您当前的位置: 首页 > 资源详细信息
资源基本信息 
来源机构: 《自然》
来源目录: Health sciences
发布日期: 2021-11-25
资源类型: 441.39KB
资源性质: 研究进展
重要度:  
资源评价:

资源推荐:

主题相关资源
同目录资源
系统抽取主题
抽取主题     
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)

Liver fibrosis promotes immunity escape but limits the size of liver tumor in a rat orthotopic transplantation model | Scientific Reports

Abstract . Liver fibrosis plays?a crucial role in promoting tumor immune escape and tumor aggressiveness for liver cancer. However, an interesting phenomenon is that the tumor size of liver cancer patients with liver fibrosis is smaller than that of patients without liver fibrosis. In this study, 16 SD rats were used to establish orthotopic liver tumor transplantation models with Walker-256 cell lines, respectively on the fibrotic liver (n?=?8, LF group) and normal liver (n?=?8, control group). MRI (magnetic resonance imaging) was used to monitor the size of the tumors. All rats were executed at the third week after modeling, and the immunohistochemical staining was used to reflect the changes in the tumor microenvironment. The results showed that, compared to the control group, the PD-L1 (programmed cell death protein receptor-L1) expression was higher, and the neutrophil infiltration increased while the effector (CD8+) T cell infiltration decreased in the LF group. Additionally, the expression of MMP-9 (matrix metalloproteinase-9) of tumor tissue in the LF group increased. Three weeks after modeling, the size of tumors in the LF group was significantly smaller than that in the control group (382.47?±?195.06?mm 3 vs. 1736.21?±?657.25?mm 3 , P?immunity escape but limited the expansion of tumor size. Download PDF Introduction . A distinct feature of hepatocellular carcinoma (HCC) is that it is closely related to liver fibrosis, and 80–90% of HCC occurred in the fibrotic or cirrhotic liver 1 , 2 . The complex pathogenesis of liver fibrosis includes activation and recruitment of immunecells, activation of hepatic stellate cells (HSCs) and hepatic?myofibroblasts (MFs), and the synthesis of fibrotic extracellular matrix (ECM) 3 , 4 , 5 . Several studies have revealed that the tumor immunity escape and angiogenesis promoted by liver fibrosis can affect the occurrence, development and recurrence of HCC 6 , 7 , 8 . However, strangely, compared with the HCC patients without cirrhosis, patients with cirrhosis have smaller tumor size 6 , 9 , 10 . As far as we know, one of the main consequences of liver fibrosis is the increased stiffness, and there is a linear relationship between the severity of liver fibrosis and liver stiffness 11 , 12 . And the physical tension produced by collagen deposition which came from MFs may restrict the growth space of the tumor 13 . Despite these theories, there is no literature to describe the relationship between tumor size and liver fibrosis. In this study, we established a rat orthotopic transplantation model with a liver fibrosis background, verified whether liver fibrosis causes tumor immunosuppression, and further explored the effect of liver fibrosis on tumor growth. Materials and methods . Animals . 16 male SD rats (280–320?g) were purchased from the Experimental Animal Center of Tongji Medical College at University of Science and Technology. All experimental methods were approved by the Ethics Committee of Tongji Medical College at Huazhong University of Science and Technology. The experimental methods were carried out in accordance with the appropriate approvals and relevant guidelines. The rats were maintained in a SPF environment, with free access to food and water. Rats?were?euthanized?with CO 2 , followed by neck dislocation. This study complies with the ARRIVE guidelines. The establishment of different liver background . 16 rats were randomly divided into two groups. Liver fibrosis was induced with the method which was described in a previous study 14 . Specifically,?8 rats were treated thrice per week for the LF group with intraperitoneal injections of 250?mg/kg Thioacetamide (TAA) for 6?weeks. Correspondingly, 8 rats were injected with isometric normal saline for the control group (Fig.? 1 A). Figure 1 ( A ) The establishment of rat orthotopic transplantation model in LF and control group; ( B ) Comparison of HE and Sirius Red staining (40×?and 400×) of the liver in LF and control group. Full size image The establishment of rat liver tumor orthotopic transplantation model . We chose Walker-256 cells (Procell Medical Co. Ltd., Wuhan, China) as the allograft cell line because it can observe the changes in the tumor microenvironment 15 , 16 , and the number of experimental animals can be reduced due to its high tumor formation rate. To obtain the tumor mass, 1?ml cell suspension containing 1?