scholarly journals HIF-1α promoted vasculogenic mimicry formation in hepatocellular carcinoma through LOXL2 up-regulation in hypoxic tumor microenvironment

2017 ◽  
Vol 36 (1) ◽  
Author(s):  
Meili Wang ◽  
Xiulan Zhao ◽  
Dongwang Zhu ◽  
Tieju Liu ◽  
Xiaohui Liang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Vasculogenic Mimicry ◽  
Hypoxic Tumor

scholarly journals Aneuploid Circulating Tumor-Derived Endothelial Cell (CTEC): A Novel Versatile Player in Tumor Neovascularization and Cancer Metastasis

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1539 ◽  
Author(s):  
Peter Ping Lin
Keyword(s):  
Endothelial Cells ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Vasculogenic Mimicry ◽  
Mesenchymal Transition ◽  
Tumor Neovascularization ◽  
Hypoxic Tumor

Hematogenous and lymphogenous cancer metastases are significantly impacted by tumor neovascularization, which predominantly consists of blood vessel-relevant angiogenesis, vasculogenesis, vasculogenic mimicry, and lymphatic vessel-related lymphangiogenesis. Among the endothelial cells that make up the lining of tumor vasculature, a majority of them are tumor-derived endothelial cells (TECs), exhibiting cytogenetic abnormalities of aneuploid chromosomes. Aneuploid TECs are generated from “cancerization of stromal endothelial cells” and “endothelialization of carcinoma cells” in the hypoxic tumor microenvironment. Both processes crucially engage the hypoxia-triggered epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndoMT). Compared to the cancerization process, endothelialization of cancer cells, which comprises the fusion of tumor cells with endothelial cells and transdifferentiation of cancer cells into TECs, is the dominant pathway. Tumor-derived endothelial cells, possessing the dual properties of cancerous malignancy and endothelial vascularization ability, are thus the endothelialized cancer cells. Circulating tumor-derived endothelial cells (CTECs) are TECs shed into the peripheral circulation. Aneuploid CD31+ CTECs, together with their counterpart CD31- circulating tumor cells (CTCs), constitute a unique pair of cellular circulating tumor biomarkers. This review discusses a proposed cascaded framework that focuses on the origins of TECs and CTECs in the hypoxic tumor microenvironment and their clinical implications for tumorigenesis, neovascularization, disease progression, and cancer metastasis. Aneuploid CTECs, harboring hybridized properties of malignancy, vascularization and motility, may serve as a unique target for developing a novel metastasis blockade cancer therapy.

scholarly journals Identifying cancer-associated fibroblasts as emerging targets for hepatocellular carcinoma

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jie Zhang ◽  
Chaoyu Gu ◽  
Qianqian Song ◽  
Mengqi Zhu ◽  
Yuqing Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Vasculogenic Mimicry ◽  
Cancer Associated Fibroblasts ◽  
Biological Functions ◽  
Ecm Remodeling ◽  
Downstream Signaling ◽  
Cellular Origin ◽  
Suppressive Phenotype

Abstract The tumor microenvironment (TME) is a complex multicellular functional compartment that includes fibroblasts, myofibroblasts, endothelial cells, immune cells, and extracellular matrix (ECM) elements. The microenvironment provides an optimum condition for the initiation, growth, and dissemination of hepatocellular carcinoma (HCC). As one of the critical and abundant components in tumor microenvironment, cancer-associated fibroblasts (CAFs) have been implicated in the progression of HCC. Through secreting various growth factors and cytokines, CAFs contribute to the ECM remodeling, stem features, angiogenesis, immunosuppression, and vasculogenic mimicry (VM), which reinforce the initiation and development of HCC. In order to restrain the CAFs-initiated HCC progression, current strategies include targeting specific markers, engineering CAFs with tumor-suppressive phenotype, depleting CAFs’ precursors, and repressing the secretions or downstream signaling. In this review, we update the emerging understanding of CAFs in HCC, with particular emphasis on cellular origin, phenotypes, biological functions and targeted strategies. It provides insights into the targeting CAFs for HCC treatment.

