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Deciphering the underlying mechanism of liver diseases through utilization of multicellular hepatic spheroid models

  • Sanghwa Kim (Advanced Biomedical Research Laboratory, Institut Pasteur Korea) ;
  • Su-Yeon Lee (Advanced Biomedical Research Laboratory, Institut Pasteur Korea) ;
  • Haeng Ran Seo (Advanced Biomedical Research Laboratory, Institut Pasteur Korea)
  • Received : 2023.01.20
  • Accepted : 2023.02.16
  • Published : 2023.04.30

Abstract

Hepatocellular carcinoma (HCC) is a very common form of cancer worldwide and is often fatal. Although the histopathology of HCC is characterized by metabolic pathophysiology, fibrosis, and cirrhosis, the focus of treatment has been on eliminating HCC. Recently, three-dimensional (3D) multicellular hepatic spheroid (MCHS) models have provided a) new therapeutic strategies for progressive fibrotic liver diseases, such as antifibrotic and anti-inflammatory drugs, b) molecular targets, and c) treatments for metabolic dysregulation. MCHS models provide a potent anti-cancer tool because they can mimic a) tumor complexity and heterogeneity, b) the 3D context of tumor cells, and c) the gradients of physiological parameters that are characteristic of tumors in vivo. However, the information provided by an multicelluar tumor spheroid (MCTS) model must always be considered in the context of tumors in vivo. This mini-review summarizes what is known about tumor HCC heterogeneity and complexity and the advances provided by MCHS models for innovations in drug development to combat liver diseases.

Keywords

Acknowledgement

This work was supported by the National Research foundation of Korea (NRF) grant (NRF-2022R1A2C1005371) and Korea National Institute of Health (KNIH) 2022-ER-1304-01 grant funded by the Korea government.

