Effect of cell microenvironment on the drug sensitivity of hepatocellular cancer cells
Bibliographic record
Abstract
// Bhaskar Bhattacharya 1 , 2 , Daniel Q. Huang 3 , 4 , Sarah Hong Hui Low 1 , Gim Hwa Tan 1 , Min Ji Han 1 , 5 , Sanamerjit Singh 1 , 5 , Benny Tang 1 , 5 , Sheng Chun Chang 1 , 5 , Joey Sze Yun Lim 1 , 2 , Mohd Feroz Mohd Omar 1 , Yock Young Dan 3 , 4 and Richie Soong 1 , 2 , 3 1 Cancer Science Institute of Singapore, National University of Singapore, Singapore 2 Pascific Laboratories, Singapore 3 Department of Medicine, National University of Singapore, Singapore 4 Division of Gastroenterology and Hepatology, National University Health System, Singapore 5 Integrated Science, University of British Columbia, Vancouver, Canada Correspondence to: Richie Soong, email: mdcrcts@nus.edu.sg Bhaskar Bhattacharya, email: bhaskar@pascific.com Keywords: drug development; microenvironment; glycolysis Abbreviations: HCC: hepatocellular carcinoma; TCGA: The Cancer Genome Atlas Received: September 23, 2020     Accepted: February 19, 2021     Published: March 30, 2021 Copyright: © 2021 Bhattacharya et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. ABSTRACT The native hepatocellular cancer (HCC) microenvironment is characterized by more hypoxic, hypoglycemic, and acidic conditions than those used in standard cell culture. This study aimed to investigate whether HCC cells cultured in more native conditions have an altered phenotype and drug sensitivity compared to those cultured in standard conditions. Six HCC cell lines were cultured in “standard” (21% O 2 , 25 mM glucose) or more “native” (1% O 2 , 5 mM glucose, 10 mM lactate) conditions. Cells were assessed for growth rates, cell cycle distribution, relevant metabolite and protein levels, genome-wide gene expression, mitochondrial DNA sequence and sensitivity to relevant drugs. Many differences in cellular and molecular phenotypes and drug sensitivity were observed between the cells. HCC cells cultured in native conditions had slower doubling times, increased HK2 and GLUT, lower PHDA and ATP levels, and mutations in mitochondrial DNA. Thirty-one genes, including the hypoxia-associated NDRG1 , were differentially expressed between the cells. HCC patients in The Cancer Genome Atlas (TCGA) with tumors with a high score based on these 31 genes had a poorer prognosis than those with a low score ( p = 0.002). From 90 comparisons of drug sensitivity, increased resistance and sensitivity for cells cultured in native conditions was observed in 14 (16%) and 8 (9%) comparisons respectively. In conclusion, cells cultured in more native conditions can have a more glycolytic and aggressive phenotype and varied drug sensitivity to those cultured in standard conditions, and may provide new insights to understanding tumor biology and drug development.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".