ArticleIntegrative biology : quantitative biosciences from nano to macro2014
Rapid uptake of glucose and lactate, and not hypoxia, induces apoptosis in three-dimensional tumor tissue culture.
Article in Integrative biology : quantitative biosciences from nano to macro, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 43 citations in OpenAlex.
- 2D versus 3D tumor-on-chip models to study the impact of tumor organization on metabolic patterns in vitro.Scientific reports · 2025Article
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- Low glucose metabolite 3-phosphoglycerate switches PHGDH from serine synthesis to p53 activation to control cell fate.Cell research · 2023Article
- A three-dimensional spheroid co-culture system of neurons and astrocytes derived from Alzheimer's disease patients for drug efficacy testing.Cell proliferation · 2023Article
- Cellular Invasion Assay for the Real-Time Tracking of Individual Cells in Spheroid or Tumor-like Mimics.Analytical chemistry · 2023Article
- Metabolic flux analysis of 3D spheroids reveals significant differences in glucose metabolism from matched 2D cultures of colorectal cancer and pancreatic ductal adenocarcinoma cell lines.Cancer & metabolism · 2022Article
- Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response.Journal of hematology & oncology · 2021Review
- Fabrication of PNIPAm-based thermoresponsive hydrogel microwell arrays for tumor spheroid formation.Materials science & engineering. C, Materials for biological applications · 2021Article
- Metabolome-Driven Regulation of Adenovirus-Induced Cell Death.International journal of molecular sciences · 2021Review
- Sensitization of hepatocellular carcinoma cells towards doxorubicin and sorafenib is facilitated by glucosedependent alterations in reactive oxygen species, P-glycoprotein and DKK4.Journal of biosciences · 2020Article
- Size-Dependent Cortical Compaction Induces Metabolic Adaptation in Mesenchymal Stem Cell Aggregates.Tissue engineering. Part A · 2019Article
- Mesenchymal stem cell cultivation in electrospun scaffolds: mechanistic modeling for tissue engineering.Journal of biological physics · 2018Review
- Oxygenation in cell culture: Critical parameters for reproducibility are routinely not reported.PloS one · 2018Article
- A novel individual-cell-based mathematical model based on multicellular tumour spheroids for evaluating doxorubicin-related delivery in avascular regions.British journal of pharmacology · 2017Article
- High-Content Monitoring of Drug Effects in a 3D Spheroid Model.Frontiers in oncology · 2017Article
- Engineered bacteria detect spatial profiles in glucose concentration within solid tumor cell masses.Biotechnology and bioengineering · 2016Article
- Inferring Growth Control Mechanisms in Growing Multi-cellular Spheroids of NSCLC Cells from Spatial-Temporal Image Data.PLoS computational biology · 2016Article
- Persistent enhancement of bacterial motility increases tumor penetration.Biotechnology and bioengineering · 2015Article
- Trg-deficient Salmonella colonize quiescent tumor regions by exclusively penetrating or proliferating.Journal of controlled release : official journal of the Controlled Release Society · 2015Article
Corrections and comments
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Authors and funding
3 authors at 3 institutions in 1 country.
Funding
Abstract
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, >500 μm 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.