References

  1. El-Serag HB and Rudolph KL (2007) Hepatocellular carcinoma: epidemiology and molecular carcinogenesis. Gastroenterology 132, 2557-2576 https://doi.org/10.1053/j.gastro.2007.04.061
  2. Sakurai T and Kudo M (2013) Molecular link between liver fibrosis and hepatocellular carcinoma. Liver Cancer 2, 365-366 https://doi.org/10.1159/000343851
  3. Kwon OS, Choi SH and Kim JH (2015) Inflammation and hepatic fibrosis, then hepatocellular carcinoma. Korean J Gastroenterol 66, 320-324 https://doi.org/10.4166/kjg.2015.66.6.320
  4. Filozof C, Goldstein BJ, Williams RN and Sanyal A (2015) Non-alcoholic steatohepatitis: limited available treatment options but promising drugs in development and recent progress towards a regulatory approval pathway. Drugs 75, 1373-1392 https://doi.org/10.1007/s40265-015-0437-3
  5. Llovet JM, Castet F, Heikenwalder M et al (2022) Immunotherapies for hepatocellular carcinoma. Nat Rev Clin Oncol 19, 151-172 https://doi.org/10.1038/s41571-021-00573-2
  6. Luo XY, Wu KM and He XX (2021) Advances in drug development for hepatocellular carcinoma: clinical trials and potential therapeutic targets. J Exp Clin Cancer Res 40, 172
  7. Kammerer S (2021) Three-dimensional liver culture systems to maintain primary hepatic properties for toxicological analysis in vitro. Int J Mol Sci 22, 10214
  8. Song Y, Kim SH, Kim KM, Choi EK, Kim J and Seo HR (2016) Activated hepatic stellate cells play pivotal roles in hepatocellular carcinoma cell chemoresistance and migration in multicellular tumor spheroids. Sci Rep 6, 36750
  9. Barry AE, Baldeosingh R, Lamm R et al (2020) Hepatic stellate cells and hepatocarcinogenesis. Front Cell Dev Biol 8, 709
  10. Tsuchida T and Friedman SL (2017) Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol 14, 397-411 https://doi.org/10.1038/nrgastro.2017.38
  11. Ali E, Trailin A, Ambrozkiewicz F, Liska V and Hemminki K (2022) Activated hepatic stellate cells in hepatocellular carcinoma: their role as a potential target for future therapies. Int J Mol Sci 23, 15292
  12. Thompson AI, Conroy KP and Henderson NC (2015) Hepatic stellate cells: central modulators of hepatic carcinogenesis. BMC Gastroenterol 15, 63
  13. Myojin Y, Hikita H, Sugiyama M et al (2021) Hepatic stellate cells in hepatocellular carcinoma promote tumor growth via growth differentiation factor 15 production. Gastroenterology 160, 1741-1754 e1716
  14. Lee SY, Kim S, Choi I et al (2022) Inhibition of 11beta-hydroxysteroid dehydrogenase 1 relieves fibrosis through depolarizing of hepatic stellate cell in NASH. Cell Death Dis 13, 1011 https://doi.org/10.1038/s41419-022-05452-x
  15. Choi KJ, Nam JK, Kim JH, Choi SH and Lee YJ (2020) Endothelial-to-mesenchymal transition in anticancer therapy and normal tissue damage. Exp Mol Med 52, 781-792 https://doi.org/10.1038/s12276-020-0439-4
  16. Song Y, Lee SY, Kim AR et al (2019) Identification of radiation-induced EndMT inhibitors through cell-based phenomic screening. FEBS Open Bio 9, 82-91 https://doi.org/10.1002/2211-5463.12552
  17. Song S, Zhang R, Cao W et al (2019) Foxm1 is a critical driver of TGF-beta-induced EndMT in endothelial cells through Smad2/3 and binds to the Snail promoter. J Cell Physiol 234, 9052-9064
  18. Mahmoud MM, Serbanovic-Canic J, Feng S et al (2017) Shear stress induces endothelial-to-mesenchymal transition via the transcription factor Snail. Sci Rep 7, 3375
  19. Kim SH, Song Y and Seo HR (2019) GSK-3beta regulates the endothelial-to-mesenchymal transition via reciprocal crosstalk between NSCLC cells and HUVECs in multicellular tumor spheroid models. J Exp Clin Cancer Res 38, 46
  20. Lee M, Song Y, Choi I et al (2021) Expression of HYOU1 via reciprocal crosstalk between NSCLC cells and HUVECs control cancer progression and chemoresistance in tumor spheroids. Mol Cells 44, 50-62 https://doi.org/10.14348/molcells.2020.0212
  21. Tian Z, Hou X, Liu W, Han Z and Wei L (2019) Macrophages and hepatocellular carcinoma. Cell Biosci 9, 79
  22. Arvanitakis K, Koletsa T, Mitroulis I and Germanidis G (2022) Tumor-associated macrophages in hepatocellular carcinoma pathogenesis, prognosis and therapy. Cancers (Basel) 14, 226
  23. Xiao P, Long X, Zhang L et al (2018) Neurotensin/IL-8 pathway orchestrates local inflammatory response and tumor invasion by inducing M2 polarization of Tumor-Associated macrophages and epithelial-mesenchymal transition of hepatocellular carcinoma cells. Oncoimmunology 7, e1440166
