A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing
Hepatocellular Carcinoma (HCC) is the most common form of primary liver cancer, with cirrhosis being its strongest risk factor. Interestingly, an increasing number of HCC cases is also observed without cirrhosis. We developed an HCC model via intrasplenic injection of highly tumorigenic HCC cells, w...
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Elsevier
2025-01-01
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| Series: | Pharmacological Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S104366182400505X |
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| author | Karina Benderski Paul Schneider Panayiotis Kordeves Michael Fichter Jenny Schunke Federica De Lorenzi Feyza Durak Barbara Schrörs Özlem Akilli Fabian Kiessling Matthias Bros Mustafa Diken Stephan Grabbe Jörn M. Schattenberg Twan Lammers Alexandros Marios Sofias Leonard Kaps |
| author_facet | Karina Benderski Paul Schneider Panayiotis Kordeves Michael Fichter Jenny Schunke Federica De Lorenzi Feyza Durak Barbara Schrörs Özlem Akilli Fabian Kiessling Matthias Bros Mustafa Diken Stephan Grabbe Jörn M. Schattenberg Twan Lammers Alexandros Marios Sofias Leonard Kaps |
| author_sort | Karina Benderski |
| collection | DOAJ |
| description | Hepatocellular Carcinoma (HCC) is the most common form of primary liver cancer, with cirrhosis being its strongest risk factor. Interestingly, an increasing number of HCC cases is also observed without cirrhosis. We developed an HCC model via intrasplenic injection of highly tumorigenic HCC cells, which, due to cellular tropism, invade the liver and allow for a controllable disease progression. Specifically, C57BL/6JRj mice were intrasplenically inoculated with Dt81Hepa1–6 HCC cells, with a subgroup pre-treated with CCl4 to induce cirrhosis (C-HCC). At four weeks post-inoculation, mice were sacrificed, and diseased livers were analyzed via histology, flow cytometry, and RT-qPCR to profile the extracellular matrix (ECM), angiogenesis, and immune cells. In addition, tumor-bearing mice were treated with the first-line therapy, AtezoBev, to assess therapeutic responsiveness of the model. Dt81Hepa1–6 cells displayed similar gene expression as human HCC. After intrasplenic injection, all mice developed multifocal disease. C-HCC mice had a significantly higher tumor load than non-cirrhotic HCC mice. Both HCC and C-HCC models displayed extensive ECM formation, increased levels of vascularization, and immune cell infiltration compared to healthy and non-cancerous cirrhotic livers. AtezoBev treatment produced robust antitumor efficacy, validating the model’s suitability for therapy testing. In conclusion, we established a rapidly developing and high-yield HCC model through a simple intrasplenic injection, with or without cirrhotic damage. The model overexpressed key human HCC genes and showed high responsiveness to first-line treatment. Our model uniquely combines all the above-mentioned features, promoting its use towards HCC therapy testing. |
| format | Article |
| id | doaj-art-750c92cdfd344bd1bd1e2bdc8c4947a3 |
| institution | Kabale University |
| issn | 1096-1186 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Pharmacological Research |
| spelling | doaj-art-750c92cdfd344bd1bd1e2bdc8c4947a32025-01-09T06:13:06ZengElsevierPharmacological Research1096-11862025-01-01211107560A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testingKarina Benderski0Paul Schneider1Panayiotis Kordeves2Michael Fichter3Jenny Schunke4Federica De Lorenzi5Feyza Durak6Barbara Schrörs7Özlem Akilli8Fabian Kiessling9Matthias Bros10Mustafa Diken11Stephan Grabbe12Jörn M. Schattenberg13Twan Lammers14Alexandros Marios Sofias15Leonard Kaps16Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Forckenbeckstrasse 55, Aachen 52074, GermanyDepartment of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, Mainz 55131, GermanyDepartment of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Forckenbeckstrasse 55, Aachen 52074, GermanyDepartment of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, Mainz 55131, Germany; Max Planck Institute for Polymer Research, Ackermannweg 10, Mainz 55128, GermanyDepartment of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, Mainz 55131, Germany; TRON – Translational Oncology at the University Medical Center of the Johannes Gutenberg-University Mainz GmbH, Freiligrathstrasse 12, Mainz 55131, GermanyDepartment of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Forckenbeckstrasse 55, Aachen 52074, Germany; Mildred Scheel School of Oncology (MSSO), Center for Integrated Oncology Aachen (CIOA), RWTH Aachen University Hospital, Pauwelsstrasse 30, Aachen 52074, GermanyTRON – Translational Oncology at the University Medical Center of the Johannes Gutenberg-University Mainz GmbH, Freiligrathstrasse 12, Mainz 55131, GermanyTRON – Translational Oncology at the University Medical Center of the Johannes Gutenberg-University Mainz GmbH, Freiligrathstrasse 12, Mainz 55131, GermanyTRON – Translational Oncology at the University Medical Center of the Johannes Gutenberg-University