Intra-Tumoral Secondary Follicle-like Tertiary Lymphoid Structures Are Associated with a Superior Prognosis of Overall Survival of Perihilar Cholangiocarcinoma.

Ectopic lymphoid structures termed tertiary lymphoid structures (TLSs) have an immunomodulatory function and positively affect prognosis in certain cancers. However, their clinical relevance and prognostic utility in perihilar cholangiocarcinoma (pCCA) are unknown. Therefore, determining the involvement and prognostic utility of TLSs in pCCA is the aim of this study. Ninety-three patients with surgically resected pCCA were included retrospectively. Hematoxylin and eosin and immunohistochemical staining identified and classified the TLSs, and multiplex immunofluorescence determined the TLS composition in the pCCA sample. The correlations between clinical features and TLSs were analyzed using either Fisher's exact test or the Chi-squared test. Recurrence-free survival (RFS) and overall survival (OS) correlations with TLSs were analyzed using Cox regression and Kaplan-Meier analyses. We identified TLSs in 86% of patients with pCCA, including lymphoid aggregates (6.45%), primary (13.98%) and secondary follicles (65.59%). Patients with intra-tumoral secondary follicle-like TLSs (S-TLSs) had better OS (p = 0.003) and RFS (p = 0.0313). The multivariate analysis identified the presence of S-TLSs as a good independent prognostic indicator for OS but not for RFS. Interestingly, the presence of S-TLS only indicated better 5-year OS in 54 patients without lymph node metastasis (LNM-, p = 0.0232) but not in the 39 patients with lymph node metastasis (LNM+, p = 0.1244). Intra-tumoral S-TLSs predicted longer OS in patients with surgically resected pCCA, suggesting intra-tumoral S-TLSs' contribution to effective antitumor immunity and that S-TLSs hold promise for diagnostic and therapeutic development in pCCA.

Activation of the Notch1-c-myc-VCAM1 signalling axis initiates liver progenitor cell-driven hepatocarcinogenesis and pulmonary metastasis.

The cellular origin of hepatocellular carcinomas (HCC) and the role of Notch1 signalling in HCC initiation are controversial. Herein, we establish Notch1 as a regulator of HCC development and progression. Clinically, high Notch1 expression correlates with enhanced cancer progression, elevated lung metastasis, increased cancer stem cell (CSC)-like cells' gene signature expression, and poor overall survival in HCC patients. Notch1 intracellular domain (N1ICD) overexpression spontaneously transforms rat liver progenitor cells (LPC) into CSC-like cells (WBN1ICD C5) under a selective growth environment, while orthotopic injection of these cells generates liver tumors and spontaneous pulmonary metastasis in an isogenic rat model. Mechanistically, the elevated Notch1 activity increases c-myc expression, which then transcriptionally upregulates VCAM1 expression to activate macrophage dependent HCC transendothelial migration. In vivo, silencing c-myc prohibits the tumorigenicity of WBN1ICD C5 cells, while depletion of VCAM1 reduces spontaneous lung metastasis without affecting primary WBN1ICD C5 orthotopic liver tumor growth. Importantly, depletion of macrophage or blockade of macrophage VCAM1 binding receptor α4ß1-integrin reduces the number of WBN1ICD C5 lung nodules in an experimental metastasis model. Overall, our work discovers that the Notch1-c-myc-VCAM1 signaling axis initiates LPC-driven hepatocarcinogenesis and metastasis, providing a preclinical model for HCC study and therapeutic targets for an improved HCC treatment.

EZH2 facilitates BMI1-dependent hepatocarcinogenesis through epigenetically silencing microRNA-200c.

