems involving breathing motion in the context of thoracoabdominal tumor radiation therapy. Breathing motion management methodologies (e.g., active breathing control, breath gating, and abdominal compression) have played important roles in decreasing the motion effect on radiotherapy precision 2 . Active breathing coordinator TM (ABC; Elekta Oncology, Crawley, UK) is an active breathing control technology that helps patients achieve and maintain their breath-holding status for up to 30 s or even longer through a special pipe. Theoretically, the ABC can eliminate the errors affecting tumor target volume position and the dose delivery induced by the breathing motion, and it has been applied at our radiation oncology clinic for more than 18 years since it was first reported by Wong et al. in 1999 3 . Furthermore, encouraging dosimetric benefits have been obtained via the precise radiation therapy of non-small cell lung cancer (NSCLC), breast cancer, lymphoma and liver cancer [4][5][6][7][8] . Our preliminary work proposed a method that combined volumetric modulated radiation therapy with active breathing control during moderate deep-inspiration breath-holding. We demonstrated that the mean

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Pulsation-limited oxygen diffusion in the tumour microenvironment

Cited by 26 publications

References 44 publications

The control of acidity in tumor cells: a biophysical model

The control of acidity in tumor cells: a biophysical model

Bioengineering a novel 3D in-vitro model to recreate physiological oxygen levels and tumor-immune interactions

Study of an Oxygen Supply and Oxygen Saturation Monitoring System for Radiation Therapy Associated with the Active Breathing Coordinator

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