Dataset Information

Morphometric Analysis of Mast Cells in Tumor Predicts Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

ABSTRACT: Tumor-infiltrating immune cells are relevant prognostic and immunotherapeutic targets in hepatocellular carcinoma (HCC). Mast cells play a key role in allergic response but may also be involved in anticancer immunity. Digital morphometric analysis of patient tissue sections has become increasingly available for clinical routine and provides unbiased quantitative data. Here, we apply morphometric analysis of mast cells to retrospectively evaluate their relevance for HCC recurrence in patients after orthotopic liver transplantation (OLT). A total of 173 patients underwent OLT for HCC at the Medical University of Vienna (21 women, 152 men; 55.2 ± 7.9 years; 74 beyond Milan criteria, 49 beyond up-to-7 criteria for liver transplantation). Tissue arrays from tumors and corresponding surrounding tissues were immunohistochemically stained for mast cell tryptase. Mast cells were quantified by digital tissue morphometric analysis and correlated with HCC recurrence. Mast cells were detected in 93% of HCC tumors and in all available surrounding liver tissues. Tumor tissues revealed lower mast cell density than corresponding surrounding tissues (P < 0.0001). Patients lacking intratumoral mast cells (iMCs) displayed larger tumors and higher tumor recurrence rates both in the whole cohort (hazard ratio [HR], 2.74; 95% confidence interval [CI], 1.09-6.93; P = 0.029) and in patients beyond transplant criteria (Milan HR, 2.81; 95% CI, 1.04-7.62; P = 0.01; up-to-7 HR, 3.58; 95% CI, 1.17-10.92; P = 0.02). Notably, high iMC identified additional patients at low risk classified outside the Milan and up-to-7 criteria, whereas low iMC identified additional patients at high risk classified within the alpha-fetoprotein French and Metroticket criteria. iMCs independently predicted tumor recurrence in a multivariate Cox regression analysis (Milan HR, 2.38; 95% CI, 1.16-4.91; P = 0.019; up-to-7 HR, 2.21; 95% CI, 1.05-4.62; P = 0.035). Conclusion: Hepatic mast cells might be implicated in antitumor immunity in HCC. Morphometric analysis of iMCs refines prognosis of HCC recurrence after liver transplantation.

SUBMITTER: Rohr-Udilova N

PROVIDER: S-EPMC8557312 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:Background: Liver transplantation (LT) for Hepatocellular carcinoma (HCC) can be offered to patients beyond Milan criteria. However, there are currently no molecular markers that can be used on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to identify proteins on HCC explant predictive of recurrence post-transplant, thereby guiding surveillance strategies and identifying patients beyond Milan criteria who would fare well following LT. Methods: LT recipients who had been transplanted at the University Health Network for HCC beyond Milan criteria in the context of Hepatitis B cirrhosis were identified. Snap-frozen samples from the dominant tumors of recurrent (N=7) and non-recurrent (N=4) patients were analyzed using LC-MS/MS on a Q-Exactive Plus mass spectrometer to delineate a distinctive proteomic signature. These tumors were also profiled by a Human Gene 2.0 ST microarray platform to identify a transcriptomic signature predictive of recurrence and analyzed with R packages. STRING database was used to characterize the implicated pathways. Kaplan-Meier estimator was used to generate a combined proteomic/transcriptomic signature predictive of HCC recurrence in patients with HCC beyond Milan criteria at time of LT. Significantly predictive proteins were verified and internally validated by immunoblotting or immunohistochemistry. Results: A total of 79 proteins and 636 genes were significantly differentially expressed in recurrent HCC, compared to non-recurrent (p<0.05). Among these, LGALS3, LGALS3BP, HAL, THBS1, and BLMH, were significantly increased in recurrent HCC at the protein and gene expression level. In turn, ALDH1A1 protein and gene expression were significantly decreased in recurrent HCC. Univariate survival analysis depicted ALDH1A1 (HR=0.084, 95%CI 0.01-0.68, p=0.02), LGALS3BP (HR=7.14, 95%CI 1.20-42.96, p=0.03), and LGALS3 (HR=2.89, 95%CI 1.01-8.3, p=0.049) as the key dysregulated proteins and genes in the patients with HCC recurrence versus those with non-recurrence by both proteomic and transcriptomic analysis. Decreased ALDH1A1 and significantly increased LGALS3 protein expression in recurrent HCC was verified by immunoblotting. Increased LGALS3BP protein expression in recurrent HCC was orthogonally verified and validated by immunohistochemistry in 30 independent HCC samples. Conclusion: Protein and gene expression of the cancer stem cell marker ALDH1A1 was protective against cancer recurrence in patients transplanted for HCC beyond Milan criteria. Conversely, increased expression of LGALS3 and LGALS3BP on explant was significantly predictive of post-transplant recurrence. These findings were internally validated, suggesting potential utility in identifying patients with HCC beyond Milan who would clearly benefit from transplant with limited recurrence risk and guiding post-transplant surveillance.

Project description:Recently, evidence that Zinc transporter ZRT/IRT-like protein 4 (ZIP4) is involved in invasiveness and apoptosis has emerged in pancreatic cancer and prostate cancer. Our aim was to assess the role of ZIP4 in invasiveness, migration and apoptosis of hepatocellular carcinoma (HCC). The prognostic value of ZIP4 in HCC after liver transplantation was evaluated.The role of ZIP4 in HCC was investigated by overexpressing ZIP4 in BEL7402 and HepG2 cells and inhibiting ZIP4 in HuH-7 and HepG2 cells, using overexpression and shRNA plasmids in vitro studies. Immunohistochemical analysis was used to evaluate ZIP4 expression in HCC tissues from 60 patients undergoing liver transplantation, 36 cirrhotic tissue samples, and 6 normal tissue samples. Prognostic significance was assessed using the Kaplan-Meier method and the log-rank test.Specific suppression of ZIP4 reduced cell migration and invasiveness, whereas ZIP4 overexpression caused increases in cell migration and invasiveness. Furthermore, overexpression of ZIP4 resulted in increased expression of pro-metastatic genes (MMP-2, MMP-9) and decreased expression of pro-apoptotic genes (caspase-3, caspase-9, Bax). In contrast, suppression of ZIP4 resulted in an opposite effect. ZIP4 was more highly expressed in tumor tissues than non-tumor tissues (P < 0.0001). ZIP4 expression was significantly associated with tumor recurrence (P = 0.002), tumor node metastasis stage (P = 0.044), Child-Turcotte-Pugh score (P = 0.042), and tumor size (P = 0.022). Univariate analysis showed that ZIP4 expression was significantly associated with overall survival (P = 0.020) and tumor-free survival (P = 0.049). Multivariate analysis revealed that ZIP4 was an independent predictor of overall survival (P = 0.037) after liver transplantation.ZIP4 could promote migration, invasiveness, and suppress apoptosis in hepatocellular carcinoma, and represent a novel predictor of poor prognosis and therapeutic target for patients with HCC who undergo liver transplantation.

Dataset Information

Morphometric Analysis of Mast Cells in Tumor Predicts Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets