Flux analysis shows that hypoxia‐inducible‐factor‐1‐alpha minimally affects intracellular metabolism in tumor spheroids

Kim, Byoung-Jin; Forbes, Neil S.

doi:10.1002/bit.21205

Cited by 31 publications

(61 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using a mathematical model of cancer cell metabolism, we previously predicted that the absence of a carbon nutrients would similarly induce death 17 . Supporting this prediction, we have shown that the primary oxygen-responsive transcription factor, HIF-1α, does not affect metabolism in the absence of glucose 18 . In spheroids, the presence of central hypoxia depends on cell type 19 .…”

Section: Introductionsupporting

confidence: 57%

“…4) suggests that glutamine was primarily utilized for biosynthesis. This explanation is supported by isotopic labeling experiments that showed that cancer cells predominantly use glutamine for biosynthesis 18, 48 . Glutamate was not consumed (Fig.…”

Section: Discussionmentioning

confidence: 84%

“…One link between them is the metabolism of lactate. In the absence of oxygen, glucose is consumed and converted into lactate 28 . However, if substantial oxygen is present, both glucose and lactate can be consumed and converted into carbon dioxide by the TCA cycle 29 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture

2014

Self Cite

View full text Add to dashboard Cite

The spatial arrangement of cellular metabolism in tumor tissue critically affects the treatment of cancer. However, little is known about how diffusion and cellular uptake relate to intracellular metabolism and cell death in three-dimensions. To quantify these mechanisms, fluorescent microscopy and multicellular tumor cylindroids were used to measure pH and oxygen profiles, and quantify the distribution of viable, apoptotic and necrotic cells. Spheroid dissociation, enzymatic analysis, and mass spectrometry were used to measure concentration profiles of glucose, lactate and glutamine. A mathematical model was used to integrate these measurements and calculate metabolic rate parameters. It was found that large cylindroids, >500μm in diameter, contained apoptotic and necrotic cells, whereas small cylindroids contained apoptotic but not necrotic cells. The center of cylindroids was found to be acidic but not hypoxic. From the edge to the center, concentrations of glucose, lactate and glutamine decreased rapidly. Throughout the cell masses lactate was consumed and not produced. These measurements indicate that apoptosis was the primary mechanism of cell death; acidity was not caused by lactic acid; and cell death was caused by depletion of carbon sources and not hypoxia. The mathematical model showed that the transporter enzymes for glucose and lactate were not saturated; oxygen uptake was limited by intracellular metabolism; and oxygen uptake was not limited by membrane-transport or diffusion. Unsaturated transmembrane uptake may be the cause of both proliferative and apoptotic regimes in cancer. These results suggest that transporter enzymes are excellent targets for treating well oxygenated tumors.

show abstract

Section: Introductionsupporting

confidence: 57%

Section: Discussionmentioning

confidence: 84%

See 1 more Smart Citation

Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture

2014

Self Cite

View full text Add to dashboard Cite

show abstract

“…112 Tumor cylindroids are tumor spheroids which have been sandwiched between two parallel surfaces as seen in Figure 11(F). 330 While tumor spheroids allow for 3D diffusion, tumor cylindroids are constrained to only permit radial diffusion from the exterior edge of the structure, thus simplifying analysis. Kim et al showed that positively charged gold NPs are taken up better by tumor cells than negatively charged particles in tumor cylindroids, but that negatively charged particles penetrate deeper into tumor tissue.…”

Section: Multicell Flow-based Assaysmentioning

confidence: 99%

Testing Nanoparticles for Angiogenesis-Related Disease: Charting the Fastest Route to the Clinic

