Effect of cell microenvironment on the drug sensitivity of hepatocellular cancer cells
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Bhaskar Bhattacharya1,2, Daniel Q. Huang3,4, Sarah Hong Hui Low1, Gim Hwa Tan1, Min Ji Han1,5, Sanamerjit Singh1,5, Benny Tang1,5, Sheng Chun Chang1,5, Joey Sze Yun Lim1,2, Mohd Feroz Mohd Omar1, Yock Young Dan3,4 and Richie Soong1,2,3
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
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
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% O2, 25 mM glucose) or more “native” (1% O2, 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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