EZH2, a histone methyltransferase, has been shown to involve in cancer development and progression via epigenetic regulation of tumor suppressor microRNAs, whereas BMI1, a driver of hepatocellular carcinoma (HCC), is a downstream target of these microRNAs. However, it remains unclear whether EZH2 can epigenetically regulate microRNA expression to modulate BMI1-dependent hepatocarcinogenesis. Here, we established that high EZH2 expression correlated with enhanced tumor size, elevated metastasis, increased relapse, and poor prognosis in HCC patients. Further clinical studies revealed that EZH2 overexpression was positively correlated to its gene copy number gain/amplification in HCC. Mechanistically, EZH2 epigenetically suppressed miR-200c expression both in vitro and in vivo, and more importantly, miR-200c post-transcriptionally regulated BMI1 expression by binding to the 3'-UTR region of its mRNA. Furthermore, miR-200c overexpression inhibits the growth of HCC cells in vivo. Silencing miR-200c rescued the tumorigenicity of EZH2-depleted HCC cells, whereas knocking down BMI1 reduced the promoting effect of miR-200c depletion on HCC cell migration. Finally, combination treatment of EZH2 and BMI1 inhibitors further inhibited the viability of HCC cells compared with the cells treated with EZH2 or BMI1 inhibitor alone. Our findings demonstrated that alteration of EZH2 gene copy number status induced BMI1-mediated hepatocarcinogenesis via epigenetically silencing miR-200c, providing novel therapeutic targets for HCC treatment.

Construction of a risk score prognosis model based on hepatocellular carcinoma microenvironment.

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer with a poor prognosis. Previous studies revealed that the tumor microenvironment (TME) plays an important role in HCC progression, recurrence, and metastasis, leading to poor prognosis. However, the effects of genes involved in TME on the prognosis of HCC patients remain unclear. Here, we investigated the HCC microenvironment to identify prognostic genes for HCC. AIM: To identify a robust gene signature associated with the HCC microenvironment to improve prognosis prediction of HCC. METHODS: We computed the immune/stromal scores of HCC patients obtained from The Cancer Genome Atlas based on the ESTIMATE algorithm. Additionally, a risk score model was established based on Differentially Expressed Genes (DEGs) between high- and low-immune/stromal score patients. RESULTS: The risk score model consisting of eight genes was constructed and validated in the HCC patients. The patients were divided into high- or low-risk groups. The genes (Disabled homolog 2, Musculin, C-X-C motif chemokine ligand 8, Galectin 3, B-cell-activating transcription factor, Killer cell lectin like receptor B1, Endoglin and adenomatosis polyposis coli tumor suppressor) involved in our risk score model were considered to be potential immunotherapy targets, and they may provide better performance in combination. Functional enrichment analysis showed that the immune response and T cell receptor signaling pathway represented the major function and pathway, respectively, related to the immune-related genes in the DEGs between high- and low-risk groups. The receiver operating characteristic (ROC) curve analysis confirmed the good potency of the risk score prognostic model. Moreover, we validated the risk score model using the International Cancer Genome Consortium and the Gene Expression Omnibus database. A nomogram was established to predict the overall survival of HCC patients. CONCLUSION: The risk score model and the nomogram will benefit HCC patients through personalized immunotherapy.

Prognostic role of the pre-treatment platelet-lymphocyte ratio in pancreatic cancer: a meta-analysis.

BACKGROUND AND AIMS: Recently, the pre-treatment platelet-lymphocyte ratio (PLR), which is based on blood parameters, was accepted as a prognostic factor for patients with various cancers. Numerous studies have investigated the prognostic role of the PLR in pancreatic cancer; however, it remains unclear. Therefore, we conducted this meta-analysis to evaluate the relationship between the pre-treatment PLR and overall survival (OS) in pancreatic cancer. MATERIALS AND METHODS: We performed a systematic literature search of the PubMed, Embase and Web of Science databases for relevant studies that explored the prognostic role of the pre-treatment PLR in pancreatic cancer. The hazard ratios (HRs) and 95% confidence intervals (CIs) related to OS were pooled using a random effects model. RESULTS: Fourteen retrospective cohort studies involving 2,260 patients were included in this meta-analysis. Compared with low PLR, high PLR was a predictor of shorter OS (HR = 1.24, 95% CI: 1.10-1.39, I2 = 74%). CONCLUSIONS: In this meta-analysis, high pre-treatment PLR was a bio-predictor of short OS in patients with pancreatic cancer, suggesting that PLR could be used to predict prognosis of patients with pancreatic cancer before treatment. However, additional well-designed and large-scale studies are necessary.