Mainz GmbH, Freiligrathstrasse 12, Mainz 55131, GermanyInstitute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Forckenbeckstrasse 55, Aachen 52074, GermanyDepartment of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, Mainz 55131, GermanyTRON – Translational Oncology at the University Medical Center of the Johannes Gutenberg-University Mainz GmbH, Freiligrathstrasse 12, Mainz 55131, GermanyDepartment of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, Mainz 55131, GermanyDepartment of Medicine II, Saarland University Medical Center, Saarland University, Kirrberger Strasse 100, Saarbrücken 66123, GermanyDepartment of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Forckenbeckstrasse 55, Aachen 52074, Germany; Mildred Scheel School of Oncology (MSSO), Center for Integrated Oncology Aachen (CIOA), RWTH Aachen University Hospital, Pauwelsstrasse 30, Aachen 52074, Germany; Corresponding authors at: Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Forckenbeckstrasse 55, Aachen 52074, Germany.Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Forckenbeckstrasse 55, Aachen 52074, Germany; Mildred Scheel School of Oncology (MSSO), Center for Integrated Oncology Aachen (CIOA), RWTH Aachen University Hospital, Pauwelsstrasse 30, Aachen 52074, Germany; Corresponding authors at: Department of Nanomedicine and Theranostics, Institute for Experimental Molecular Imaging (ExMI), RWTH Aachen University Hospital, Forckenbeckstrasse 55, Aachen 52074, Germany.Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, Mainz 55131, Germany; Department of Medicine II, Saarland University Medical Center, Saarland University, Kirrberger Strasse 100, Saarbrücken 66123, Germany; Corresponding author at: Department of Dermatology, University Medical Center of the Johannes Gutenberg-University, Langenbeckstrasse 1, Mainz 55131, Germany.Hepatocellular Carcinoma (HCC) is the most common form of primary liver cancer, with cirrhosis being its strongest risk factor. Interestingly, an increasing number of HCC cases is also observed without cirrhosis. We developed an HCC model via intrasplenic injection of highly tumorigenic HCC cells, which, due to cellular tropism, invade the liver and allow for a controllable disease progression. Specifically, C57BL/6JRj mice were intrasplenically inoculated with Dt81Hepa1–6 HCC cells, with a subgroup pre-treated with CCl4 to induce cirrhosis (C-HCC). At four weeks post-inoculation, mice were sacrificed, and diseased livers were analyzed via histology, flow cytometry, and RT-qPCR to profile the extracellular matrix (ECM), angiogenesis, and immune cells. In addition, tumor-bearing mice were treated with the first-line therapy, AtezoBev, to assess therapeutic responsiveness of the model. Dt81Hepa1–6 cells displayed similar gene expression as human HCC. After intrasplenic injection, all mice developed multifocal disease. C-HCC mice had a significantly higher tumor load than non-cirrhotic HCC mice. Both HCC and C-HCC models displayed extensive ECM formation, increased levels of vascularization, and immune cell infiltration compared to healthy and non-cancerous cirrhotic livers. AtezoBev treatment produced robust antitumor efficacy, validating the model’s suitability for therapy testing. In conclusion, we established a rapidly developing and high-yield HCC model through a simple intrasplenic injection, with or without cirrhotic damage. The model overexpressed key human HCC genes and showed high responsiveness to first-line treatment. Our model uniquely combines all the above-mentioned features, promoting its use towards HCC therapy testing.http://www.sciencedirect.com/science/article/pii/S104366182400505XHepatocellular carcinoma (HCC)Liver cancerCirrhosisFibrosisNonalcoholic fatty liver diseaseNonalcoholic steatohepatitis |
| spellingShingle | Karina Benderski Paul Schneider Panayiotis Kordeves Michael Fichter Jenny Schunke Federica De Lorenzi Feyza Durak Barbara Schrörs Özlem Akilli Fabian Kiessling Matthias Bros Mustafa Diken Stephan Grabbe Jörn M. Schattenberg Twan Lammers Alexandros Marios Sofias Leonard Kaps A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing Pharmacological Research Hepatocellular carcinoma (HCC) Liver cancer Cirrhosis Fibrosis Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis |
| title | A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing |
| title_full | A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing |
| title_fullStr | A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing |
| title_full_unstemmed | A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing |
| title_short | A hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing |
| title_sort | hepatocellular carcinoma model with and without parenchymal liver damage that integrates technical and pathophysiological advantages for therapy testing |
| topic | Hepatocellular carcinoma (HCC) Liver cancer Cirrhosis Fibrosis Nonalcoholic fatty liver disease Nonalcoholic steatohepatitis |
| url | http://www.sciencedirect.com/science/article/pii/S104366182400505X |
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