×?10 6 cells was subcutaneously injected into the right flank of a rat (tumor-bearing rat). When the subcutaneous tumor reached 1?cm in length, the tumor-bearing rat was sacrificed and the tumor tissue was removed for orthotopic transplantation in experimental rats (Fig.? 1 A). The method of open orthotopic transplantation was described in the previous literatures 17 , 18 . Briefly, the fresh tumor tissue was cut and separated into cubes at the size of 1?mm 3 under sterile conditions and then these pieces were stored in saline. Next, under 1% isopentobarbital sodium anesthesia, an incision was made in rats along the abdominal white line. Under aseptic conditions, a tumor piece was embedded into each rat's hepatic left lateral lobe and then blocked with a gelatin sponge to prevent the tumor mass from falling out or liver bleeding. Finally, the wound was sutured after ensuring no bleeding or complications. MRI?scan acquisition . All rats were monitored by a 3T MR system (PHILIPS, Holland) with an eight‐channel phased‐array coil designed for rats (Medcoil Healthcare, Suzhou, China)?in the 1, 2 and 3?weeks after modeling. The T2WI-TSE images were obtained using a field of view (FOV) of 100?×?60?mm, 256?×?196 matrix, 25 slices of 1?mm thickness, repetition time?=?2500?ms, and TE?=?100?ms. The long diameter (a) and short diameter (b) of the tumor were measured independently by two experienced radiologists who did not know the rat grouping. The tumor volume was calculated as V?=?a?×?b 2 /2, and the tumor growth rate was calculated as V n /V 1 ?×?100% (V n represented the tumor volume at the n week, n?=?2, 3). Sample collection . In week 3, all rats were sacrificed immediately after the MRI scan, then the liver and tumor tissue was removed and preserved in 4% formaldehyde for 24?h before paraffin-embedded sections were made. Hematoxylin–Eosin staining and Sirius Red staining . A 4-μm paraffin serial sections of the liver per rat were stained with Hematoxylin–Eosin (HE), with Sirius Red for collagen to evaluate the collagen deposition of liver fibrosis. Immunohistochemical (IHC) staining . IHC staining was performed on formalin-fixed, paraffin-embedded tumor samples and the method was as described in the previous literature 19 .?Briefly, paraffin sections were taken and dewaxed to water. Antigen repair solutions were dripped on the sections and washed with PBS 3 times. The first antibodies were added to the sections and washed with PBS (PH7.4) 3 times at 4?°C overnight. Secondary antibodies were added and rinsed with PBS 3 times again. Immunostaining was performed with DAB. The sections were counterstained with hematoxylin. The antibodies Ki67 (1:200, Abcam), CD31 (1:400, DAKO, USA), α-SMA (1:500, Themo Fisher), PD-L1 (1:600, Abcam), CD8 (1:2000, NOVUS, USA), Ly6G (1:800, Servicebio), MMP-2 (matrix metalloproteinase-2, 1:1500, Servicebio) and MMP-9 (1:800, Servicebio) were used. Visualize staining of tissue under a microscope, acquisitive and analysis image (Nikon DS-U3, Japan). The results of IHC staining were analyzed by Image J software 1.8.0 (Media Cybernetics, Rockville, MD, USA). The Ki67 and CD8 antibody staining results were evaluated by the percentage of positive cells and the positive cells density respectively, and the percentage of positive staining areas evaluated the α-SMA, CD31, PD-L1, Ly6G, MMP-2 and MMP-9 antibody staining results. Five random visual fields were counted for?each?sample?and the average was determined. Statistical analysis . Statistical analysis was done with SPSS 24.0 (SPSS Inc., Chicago, USA) and GraphPad Prism 8.0 (GraphPad Software, La Jolla, USA) software. The data were described as mean value?