  24. Yin Z, Huang J, Ma T et al (2017) Macrophages activating chemokine (C-X-C motif) ligand 8/miR-17 cluster modulate hepatocellular carcinoma cell growth and metastasis. Am J Transl Res 9, 2403-2411
  25. Huang Y, Ge W, Zhou J, Gao B, Qian X and Wang W (2021) The role of tumor associated macrophages in hepatocellular carcinoma. J Cancer 12, 1284-1294 https://doi.org/10.7150/jca.51346
  26. Dong P, Ma L, Liu L et al (2016) CD86(+)/CD206(+), Diametrically polarized tumor-associated macrophages, predict hepatocellular carcinoma patient prognosis. Int J Mol Sci 17, 320
  27. Kubo N, Araki K, Kuwano H and Shirabe K (2016) Cancer-associated fibroblasts in hepatocellular carcinoma. World J Gastroenterol 22, 6841-6850 https://doi.org/10.3748/wjg.v22.i30.6841
  28. Jia W, Liang S, Cheng B and Ling C (2021) The role of cancer-associated fibroblasts in hepatocellular carcinoma and the value of traditional chinese medicine treatment. Front Oncol 11, 763519
  29. Duran A, Hernandez ED, Reina-Campos M et al (2016) p62/SQSTM1 by binding to vitamin D receptor inhibits hepatic stellate cell activity, fibrosis, and liver cancer. Cancer Cell 30, 595-609 https://doi.org/10.1016/j.ccell.2016.09.004
  30. Zhao Z, Bai S, Wang R et al (2019) Cancer-associated fibroblasts endow stem-like qualities to liver cancer cells by modulating autophagy. Cancer Manag Res 11, 5737-5744 https://doi.org/10.2147/CMAR.S197634
  31. Song Y, Kim JS, Kim SH et al (2018) Patient-derived multicellular tumor spheroids towards optimized treatment for patients with hepatocellular carcinoma. J Exp Clin Cancer Res 37, 109
  32. Al Hrout A, Cervantes-Gracia K, Chahwan R and Amin A (2022) Modelling liver cancer microenvironment using a novel 3D culture system. Sci Rep 12, 8003
  33. Lee KH and Kim TH (2021) Recent advances in multicellular tumor spheroid generation for drug screening. Biosensors (Basel) 11, 445
  34. Wang Q, Liu J, Yin W et al (2022) Generation of multicellular tumor spheroids with micro-well array for anticancer drug combination screening based on a valuable biomarker of hepatocellular carcinoma. Front Bioeng Biotechnol 10, 1087656
  35. Song Y, Kim S, Heo J et al (2021) Identification of hepatic fibrosis inhibitors through morphometry analysis of a hepatic multicellular spheroids model. Sci Rep 11, 10931
  36. Lim JTC, Kwang LG, Ho NCW et al (2022) Hepatocellular carcinoma organoid co-cultures mimic angiocrine crosstalk to generate inflammatory tumor microenvironment. Biomaterials 284, 121527
  37. Doumba PP, Nikolopoulou M, Gomatos IP, Konstadoulakis MM and Koskinas J (2013) Co-culture of primary human tumor hepatocytes from patients with hepatocellular carcinoma with autologous peripheral blood mononuclear cells: study of their in vitro immunological interactions. BMC Gastroenterol 13, 17
  38. Kim S, Lee M, Song Y et al (2021) Argininosuccinate synthase 1 suppresses tumor progression through activation of PERK/eIF2alpha/ATF4/CHOP axis in hepatocellular carcinoma. J Exp Clin Cancer Res 40, 127
  39. Makridakis M and Vlahou A (2010) Secretome proteomics for discovery of cancer biomarkers. J Proteomics 73, 2291-2305 https://doi.org/10.1016/j.jprot.2010.07.001
  40. Lee SY, Kim S, Song Y et al (2022) Sorbitol dehydrogenase induction of cancer cell necroptosis and macrophage polarization in the HCC microenvironment suppresses tumor progression. Cancer Lett 551, 215960
  41. Rawal P, Tripathi DM, Nain V and Kaur S (2022) VEGFmediated tumour growth and EMT in 2D and 3D cell culture models of hepatocellular carcinoma. Oncol Lett 24, 315
  42. Chen R, Dong Y, Xie X et al (2014) Screening candidate metastasis-associated genes in three-dimensional HCC spheroids with different metastasis potential. Int J Clin Exp Pathol 7, 2527-2535
  43. Kimlin LC, Casagrande G and Virador VM (2013) In vitro three-dimensional (3D) models in cancer research: an update. Mol Carcinog 52, 167-182 https://doi.org/10.1002/mc.21844
  44. Chen RX, Song HY, Dong YY et al (2014) Dynamic expression patterns of differential proteins during early invasion of hepatocellular carcinoma. PLoS One 9, e88543
  45. Lee SH, Nam JK, Park JK, Lee JH, Min do S and Kuh HJ (2014) Differential protein expression and novel biomarkers related to 5-FU resistance in a 3D colorectal adenocarcinoma model. Oncol Rep 32, 1427-1434 https://doi.org/10.3892/or.2014.3337
  46. Song Y, Kim JS, Choi EK, Kim J, Kim KM and Seo HR (2017) TGF-beta-independent CTGF induction regulates cell adhesion mediated drug resistance by increasing collagen I in HCC. Oncotarget 8, 21650-21662 https://doi.org/10.18632/oncotarget.15521
