Recently, Stefan Hoehme and colleagues from Leipzig University published a study simulating the spatiotemporal development of early hepatocellular cancer (Hoehme et al. 2018). Research on tumor initiation and development of hepatocellular cancer represents a major field of research in toxicology (Grasl-Kraupp et al. 2000; Braeuning and Schwarz 2016; Williams et al. 2016; Rennert et al. 2017; Braeuning et al. 2016; Amereh et al. 2017; Moghbel et al. 2016). However, little is known about early tumor development, when single-initiated cells gain a selection advantage over their neighbours, e.g., increased proliferation or resistance to cell death. Intuitively, one may assume that a tumor that originates from a single-initiated hepatocyte will grow with a spherical shape (Hoehme et al. 2018). Interestingly, the spatiotemporal model of Hoehme and colleagues came to another prediction. Rather, early hepatocellular tumors grow in extremely elongated cell arrangements. Only later, when tumors reach cell numbers of approximately 4000 elongated arrangements, they transform into spherical structures. Importantly, this model prediction could be experimentally confirmed. A rat liver tumor initiation study with single dose of 250 mg/kg N-nitrosomorpholine showed that small clusters of glutathione-transferase-P-positive cells showed an elongated, columnar architecture and only adopted a spherical shape, when they grew larger (Hoehme et al. 2018). The simulation of Hoehme and colleagues was based on previous work, where techniques of spatiotemporal tissue modeling have been developed (Hoehme et al. 2017; Ghallab et al. 2016; Friebel et al. 2015; Hammad et al. 2014; Schliess et al. 2014; Vartak et al. 2016). It has been shown that the hepatocytes arrange themselves in the orientation of the closest sinusoid, a mechanism also named ‘hepatocyte–sinusoid-alignment’ (HSA) (Hoehme et al. 2010; Höhme et al. 2007). If one assumes that HSA is maintained for some time even after initiation of tumor cells, elongated patterns of early hepatocellular cancer are inevitable. The work of Stefan Hoehme et al. adds some important details to our knowledge on the behavior of hepatocytes early after initiation.
References
Amereh Z, Hatami N, Shirazi FH, Andalib S, Keyhanfar F, Eskandari MR (2017) Cancer chemoprevention by oleaster (Elaeagnus angustifolia L.) fruit extract in a model of hepatocellular carcinoma induced by diethylnitrosamine in rats. EXCLI J 16:1046–1056. https://doi.org/10.17179/excli2017-389 (eCollection 2017)
Braeuning A, Schwarz M (2016) Is the question of phenobarbital as potential liver cancer risk factor for humans really resolved? Arch Toxicol 90(6):1525–1526. https://doi.org/10.1007/s00204-016-1712-0 (Epub 2016 Apr 22, no abstract available)
Braeuning A, Gavrilov A, Römer M, Zell A, Schwarz M (2016) Tumor promotion and inhibition by phenobarbital in livers of conditional Apc-deficient mice. Arch Toxicol 90(6):1481–1494. https://doi.org/10.1007/s00204-016-1667-1 (Epub 2016 Feb 2)
Friebel A, Neitsch J, Johann T, Hammad S, Hengstler JG, Drasdo D, Hoehme S (2015) TiQuant: software for tissue analysis, quantification and surface reconstruction. Bioinformatics 31(19):3234–3236. https://doi.org/10.1093/bioinformatics/btv346 (Epub 2015 Jun 3)
Ghallab A, Cellière G, Henkel SG, Drasdo D, Gebhardt R, Hengstler JG (2016) Model-guided identification of a therapeutic strategy to reduce hyperammonemia in liver diseases. J Hepatol 64(4):860–871. https://doi.org/10.1016/j.jhep.2015.11.018 (Epub 2015 Nov 27)