±?standard deviation or frequency (percentages). Calibrated Chi-square test?and unpaired?t-tests were applied, as well as the?Fisher?exact test. Spearman’s correlation test was used for correlation analysis. P value?collagen deposition formed, and there was fibrosis between the vascular areas. Additionally, as expected, MMPs of liver tissue were abundantly expressed in the LF group (Fig.? 4 B,C). Based on these, we deemed that the rats in the LF group suffered liver fibrosis from TAA injection was stopped until they were sacrificed, while the liver anatomy of the control group showed no apparent abnormalities. Furthermore, we observed that although given the same dose of TAA simultaneously, the degree of fibrosis between rats in the LF group was slightly different due to the individual divergence. Liver fibrosis promoted immunity escape and tumor angiogenesis . We simultaneously observed the IHC results of the tumor and adjacent liver tissue. The presentative pictures of the IHC staining of the tumor and liver were shown in Fig.? 2 . In tumor tissues, compared to the control group, the PD-L1 expression was significantly higher (P?cell density decreased (P?control group (P?tumor angiogenesis and tumor cell proliferation increased. Although there is still controversy, cancer-associated myofibroblasts (CAFs) are widely considered to be derived from HSCs, and α-SMA is one of the markers of CAFs 20 , 21 . It made sense that a large number of activated HSCs in adjacent liver tissues infiltrated into the tumor and became a part of the tumor immune microenvironment (Fig.? 3 D) 22 . Although the liver tissue suffered immunosuppression which was similar to tumor tissue, which to a certain extent corroborated the changes in precancerous microenvironment (PME), there is no difference between the LF group and control group in the expression of Ki67 and CD31 (Fig.? 3 A,B). Figure 2 Representative pictures of IHC staining of tumor and liver in LF group and control group (400×). Full size image Figure 3 Quantitative analysis of immunohistochemistry results of Ki67, CD31, PD-L1, α-SMA, CD8?+?T cell and Ly6G. Full size image Similar to the previous studies, after TAA injection, the expression of MMP-2 and MMP-9 in the liver of the LF group increased (Fig.? 4 A–C) 23 . In tumor tissue, we found that the expression of MMP-2 was not statistically significant between the two groups (Fig.? 4 B), while the expression of MMP-9 in the LF group was higher than that in the control group (Fig.? 4 C). Figure 4 ( A ) Representative pictures of IHC staining of MMP-2 and MMP-9 in LF group and control group (400×); ( B ), ( C ) Quantitative analysis of immunohistochemistry results of MMP-2 and MMP-9. P?Full size image In addition, we also observed the metastasis of tumors on MRI. The intrahepatic metastasis was defined as metastasis confined to the liver (Fig.? 5 A), and the extrahepatic metastasis including epigastric and chest-wall metastasis (Fig.? 5 B). Although there was no statistical difference, the tumors in the LF group were generally more likely to metastasize than those in the control group (Table 1 ). Figure 5 ( A ) In the third week, T2WI image of a rat in LF group showing intrahepatic metastasis (white arrow), ascites (black arrow) and epigastric metastasis (white arrow); ( B ) T2WI image showing chest-wall metastasis (white arrow). Full size image Table 1 Tumor metastasis in LF group and control group. Full size table Tumor size in LF group was smaller . The tumors were presented clearly on MRI (Fig.? 6 A). The tumor volume of the LF group and control group in the 1–3?weeks was: 41.43?±?8.11?mm 3 vs. 58.22?±?9.26?mm 3 (P?=?0.002), 181.66?±?79.41?mm 3 vs. 438.06?±?163.21?mm 3 (P?=?0.001), 382.47?±?195.06?mm 3 vs. 1736.21?±?657.25?mm 3 (P?growth rates of the LF group and control group at week 2 and 3 were 457.01?±?207.11% vs. 795.43?±?396.70% (P?=?0.051) and 951.43?±?470.42% vs. 3118.01?±?1468.32% (P?=?0.001) (Fig.? 6 C). Figure 6 ( A ) MR dynamic detection of LF group and control group, tumor tissue showed high signal in T2WI sequence (white arrow); ( B ) Tumor volume changes of LF group and control group; ( C ) The tumor growth rates of LF group and control group. P?Full size image We measured the degree of collagen deposition of all rats’ livers, which was quantified by the percentage of collagen area in the sirius red staining (Fig.? 1 B). Then the spearman’s correlation test was used to analyze the correlation between tumor size and liver collagen deposition (Table 2 ). These data showed that tumor volume was strongly correlated with the percentage of collagen area (r?=???0.823, P?correlation analysis between tumor size and tumor immunosuppressive or liver collagen deposition (n?