  47. Hsiao YC, Chu LJ, Chen JT, Yeh TS and Yu JS (2017) Proteomic profiling of the cancer cell secretome: informing clinical research. Expert Rev Proteomics 14, 737-756 https://doi.org/10.1080/14789450.2017.1353913
  48. Jeon D, Choi WM, Kim JS et al (2021) Serum sorbitol dehydrogenase as a novel prognostic factor for hepatocellular carcinoma after surgical resection. Cancers (Basel) 13, 6143
  49. Zanoni M, Pignatta S, Arienti C, Bonafe M and Tesei A (2019) Anticancer drug discovery using multicellular tumor spheroid models. Expert Opin Drug Discov 14, 289-301 https://doi.org/10.1080/17460441.2019.1570129
  50. Thanapirom K, Caon E, Papatheodoridi M et al (2021) Optimization and validation of a novel three-dimensional co-culture system in decellularized human liver scaffold for the study of liver fibrosis and cancer. Cancers (Basel) 13, 4936
  51. Lafnoune A, Lee SY, Heo JY et al (2022) Anti-cancer activity of buthus occitanus venom on hepatocellular carcinoma in 3D cell culture. Molecules 27, 2219
  52. Lafnoune A, Lee SY, Heo JY et al (2021) Anti-cancer effect of moroccan cobra naja haje venom and its fractions against hepatocellular carcinoma in 3D cell culture. Toxins (Basel) 13, 402
  53. Liao W, Yang W, Xu J et al (2021) Therapeutic potential of CUDC-907 (fimepinostat) for hepatocarcinoma treatment revealed by tumor spheroids-based drug screening. Front Pharmacol 12, 658197
  54. Hou J, Hong Z, Feng F et al (2017) A novel chemotherapeutic sensitivity-testing system based on collagen gel droplet embedded 3D-culture methods for hepatocellular carcinoma. BMC Cancer 17, 729
  55. Song Y, Lee SY, Kim S et al (2020) Inhibitors of Na(+)/K(+) ATPase exhibit antitumor effects on multicellular tumor spheroids of hepatocellular carcinoma. Sci Rep 10, 5318
  56. Rehman M, Vodret S, Braga L et al (2019) High-throughput screening discovers antifibrotic properties of haloperidol by hindering myofibroblast activation. JCI Insight 4, e123987
  57. Arai K, Eguchi T, Rahman MM et al (2016) A novel high-throughput 3D screening system for EMT inhibitors: a pilot screening discovered the EMT inhibitory activity of CDK2 inhibitor SU9516. PLoS One 11, e0162394
  58. Di Sanzo M, Cipolloni L, Borro M et al (2017) Clinical applications of personalized medicine: a new paradigm and challenge. Curr Pharm Biotechnol 18, 194-203 https://doi.org/10.2174/1389201018666170224105600
  59. Fong ELS, Toh TB, Lin QXX et al (2018) Generation of matched patient-derived xenograft in vitro-in vivo models using 3D macroporous hydrogels for the study of liver cancer. Biomaterials 159, 229-240 https://doi.org/10.1016/j.biomaterials.2017.12.026
  60. Zhang L, Liu F, Weygant N et al (2021) A novel integrated system using patient-derived glioma cerebral organoids and xenografts for disease modeling and drug screening. Cancer Lett 500, 87-97 https://doi.org/10.1016/j.canlet.2020.12.013
  61. Imamura Y, Mukohara T, Shimono Y et al (2015) Comparison of 2D- and 3D-culture models as drug-testing platforms in breast cancer. Oncol Rep 33, 1837-1843 https://doi.org/10.3892/or.2015.3767
  62. Kaur G, Evans DM, Teicher BA and Coussens NP (2021) Complex tumor spheroids, a tissue-mimicking tumor model, for drug discovery and precision medicine. SLAS Discov 26, 1298-1314 https://doi.org/10.1177/24725552211038362
  63. Kronemberger GS, Carneiro FA, Rezende DF and Baptista LS (2021) Spheroids and organoids as humanized 3D scaffold-free engineered tissues for SARS-CoV-2 viral infection and drug screening. Artif Organs 45, 548-558 https://doi.org/10.1111/aor.13880
  64. Hwang KS, Seo EU, Choi N, Kim J and Kim HN (2023) 3D engineered tissue models for studying human-specific infectious viral diseases. Bioact Mater 21, 576-594 https://doi.org/10.1016/j.bioactmat.2022.09.010
  65. de Dios-Figueroa GT, Aguilera-Marquez JDR, Camacho-Villegas TA and Lugo-Fabres PH (2021) 3D cell culture models in COVID-19 times: a review of 3D technologies to understand and accelerate therapeutic drug discovery. Biomedicines 9, 602
  66. Salgueiro L, Kummer S, Sonntag-Buck V et al (2022) Generation of human lung organoid cultures from healthy and tumor tissue to study infectious diseases. J Virol 96, e0009822
  67. Loy LM, Low HM, Choi JY, Rhee H, Wong CF and Tan CH (2022) Variant hepatocellular carcinoma subtypes according to the 2019 WHO classification: an imagingfocused review. AJR Am J Roentgenol 219, 212-223 https://doi.org/10.2214/AJR.21.26982