Status and Development of The Tumor Microenvironment in Hepatocellular Carcinoma*

2012 ◽  
Vol 39 (5) ◽  
pp. 416-422
Author(s):  
Zhi-Lei LIU ◽  
Wei SUN ◽  
Fu-Chu HE ◽  
Xian-Ling CONG ◽  
Ying JIANG
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment

scholarly journals Is the Rationale of Anatomical Liver Resection for Hepatocellular Carcinoma Universally Adoptable? A Hypothesis-Driven Review

Medicina ◽  
2021 ◽  
Vol 57 (2) ◽  
pp. 131
Author(s):  
Young-Jen Lin ◽  
Cheng-Maw Ho
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Surgical Resection ◽  
Tumor Recurrence ◽  
Hepatic Metastases ◽  
Vascular Supply ◽  
Tumor Ablation ◽  
Supporting Evidence ◽  
En Bloc ◽  
Margin Width

Surgical resection is the first-line curative treatment modality for resectable hepatocellular carcinoma (HCC). Anatomical resection (AR), described as systematic removal of a liver segment confined by tumor-bearing portal tributaries, may improve survival by reducing the risk of tumor recurrence compared with non-AR. In this article, we propose the rationale for AR and its universal adoption by providing supporting evidence from the advanced understanding of a tumor microenvironment and accumulating clinical experiences of locoregional tumor ablation therapeutics. AR may be advantageous because it completely removes the en-bloc by interrupting tumor vascular supply and thus extirpates the spreading of tumor microthrombi, if they ever exist, within the supplying portal vein. However, HCC is a hypervascular tumor that can promote neoangiogenesis in the local tumor microenvironment, which in itself can break through the anatomical boundary within the liver and even retrieve nourishment from extrahepatic vessels, such as inferior phrenic or omental arteries. Additionally, increasing clinical evidence for locoregional tumor ablation therapies, such as radiofrequency ablation, predominantly performed as a non-anatomical approach, suggests comparable outcomes for surgical resection, particularly in small HCC and colorectal, hepatic metastases. Moreover, liver transplantation for HCC, which can be considered as AR of the whole liver followed by implantation of a new graft, is not universally free from post-transplant tumor recurrence. Overall, AR should not be considered the gold standard among all surgical resection methods. Surgical resection is fundamentally reliant on choosing the optimal margin width to achieve en-bloc tumor niche removal while balancing between oncological radicality and the preservation of postoperative liver function. The importance of this is to liberate surgical resilience in hepatocellular carcinoma. The overall success of HCC treatment is determined by the clearance of the theoretical niche. Developing biomolecular-guided navigation device/technologies may provide surgical guidance toward the total removal of microscopic tumor niche to achieve superior oncological outcomes.

scholarly journals New Insights into the Role of miR-29a in Hepatocellular Carcinoma: Implications in Mechanisms and Theragnostics

2021 ◽  
Vol 11 (3) ◽  
pp. 219
Author(s):  
Ya-Ling Yang ◽  
Yen-Hsiang Chang ◽  
Chia-Jung Li ◽  
Ying-Hsien Huang ◽  
Ming-Chao Tsai ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Crucial Role ◽  
Human Cancer ◽  
Metabolic Adaptation ◽  
Advanced Hcc ◽  
Diagnosis And Prognosis ◽  
Competitive Endogenous Rnas ◽  
Growing Body

Hepatocellular carcinoma (HCC) remains one of the most lethal human cancer globally. For advanced HCC, curable plan for advanced HCC is yet to be established, and the prognosis remains poor. The detail mechanisms underlying the progression of HCC tumorigenicity and the corruption of tumor microenvironment (TME) is complex and inconclusive. A growing body of studies demonstrate microRNAs (miRs) are important regulators in the tumorigenicity and TME development. Notably, mounting evidences indicate miR-29a play a crucial role in exerting hepatoprotective effect on various types of stress and involved in the progression of HCC, which elucidates their potential theragnostic implications. In this review, we reviewed the advanced insights into the detail mechanisms by which miR-29a dictates carcinogenesis, epigenetic program, and metabolic adaptation, and implicated in the sponging activity of competitive endogenous RNAs (ceRNA) and the TME components in the scenario of HCC. Furthermore, we highlighted its clinical significance in diagnosis and prognosis, as well as the emerging therapeutics centered on the activation of miR-29a.

scholarly journals Prognostic and clinicopathological significance of hypoxia-inducible factors 1α and 2α in hepatocellular carcinoma: a systematic review with meta-analysis

2021 ◽  
Vol 13 ◽  
pp. 175883592098707
Author(s):  
Carolina Méndez-Blanco ◽  
Paula Fernández-Palanca ◽  
Flavia Fondevila ◽  
Javier González-Gallego ◽  
José L. Mauriz
Keyword(s):  
Hepatocellular Carcinoma ◽  
Subgroup Analysis ◽  
Tumor Size ◽  
Vasculogenic Mimicry ◽  
Disease Free Survival ◽  
Clinicopathological Features ◽  
Hypoxia Inducible Factors ◽  
Free Survival ◽  
Node Metastasis ◽  
Clinicopathological Significance