=?16). Full size table Discussion . The impact of liver fibrosis on the growth of HCC has attracted significant attention in recent years because of the prevalence of liver cancer patients with cirrhosis 24 , 25 , 26 . Much research has focused on the impact of liver fibrosis on the tumor microenvironment 24 , 27 , 28 , 29 , but few studies focused on the effect of liver fibrosis on tumor size. In fact, the tumor size is a critical yardstick for determining suitable treatment and assessing treatment responses for clinicians 9 , 30 . And an interesting phenomenon is that the size of the tumor with liver fibrosis does not match the immune escape characteristics. In this current study, we observed the effect of liver fibrosis on the growth of liver tumors in a rat orthotopic transplantation model, and we found that although the size of the tumors in the LF group was smaller, they had a stronger immunosuppressive state and aggressiveness. Many aspects of liver fibrosis can be involved in promoting immune escape for tumors. The activation of HSCs is considered the core event in developing liver fibrosis and final cirrhosis 8 , 31 . In addition to directly affect the development of HCC by secreting key cytokines and chemokines, such as HGF, TGF-β, PDGF, interleukin-6 and Wnt ligands 24 , 32 , 33 , the activated HSCs also secrete vascular endothelial growth factor (VEGF), CXC chemokine to promote vascular and actively participates in the occurrence and development of tumor blood vessels remodeling 8 , 27 , 34 . In addition, activated HSCs also exhibit immunomodulatory activity by expressing proteins such as PD-L1 and B7-H4, and promoting the expansion of immunosuppressive cells such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSC) 26 , 35 , 36 , 37 . The accumulation of collagens, predominantly type I collagen, resulting in a two to five fold increase of total collagen content in the cirrhotic liver 1 , 38 . Several of the ECM components such as collagens, laminins, fibronectin, glycosaminoglycans and proteoglycans interact directly and indirectly with HCC cells and the stroma cell types, thereby changing the tumor microenvironment 39 . These ECM proteins also store growth factors such as HGF, PDGF, TGF-β, CTGF, and VEGF, which influence the immunity escape of tumor environment 1 . Changes in the biomechanical environment of HCC can transmit signals to HCC cells through mechanoreceptors such as integrin, which activates signal pathways such as YAP/TAZ and promotes the proliferation, invasion and metastasis of HCC 28 , 39 , 40 , 41 . Tumor-associated neutrophils (TANs) in hepatocellular carcinoma received attention in recent years. TGF-β, which was secreted by activated HSCs, plays a major role in neutrophil plasticity, driving the acquisition of an N2 phenotype 42 . The N2 TANs have been proved that they can recruit macrophages and Treg cells into HCCs to promote their growth, progression 43 . In the present study, we did observed that the TANs infiltration in the LF group was higher than that in the control group. At the same time, the immunosuppression of liver fibrosis on tumors was also reflected in the increased expression of PD-L1 and decreased CD8?+?T cell infiltration in the LF group. MMPs are calcium-dependent zinc-containing peptidases and are responsible for the degradation and turnover of most components in the ECM during fibrogenesis 44 . MMPs also have other functions besides participating in ECM turnover, including regulating signaling pathways that control cell growth, inflammation, or angiogenesis and may even work in a nonproteolytic manner 5 . MMP-2 and MMP-9 are two key MMPs secreted from HSCs and have been proved highly expression during TAA induced fibrogenesis 23 , 45 , 46 . High expression of MMP-2, MMP-9, and both has been associated with tumor progression and poor survival of HCC patients 47 . Overexpression of MMPs in tumor cells will enhance degradation of the basement membrane to facilitate invasion of nearby blood vessels, followed by extravasion to distant tissues to seed new metastatic sites and tumor cells mainly express MMP-9 instead of MMP-2 in HCC 47 . In the tumor tissue of LF group, we observed that the expression of MMP-9 was higher than that of control group in liver tissue while there was no statistical difference in the MMP-2 expression between two groups, which may be related to the characteristics of tumor cell lines. The harder the liver, the smaller the space for tumor growth, which was reflected in this study's negative linear relationship between collagen deposition and tumor size. Nevertheless, this does not mean that liver fibrosis can reduce the degree of “tumor damage”. In fact, despite the smaller tumor size, the HCC patients with cirrhosis have a worse prognosis and higher-level pathological typing 6 , 9 . Liver stiffness is positively correlated with the risk of HCC, patients with a liver stiffness value greater than 12.5 to 13?kPa have a 4 to 13 times higher risk of HCC occurrence 48 , 49 . Schrader et al. 50 found that when cells were cultured on hard (12?kPa) supports, the proliferation index (assessed by Ki67) of Huh7 and HepG2 cells were respectively 2.7 and 12.2 times higher than those were cultured on soft (1?kPa) supports. In addition, we also found a relatively moderate correlation between tumor volume and related indicators reflecting immune escape. For patients who accepted immunity therapy, an apparent initial increase in tumor burden may be present, a finding that is likely related to transient immunity cell infiltration 51 . Moreover, CD8?+?T cell infiltration was related to tumor size in this study, but more shreds of evidence are needed to prove the relationship between tumor size and immunity cells 51 , 52 . Different from the previous focus on the effect of stiffness on the biological behavior of tumor cells 50 , 53 , the model we constructed in this study can directly observe the effect of liver fibrosis on tumor size. A limitation to the study is that the number of animals in each group was relatively small, which might reduce statistical efficiency. In summary, liver fibrosis facilitated tumor immunity escape but limited the expansion of tumor size, and this phenomenon may be related to the accumulation of collagen in the liver and the decrease of lymphocyte infiltration in the tumor. References . 1. Affo, S., Yu, L. X. & Schwabe, R. F. The role of cancer-associated fibroblasts and fibrosis in liver cancer. Annu. Rev. Pathol. 12 (1553–4014 (Electronic)), 153–186. https://doi.org/10.1146/annurev-pathol-052016-100322 (2017). CAS ? Article ? PubMed ? Google Scholar ? 2. El-Serag, H. B. Hepatocellular carcinoma. N. Engl. J. Med. 365 (12), 1118–1127 (2011). CAS ? Article ? Google Scholar ? 3. Friedman, S. L. Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver. Physiol. Rev. 88 (1), 125–172. https://doi.org/10.1152/physrev.00013.2007 (2008). CAS ? Article ? PubMed ? Google Scholar ? 4. Hernandez-Gea, V. & Friedman, S. L. Pathogenesis of liver fibrosis. Annu. Rev. Pathol. 6 (1553-4014 (Electronic)), 425–456. https://doi.org/10.1146/annurev-pathol-011110-130246 (2011). CAS ? Article ? PubMed ? Google Scholar ? 5. Kessenbrock, K., Plaks V Fau-Werb, Z. & Werb, Z. Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell 141 (1097-4172 (Electronic)), 52–67. https://doi.org/10.1016/j.cell.2010.03.015 (2010). CAS ? Article ? PubMed ? PubMed Central ? Google Scholar ? 6. Beard, R. E. et al. A comparison of surgical outcomes for noncirrhotic and cirrhotic hepatocellular carcinoma patients in a Western institution. Surgery. 154 (3), 545–555. https://doi.org/10.1016/j.surg.2013.02.019 (2013). Article ? PubMed ? Google Scholar ? 7. Kim, M. N. et al. Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with transient elastography-defined subclinical cirrhosis. Hepatology 61 (6), 1851–1859. https://doi.org/10.1002/hep.27735 (2015). Article ? PubMed ? Google Scholar ? 8. Taura, K. et al. Hepatic stellate cells secrete angiopoietin 1 that induces angiogenesis in liver fibrosis. Gastroenterology 135 (5), 1729–1738. https://doi.org/10.1053/j.gastro.2008.07.065 (2008). CAS ? Article ? PubMed ? Google Scholar ? 9. Nzeako, U. C., Goodman, Z. D. & Ishak, K. G. Hepatocellular carcinoma in cirrhotic and noncirrhotic livers. A clinico-histopathologic study of 804 North American patients. Am. J. Clin. Pathol. 105 (1), 65–75. https://doi.org/10.1093/ajcp/105.1.65 (1996). CAS ? Article ? PubMed ? Google Scholar ? 10. van Meer, S. et al. Hepatocellular carcinoma in cirrhotic versus noncirrhotic livers: Results from a large cohort in the Netherlands. Eur. J. Gastroenterol. Hepatol. 28 (3), 352–359. https://doi.org/10.1097/MEG.0000000000000527 (2016). Article ? PubMed ? Google Scholar ? 11. Huwart, L. et al. Liver fibrosis: Non-invasive assessment with MR elastography. NMR Biomed. 19 (2), 173–179. https://doi.org/10.1002/nbm.1030 (2006). Article ? PubMed ? Google Scholar ? 12. Rouviere, O. et al. MR elastography of the liver: Preliminary results. Radiology 240 (2), 440–448. https://doi.org/10.1148/radiol.2402050606 (2006). Article ? PubMed ? Google Scholar ? 13. Garrido, A. & Djouder, N. Cirrhosis: A questioned risk factor for hepatocellular carcinoma. Trends Cancer. 7 (1), 29–36. https://doi.org/10.1016/j.trecan.2020.08.005 (2021). CAS ? Article ? PubMed ? Google Scholar ? 