Grasl-Kraupp B, Luebeck G, Wagner A, Löw-Baselli A, de Gunst M, Waldhör T, Moolgavkar S, Schulte-Hermann R (2000) Quantitative analysis of tumor initiation in rat liver: role of cell replication and cell death (apoptosis). Carcinogenesis 21(7):1411–1421
Hammad S, Hoehme S, Friebel A, Gebhardt R, Drasdo D, Hengstler JG (2014) Protocols for staining of bile canalicular and sinusoidal networks of human, mouse and pig livers, three-dimensional reconstruction and quantification of tissue microarchitecture by image processing and analysis. Arch Toxicol 88(5):1161–1183. https://doi.org/10.1007/s00204-014-1243-5 (Epub 2014 Apr 19)
Hoehme S, Brulport M, Bauer A, Bedawy E, Schormann W, Hermes M, Puppe V, Gebhardt R, Zellmer S, Schwarz M, Bockamp E, Timmel T, Hengstler JG, Drasdo D (2010) Prediction and validation of cell alignment along microvessels as order principle to restore tissue architecture in liver regeneration. Proc Natl Acad Sci USA 107(23):10371–10376. https://doi.org/10.1073/pnas.0909374107 (Epub 2010 May 19)
Hoehme S, Friebel A, Hammad S, Drasdo D, Hengstler JG (2017) Creation of three-dimensional liver tissue models from experimental images for systems medicine. Methods Mol Biol 1506:319–362
Hoehme S, Bertaux F, Weens W, Grasl-Kraupp B, Hengstler JG, Drasdo D (2018) Model prediction and validation of an order mechanism controlling the spatiotemporal phenotype of early hepatocellular carcinoma. Bull Math Biol 80(5):1134–1171. https://doi.org/10.1007/s11538-017-0375-1 (Epub 2018 Mar 22)
Höhme S, Hengstler JG, Brulport M, Schäfer M, Bauer A, Gebhardt R, Drasdo D (2007) Mathematical modelling of liver regeneration after intoxication with CCl(4). Chem Biol Interact 168(1):74–93 (Epub 2007 Feb 2)
Moghbel M, Mashohor S, Mahmud R, Saripan MI (2016) Automatic liver tumor segmentation on computed tomography for patient treatment planning and monitoring. EXCLI J 15:406–423. https://doi.org/10.17179/excli2016-402 (eCollection 2016)
Rennert C, Eplinius F, Hofmann U, Johänning J, Rolfs F, Schmidt-Heck W, Guthke R, Gebhardt R, Ricken AM, Matz-Soja M (2017) Conditional loss of hepatocellular Hedgehog signaling in female mice leads to the persistence of hepatic steroidogenesis, androgenization and infertility. Arch Toxicol 91(11):3677–3687. https://doi.org/10.1007/s00204-017-1999-5 (Epub 2017 May 30)
Schliess F, Hoehme S, Henkel SG, Ghallab A, Driesch D, Böttger J, Guthke R, Pfaff M, Hengstler JG, Gebhardt R, Häussinger D, Drasdo D, Zellmer S (2014) Integrated metabolic spatial-temporal model for the prediction of ammonia detoxification during liver damage and regeneration. Hepatology 60(6):2040–2051. https://doi.org/10.1002/hep.27136 (Epub 2014 May 12)
Vartak N, Damle-Vartak A, Richter B, Dirsch O, Dahmen U, Hammad S, Hengstler JG (2016) Cholestasis-induced adaptive remodeling of interlobular bile ducts. Hepatology 63(3):951–964
Williams GM, Duan JD, Iatropoulos MJ, Perrone CE (2016) Sex differences in DNA damage produced by the carcinogen 2-acetylaminofluorene in cultured human hepatocytes compared to rat liver and cultured rat hepatocytes. Arch Toxicol 90(2):427–432. https://doi.org/10.1007/s00204-014-1415-3 (Epub 2014 Dec 16)
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The author declares that he has no conflict of interest.
Rights and permissions
About this article
Cite this article
Ghallab, A. Modeling of early hepatocellular carcinoma. Arch Toxicol 92, 2401–2402 (2018). https://doi.org/10.1007/s00204-018-2243-7
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00204-018-2243-7