Background: Hepatocellular carcinoma (HCC) is a highly recurrent tumor after resection and has been closely related to hypoxia. Hypoxia-inducible factors 1α and 2α (HIF-1α and HIF-2α) have been shown to contribute to tumor progression and therapy resistance in HCC. We evaluated the prognostic and clinicopathological significance of HIF-1α and HIF-2α in HCC patients. Methods: We systematically searched Embase, Cochrane, PubMed, Scopus and Web of Science (WOS) from inception to 1 June 2020 for studies evaluating HIF-1α and/or HIF-2α expression in HCC. Selected articles evaluate at least one factor by immunohistochemistry (IHC) in HCC patients who underwent surgical resection, and its relationship with prognosis and/or clinicopathological features. Study protocol was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CDR42020191977). We meta-analyzed the data extracted or estimated according to the Parmar method employing STATA software. We evaluated the overall effect size for the hazard ratio (HR) and odds ratio (OR) with 95% confidence interval (CI), as well as heterogeneity across studies with the I2 statistic and chi-square-based Q test. Moreover, we conducted subgroup analysis when heterogeneity was substantial. Publication bias was assessed by funnel plot asymmetry and Egger’s test. Results: HIF-1α overexpression was correlated with overall survival (OS), disease-free survival (DFS)/recurrence-free survival (RFS) and clinicopathological features including Barcelona Clinic Liver Cancer (BCLC), capsule infiltration, intrahepatic metastasis, lymph node metastasis, tumor–node–metastasis (TNM), tumor differentiation, tumor number, tumor size (3 cm), vascular invasion and vasculogenic mimicry. We also detected a possible correlation of HIF-1α with alpha-fetoprotein (AFP), cirrhosis, histological grade, tumor size (5 cm) and albumin after subgroup analysis. Initially, only DFS/RFS appeared to be associated with HIF-2α overexpression. Subgroup analysis denoted that HIF-2α overexpression was related to OS and capsule infiltration. Conclusions: HIF-1α and HIF-2α overexpression is related to poor OS, DFS/RFS and some clinicopathological features of HCC patients, suggesting that both factors could be useful HCC biomarkers.

scholarly journals Multiparametric Analyses of Hepatocellular Carcinoma Somatic Mouse Models and Their Associated Tumor Microenvironment

2021 ◽  
Vol 1 (6) ◽  
Author(s):  
Daniel Taranto ◽  
Christel F.A. Ramirez ◽  
Serena Vegna ◽  
Marnix H.P. Groot ◽  
Niels Wit ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Mouse Models

scholarly journals Cyclin B1 acts as a tumor microenvironment-related cancer promoter and prognostic biomarker in hepatocellular carcinoma

2021 ◽  
Vol 49 (5) ◽  
pp. 030006052110162
Author(s):  
Yangming Hou ◽  
Xin Wang ◽  
Junwei Wang ◽  
Xuemei Sun ◽  
Xinbo Liu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Proportional Hazards ◽  
Enrichment Analysis ◽  
Gene Signature ◽  
Cyclin B1 ◽  
Cox Proportional Hazards ◽  
Gene Set Enrichment Analysis ◽  
Tumor Promoter ◽  
Protein Protein Interaction

Objectives The present study aimed to develop a gene signature based on the ESTIMATE algorithm in hepatocellular carcinoma (HCC) and explore possible cancer promoters. Methods The ESTIMATE and CIBERSORT algorithms were applied to calculate the immune/stromal scores and the proportion of tumor-infiltrating immune cells (TICs) in a cohort of HCC patients. The differentially expressed genes (DEGs) were screened by Cox proportional hazards regression analysis and protein–protein interaction (PPI) network construction. Cyclin B1 (CCNB1) function was verified using experiments. Results The stromal and immune scores were associated with clinicopathological factors and recurrence-free survival (RFS) in HCC patients. In total, 546 DEGs were up-regulated in low score groups, 127 of which were associated with RFS. CCNB1 was regarded as the most predictive factor closely related to prognosis of HCC and could be a cancer promoter. Gene Set Enrichment Analysis (GSEA) and CIBERSORT analyses indicated that CCNB1 levels influenced HCC tumor microenvironment (TME) immune activity. Conclusions The ESTIMATE signature can be used as a prognosis tool in HCC. CCNB1 is a tumor promoter and contributes to TME status conversion.

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