14. Yanguas, S. C. et al. Experimental models of liver fibrosis. Arch. Toxicol. 90 (5), 1025–1048. https://doi.org/10.1007/s00204-015-1543-4 (2016). CAS ? Article ? PubMed ? Google Scholar ? 15. Li, X. et al. Influence of transarterial chemoembolization on angiogenesis and expression of vascular endothelial growth factor and basic fibroblast growth factor in rat with Walker-256 transplanted hepatoma: An experimental study. World J. Gastroenterol. 9 , 2445–2449. https://doi.org/10.3748/wjg.v9.i11.2445 (2003). CAS ? Article ? PubMed ? PubMed Central ? Google Scholar ? 16. Kuczera, D. et al. Bax/Bcl-2 protein expression ratio and leukocyte function are related to reduction of Walker-256 tumor growth after β-hydroxy-β-methylbutyrate (HMB) administration in Wistar rats. Nutr. Cancer. 64 (2), 286–293 (2012). CAS ? Article ? Google Scholar ? 17. Muta, M. et al. Mechanical analysis of tumor growth regression by the cyclooxygenase-2 inhibitor, DFU, in a Walker256 rat tumor model: Importance of monocyte chemoattractant protein-1 modulation. Clin. Cancer Res. 12 (1), 264–272. https://doi.org/10.1158/1078-0432.CCR-05-1052 (2006). CAS ? Article ? PubMed ? Google Scholar ? 18. Ogawa, T. et al. Rho-associated kinase inhibitor reduces tumor recurrence after liver transplantation in a rat hepatoma model. Am. J. Transplant. 7 (2), 347–355. https://doi.org/10.1111/j.1600-6143.2006.01647.x (2007). CAS ? Article ? PubMed ? Google Scholar ? 19. Zong, C. et al. The distinct roles of mesenchymal stem cells in the initial and progressive stage of hepatocarcinoma. Cell Death Dis. 9 (3), 345. https://doi.org/10.1038/s41419-018-0366-7 (2018). CAS ? Article ? PubMed ? PubMed Central ? Google Scholar ? 20. Puche, J. E. et al. A novel murine model to deplete hepatic stellate cells uncovers their role in amplifying liver damage in mice. Hepatology 57 (1), 340–350. https://doi.org/10.1002/hep.26053 (2013). CAS ? Article ? Google Scholar ? 21. Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nat. Commun. 4 , 2823. https://doi.org/10.1038/ncomms3823 (2013). ADS ? CAS ? Article ? PubMed ? Google Scholar ? 22. Caja, L.A.-O. et al. TGF-β and the tissue microenvironment: Relevance in fibrosis and cancer. Int. J. Mol Sci. 19 (5), 1294 (2018) ( 1422–0067 (Electronic) ). Article ? Google Scholar ? 23. Wen, S. L. et al. Celecoxib attenuates hepatic cirrhosis through inhibition of epithelial-to-mesenchymal transition of hepatocytes. J. Gastroenterol. Hepatol. 29 , 1932–1942. https://doi.org/10.1111/jgh.12641 (2014). CAS ? Article ? PubMed ? Google Scholar ? 24. Dhar, D. et al. Mechanisms of liver fibrosis and its role in liver cancer. Exp. Biol. Med. (Maywood). 245 (2), 96–108. https://doi.org/10.1177/1535370219898141 (2020). CAS ? Article ? PubMed ? PubMed Central ? Google Scholar ? 25. Calvo, F. et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat. Cell Biol. 15 (6), 637. https://doi.org/10.1038/ncb2756 (2013). CAS ? Article ? PubMed ? Google Scholar ? 26. Chinnadurai, R. & Grakoui, A. B7–H4 mediates inhibition of T cell responses by activated murine hepatic stellate cells. Hepatology 52 (6), 2177–2185. https://doi.org/10.1002/hep.23953 (2010). CAS ? Article ? PubMed ? Google Scholar ? 27. Kang, N., Gores, G. J. & Shah, V. H. Hepatic stellate cells: Partners in crime for liver metastases?. Hepatology 54 (2), 707–713. https://doi.org/10.1002/hep.24384 (2011). CAS ? Article ? PubMed ? Google Scholar ? 28. Filliol, A. & Schwabe, R. F. Contributions of fibroblasts, extracellular matrix, stiffness, and mechanosensing to hepatocarcinogenesis. Semin. Liver Dis. 39 (3), 315–333. https://doi.org/10.1055/s-0039-1685539 (2019). CAS ? Article ? PubMed ? Google Scholar ? 29. Ke, M. Y. et al. Liver fibrosis promotes immune escape in hepatocellular carcinoma via GOLM1-mediated PD-L1 upregulation. Cancer Lett. 513 , 14–25. https://doi.org/10.1016/j.canlet.2021.05.007 (2021). CAS ? Article ? PubMed ? Google Scholar ? 30. European Association for the Study of the Liver. EASL clinical practice guidelines: Management of hepatocellular carcinoma. J. Hepatol. 69 (1), 182–236 (2018). Article ? Google Scholar ? 31. Gabele, E., Brenner, D. A. & Rippe, R. A. Liver fibrosis: Signals leading to the amplification of the fibrogenic hepatic stellate cell. Front. Biosci. Landmark. 8 , D69–D77. https://doi.org/10.2741/887 (2003) ( 1093–9946 (Print) ). CAS ? Article ? Google Scholar ? 32. Henderson, N. C. et al. Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs. Nat. Med. 19 (12), 1617–1624. https://doi.org/10.1038/nm.3282 (2013). CAS ? Article ? PubMed ? Google Scholar ? 33. Flavell, R. A. et al. The polarization of immune cells in the tumour environment by TGFbeta. Nat. Rev. Immunol. 10 (8), 554–567. https://doi.org/10.1038/nri2808 (2010). CAS ? Article ? PubMed ? Google Scholar ? 34. Strieter, R. M. et al. CXC chemokines in angiogenesis. Cytokine Growth Factor Rev. 16 (6), 593–609 (2005) ( 1359–6101 (Print) ). CAS ? Article ? Google Scholar ? 35. Yu, M. C. et al. Inhibition of T-cell responses by hepatic stellate cells via B7–H1-mediated T-cell apoptosis in mice. Hepatology 40 (6), 1312–1321. https://doi.org/10.1002/hep.20488 (2004). CAS ? Article ? PubMed ? Google Scholar ? 36. Jiang, G. et al. Hepatic stellate cells preferentially expand allogeneic CD4+ CD25+ FoxP3+ regulatory T cells in an IL-2-dependent manner. Transplantation 86 (11), 1492–1502. https://doi.org/10.1097/TP.0b013e31818bfd13 (2008). CAS ? Article ? PubMed ? PubMed Central ? Google Scholar ? 37. Zhao, W. et al. Hepatic stellate cells promote tumor progression by enhancement of immunosuppressive cells in an orthotopic liver tumor mouse model. Lab Investig. 94 (2), 182–191. https://doi.org/10.1038/labinvest.2013.139 (2014). CAS ? Article ? PubMed ? Google Scholar ? 38. Rojkind M Fau-Giambrone, M. A., Giambrone Ma Fau-Biempica, L. & Biempica, L. Collagen types in normal and cirrhotic liver. Gastroenterology 76 (4), 710–719 (1979). Article ? Google Scholar ? 39. Carloni, V., Luong, T. V. & Rombouts, K. Hepatic stellate cells and extracellular matrix in hepatocellular carcinoma: More complicated than ever. Liver Int. 34 (6), 834–843. https://doi.org/10.1111/liv.12465 (2014). Article ? PubMed ? Google Scholar ? 40. Hynes, R. O. The extracellular matrix: Not just pretty fibrils. Science 326 (5957), 1216–1219 (2009) ( 1095–9203 (Electronic) ). ADS ? CAS ? Article ? Google Scholar ? 41. Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139 (5), 891–906. https://doi.org/10.1016/j.cell.2009.10.027 (2009). CAS ? Article ? PubMed ? PubMed Central ? Google Scholar ? 42. Lu, C. et al. Current perspectives on the immunosuppressive tumor microenvironment in hepatocellular carcinoma: Challenges and opportunities. Mol. Cancer. 18 , 130. https://doi.org/10.1186/s12943-019-1047-6 (2019) ( 1476–4598 (Electronic) ). CAS ? Article ? PubMed ? PubMed Central ? Google Scholar ? 43. Zhou, S. L. et al. Tumor-associated neutrophils recruit macrophages and T-regulatory cells to promote progression of hepatocellular carcinoma and resistance to sorafenib. Gastroenterology 150 , 1646-1658 e1617. https://doi.org/10.1053/j.gastro.2016.02.040 (2016) ( 1528-0012 (Electronic) ). CAS ? Article ? PubMed ? Google Scholar ? 44. Friedman, S. L. Mechanisms of hepatic fibrogenesis. Gastroenterology 134 (6), 1655–1669. https://doi.org/10.1053/j.gastro.2008.03.003 (2008). CAS ? Article ? PubMed ? Google Scholar ? 45. Lachowski, D.A.-O. et al. Matrix stiffness modulates the activity of MMP-9 and TIMP-1 in hepatic stellate cells to perpetuate fibrosis. Sci. Rep. 9 , 7299. https://doi.org/10.1038/s41598-019-43759-6 (2019) ( 2045–2322 (Electronic) ). ADS ? CAS ? Article ? PubMed ? PubMed Central ? Google Scholar ? 46. Calabro, S. R. et al. Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis. PLoS?One. 9 , e90571. https://doi.org/10.1371/journal.pone.0090571 (2014) ( 1932–6203 (Electronic) ). ADS ? CAS ? Article ? PubMed ? PubMed Central ? Google Scholar ? 47. Chen, R. et al. The significance of MMP-9 over MMP-2 in HCC invasiveness and recurrence of hepatocellular carcinoma after curative resection. Ann. Surg. Oncol. 19 (Suppl 3), S375-384. https://doi.org/10.1245/s10434-011-1836-7 (2012). Article ? PubMed ? Google Scholar ? 48. Akima, T., Tamano, M. & Hiraishi, H. Liver stiffness measured by transient elastography is a predictor of hepatocellular carcinoma development in viral hepatitis. Hepatol. Res. 41 (10), 965–970. https://doi.org/10.1111/j.1872-034X.2011.00846.x (2011). Article ? PubMed ? Google Scholar ? 49. Wang, H. M. et al. Liver stiffness measurement as an alternative to fibrotic stage in risk assessment of hepatocellular carcinoma incidence for chronic hepatitis C patients. Liver Int. 33 (5), 756–761. https://doi.org/10.1111/liv.12118 (2013). CAS ? Article ? PubMed ? Google Scholar ? 50. Schrader, J. et al. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology 53 (4), 1192–1205. https://doi.org/10.1002/hep.24108 (2011). CAS ? Article ? PubMed ? Google Scholar ? 