Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma
Background: Despite advances in therapeutics, outcomes for hepatocellular carcinoma (HCC) remain poor and there is an urgent need for efficacious systemic therapy. Unfortunately, drugs that are successful in preclinical studies often fail in the clinical setting, and we hypothesize that this is due...
| Main Authors: | , , , , , , , , , , |
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| Format: | Journal Article |
| Language: | English |
| Published: |
2015
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| Online Access: | https://hdl.handle.net/10356/80966 http://hdl.handle.net/10220/38996 |
| _version_ | 1826112559592243200 |
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| author | Wang, Weining Iyer, N. Gopalakrishna Tay, Hsien Ts’ung Wu, Yonghui Lim, Tony K. H. Zheng, Lin Song, In Chin Kwoh, Chee Keong Huynh, Hung Tan, Patrick O. B. Chow, Pierce K. H. |
| author2 | School of Computer Engineering |
| author_facet | School of Computer Engineering Wang, Weining Iyer, N. Gopalakrishna Tay, Hsien Ts’ung Wu, Yonghui Lim, Tony K. H. Zheng, Lin Song, In Chin Kwoh, Chee Keong Huynh, Hung Tan, Patrick O. B. Chow, Pierce K. H. |
| author_sort | Wang, Weining |
| collection | NTU |
| description | Background: Despite advances in therapeutics, outcomes for hepatocellular carcinoma (HCC) remain poor and there is an urgent need for efficacious systemic therapy. Unfortunately, drugs that are successful in preclinical studies often fail in the clinical setting, and we hypothesize that this is due to functional differences between primary tumors and commonly used preclinical models. In this study, we attempt to answer this question by comparing tumor morphology and gene expression profiles between primary tumors, xenografts and HCC cell lines. Methods: Hep G2 cell lines and tumor cells from patient tumor explants were subcutaneously (ectopically) injected into the flank and orthotopically into liver parenchyma of Mus Musculus SCID mice. The mice were euthanized after two weeks. RNA was extracted from the tumors, and gene expression profiling was performed using the Gene Chip Human Genome U133 Plus 2.0. Principal component analyses (PCA) and construction of dendrograms were conducted using Partek genomics suite. Results: PCA showed that the commonly used HepG2 cell line model and its xenograft counterparts were vastly different from all fresh primary tumors. Expression profiles of primary tumors were also significantly divergent from their counterpart patient-derived xenograft (PDX) models, regardless of the site of implantation. Xenografts from the same primary tumors were more likely to cluster together regardless of site of implantation, although heat maps showed distinct differences in gene expression profiles between orthotopic and ectopic models. Conclusions: The data presented here challenges the utility of routinely used preclinical models. Models using HepG2 were vastly different from primary tumors and PDXs, suggesting that this is not clinically representative. Surprisingly, site of implantation (orthotopic versus ectopic) resulted in limited impact on gene expression profiles, and in both scenarios xenografts differed significantly from the original primary tumors, challenging the long-held notion that orthotopic PDX model is the gold standard preclinical model for HCC. |
| first_indexed | 2024-10-01T03:09:03Z |
| format | Journal Article |
| id | ntu-10356/80966 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T03:09:03Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | ntu-10356/809662022-02-16T16:26:46Z Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma Wang, Weining Iyer, N. Gopalakrishna Tay, Hsien Ts’ung Wu, Yonghui Lim, Tony K. H. Zheng, Lin Song, In Chin Kwoh, Chee Keong Huynh, Hung Tan, Patrick O. B. Chow, Pierce K. H. School of Computer Engineering Orthotopic Xenograft HepG2 cell line Hepatocellular carcinoma Ectopic Background: Despite advances in therapeutics, outcomes for hepatocellular carcinoma (HCC) remain poor and there is an urgent need for efficacious systemic therapy. Unfortunately, drugs that are successful in preclinical studies often fail in the clinical setting, and we hypothesize that this is due to functional differences between primary tumors and commonly used preclinical models. In this study, we attempt to answer this question by comparing tumor morphology and gene expression profiles between primary tumors, xenografts and HCC cell lines. Methods: Hep G2 cell lines and tumor cells from patient tumor explants were subcutaneously (ectopically) injected into the flank and orthotopically into liver parenchyma of Mus Musculus SCID mice. The mice were euthanized after two weeks. RNA was extracted from the tumors, and gene expression profiling was performed using the Gene Chip Human Genome U133 Plus 2.0. Principal component analyses (PCA) and construction of dendrograms were conducted using Partek genomics suite. Results: PCA showed that the commonly used HepG2 cell line model and its xenograft counterparts were vastly different from all fresh primary tumors. Expression profiles of primary tumors were also significantly divergent from their counterpart patient-derived xenograft (PDX) models, regardless of the site of implantation. Xenografts from the same primary tumors were more likely to cluster together regardless of site of implantation, although heat maps showed distinct differences in gene expression profiles between orthotopic and ectopic models. Conclusions: The data presented here challenges the utility of routinely used preclinical models. Models using HepG2 were vastly different from primary tumors and PDXs, suggesting that this is not clinically representative. Surprisingly, site of implantation (orthotopic versus ectopic) resulted in limited impact on gene expression profiles, and in both scenarios xenografts differed significantly from the original primary tumors, challenging the long-held notion that orthotopic PDX model is the gold standard preclinical model for HCC. Published version 2015-12-08T03:02:35Z 2019-12-06T14:18:29Z 2015-12-08T03:02:35Z 2019-12-06T14:18:29Z 2015 Journal Article Wang, W., Iyer, N. G., Tay, H. T., Wu, Y., Lim, T. K. H., Zheng, L., et al. (2015). Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma. BMC Cancer, 15, 828-. 1471-2407 https://hdl.handle.net/10356/80966 http://hdl.handle.net/10220/38996 10.1186/s12885-015-1814-8 26520397 en BMC Cancer © 2015 Wang et al. Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. 10 p. application/pdf |
| spellingShingle | Orthotopic Xenograft HepG2 cell line Hepatocellular carcinoma Ectopic Wang, Weining Iyer, N. Gopalakrishna Tay, Hsien Ts’ung Wu, Yonghui Lim, Tony K. H. Zheng, Lin Song, In Chin Kwoh, Chee Keong Huynh, Hung Tan, Patrick O. B. Chow, Pierce K. H. Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma |
| title | Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma |
| title_full | Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma |
| title_fullStr | Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma |
| title_full_unstemmed | Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma |
| title_short | Microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma |
| title_sort | microarray profiling shows distinct differences between primary tumors and commonly used preclinical models in hepatocellular carcinoma |
| topic | Orthotopic Xenograft HepG2 cell line Hepatocellular carcinoma Ectopic |
| url | https://hdl.handle.net/10356/80966 http://hdl.handle.net/10220/38996 |
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