Sarsons¹,

Tekrony²,

Yaehne³

et al. 2014

j biomed nanotechnol

View full text Add to dashboard Cite

Recently, nanoparticles (NPs) have been established as ideal drug delivery vehicles for treating cancer. This is due to the enhanced permeability and retention (EPR) effect that is a direct result of the angiogenic nature of the tumor tissue and its ability to sequester chemotherapeutics from healthy tissues. Ideal drug delivery nanocarriers will exploit the EPR effect, accumulate in the tumorous tissue, and be able to release the drugs at a high concentration where needed, thereby reducing undesirable side effects. In order to determine ideal NP qualities that enable drugs to be delivered in such a manner, extensive testing in biological systems is required. However, it is impractical to study new potential nanocarriers in humans or in mammalian models due to the potential adverse consequences, low throughput, and high cost. Simpler models would allow for higher throughput screening of nanocarrier vehicles. This review outlines the most recent advances in alternative model assays and their significance in testing NPs en route to the clinic. In decreasing complexity, we examine zebrafish embryos, the chorioallantoic membrane of the chicken embryo, multicell static and flow-based assays, and single cell assays for efficacy, accuracy and utility as predictors for human therapeutic outcomes.

show abstract

“…The ratio of various nutrients consumed via different pathways is, in fact, the result of the shift of cellular metabolic status. Particularly, in recent years, there have been a great deal of scientific reports concerning the distribution of metabolic flux, and the regulation of metabolism at genetic and cellular levels [36,37]. Therefore, there is likely to be a substantial breakthrough for the realization of the optimization of an animal cell cultivation process with regulation and control of relevant parameters through the study of multiparameters transducer technology and the data acquisition system of a computer [38,39]; taking the metabolic flux determination as a target, we may achieve such a great breakthrough in the optimization of bioprocess.…”

Section: Study On Bioreactor Process By Integration Of the Flow Fieldmentioning

confidence: 99%

Bioreactors and Bioseparation

Zhang

Cao

Chu

et al. 2010

Biotechnology in China II

View full text Add to dashboard Cite

Along with the rapid development of life science, great attention has been increasingly given to the biotechnological products of cell cultivation technology. In the course of industrialization, bioreactor and bioproduct separation techniques are the two essential technical platforms. In this chapter, the current situation and development prospects of bioreactor techniques in China are systematically discussed, starting with the elucidation of bioreactor processes and the principle of process optimization. Separation technology for biological products is also briefly introduced.At present, a series of bioreactors made by Chinese enterprises have been widely used for laboratory microbial cultivation, process optimization studies, and large-scale production. In the course of bioprocess optimization studies, the complicated bioprocesses in a bioreactor could be resolved into different reaction processes on three scales, namely genetic, cellular, and bioreactor scales. The structural varieties and nonlinear features of various scales of bioprocess systems was discussed through considering the mutual effects of different scale events, namely material flux, energy flux, and information flux, and the optimization approach for bioprocesses was proposed by taking the analysis of metabolic flux and multiscale consideration as a core strategy.In order to realize such an optimization approach, a bioreactor system based on association analysis of multiscale parameters was elaborated, and process optimization of many biological products were materialized, which resulted in great improvement in production efficiency. In designing and manufacturing large-scale bioreactors, the principle of scaling up a process incorporated with flow field study and physiological features in a bioreactor was suggested according to the criterion for the scale-up of cellular physiological and metabolic traits. The flow field features of a bioreactor were investigated through computational fluid dynamics (CFD), and the design of a bioreactor configuration was carried out depending on multiscale studies of parameters correlation in a bioprocess. With respect to the development trend of bioreactor studies in China, the significance of the development of microbioreactors for high throughput strain screening and large-scale bioreactors for animal cell cultivation were put forward. Finally, the importance of studies of systems biology for bioprocesses based on bioinformation processing was raised, and the necessity of establishing a bioprocess information database and local area network (LAN) were emphasized as well.Bioseparation engineering plays a key role in biotechnology production. At present, many difficulties need to be resolved in the area. Scientists of China have made considerable progress in bioseparation engineering. This progress includes chromatography media, recycling aqueous two-phase systems (ATPS), affinity precipitation, molecular imprinting, renaturation and modification of proteins, protein fractionation using ultrafiltration (UF), i...

show abstract

Flux analysis shows that hypoxia‐inducible‐factor‐1‐alpha minimally affects intracellular metabolism in tumor spheroids

Cited by 31 publications

References 41 publications

Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture

Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture

Testing Nanoparticles for Angiogenesis-Related Disease: Charting the Fastest Route to the Clinic

Bioreactors and Bioseparation

Contact Info

Product

Resources

About