51. Gonzalez-Guindalini, F. D. et al. Assessment of liver tumor response to therapy: Role of quantitative imaging. Radiographics 33 , 1781–1800. https://doi.org/10.1148/rg.336135511 (2013). Article ? PubMed ? Google Scholar ? 52. Patella, F. et al. Assessment of the response of hepatocellular carcinoma to interventional radiology treatments. Future Oncol. 15 (15), 1791–1804. https://doi.org/10.2217/fon-2018-0747 (2019). CAS ? Article ? PubMed ? PubMed Central ? Google Scholar ? 53. Liu, Q. P. et al. Stiffer matrix accelerates migration of hepatocellular carcinoma cells through enhanced aerobic glycolysis via the MAPK-YAP signaling. LID-10.3390/cancers12020490 [doi] LID-490. Cancers (Basel). 12 (2), 490. https://doi.org/10.3390/cancers12020490 (2020). CAS ? Article ? PubMed Central ? Google Scholar ? Download references Acknowledgements . This work was financially supported by grants from China's National Natural Science Foundation (No. 81873917). Author information . Author notes These authors contributed equally: Tongqiang Li, Jiacheng Liu and Yingliang Wang. Affiliations . Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Jiefang Avenue #1277, Wuhan, 430022, China Tongqiang Li,?Jiacheng Liu,?Yingliang Wang,?Chen Zhou,?Qin Shi,?Songjiang Huang,?Chongtu Yang,?Yang Chen,?Yaowei Bai?&?Bin Xiong Hubei Province Key Laboratory of Molecular Imaging, Wuhan, 430022, China Tongqiang Li,?Jiacheng Liu,?Yingliang Wang,?Chen Zhou,?Qin Shi,?Songjiang Huang,?Chongtu Yang,?Yang Chen,?Yaowei Bai?&?Bin Xiong Authors Tongqiang Li View author publications You can also search for this author in PubMed ? Google Scholar Jiacheng Liu View author publications You can also search for this author in PubMed ? Google Scholar Yingliang Wang View author publications You can also search for this author in PubMed ? Google Scholar Chen Zhou View author publications You can also search for this author in PubMed ? Google Scholar Qin Shi View author publications You can also search for this author in PubMed ? Google Scholar Songjiang Huang View author publications You can also search for this author in PubMed ? Google Scholar Chongtu Yang View author publications You can also search for this author in PubMed ? Google Scholar Yang Chen View author publications You can also search for this author in PubMed ? Google Scholar Yaowei Bai View author publications You can also search for this author in PubMed ? Google Scholar Bin Xiong View author publications You can also search for this author in PubMed ? Google Scholar Contributions . T.L.: conceived and designed research, performed experiments, analyzed data, interpreted results of experiments, prepared figures, drafted manuscript edited and revised manuscript, approved final version of manuscript. J.L.: conceived and designed research, performed experiments, analyzed data, interpreted results of experiments, prepared figures, drafted manuscript edited and revised manuscript, approved final version of manuscript. Y.W.: performed experiments, analyzed data. C.Z.: analyzed data. Q.S.: analyzed data. S.H.: performed experiments. C.Y.: performed experiments. Y.C.: performed experiments. Y.B.: performed experiments. B.X.: conceived and designed research, performed experiments, analyzed data, interpreted results of experiments, prepared figures, drafted manuscript edited and revised manuscript, approved final version of manuscript. Corresponding author . Correspondence to Bin Xiong . Ethics declarations . Competing interests . The authors declare no competing interests. Additional information . Publisher's note . Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Rights and permissions . Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ . Reprints and Permissions About this article . Cite this article . Li, T., Liu, J., Wang, Y. et al. Liver fibrosis promotes immunity escape but limits the size of liver tumor in a rat orthotopic transplantation model. Sci Rep 11, 22846 (2021). https://doi.org/10.1038/s41598-021-02155-9 Download citation Received : 01 September 2021 Accepted : 10 November 2021 Published : 24 November 2021 DOI : https://doi.org/10.1038/s41598-021-02155-9 Share this article . Anyone you share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the Springer Nature SharedIt content-sharing initiative Comments . By submitting a comment you agree to abide by our Terms and Community Guidelines . If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate. .

原始网站图片
 增加监测目标对象/主题,请 登录 直接在原文中划词!