scholarly journals The interaction between cancer associated fibroblasts and tumor associated macrophages via the osteopontin pathway in the tumor microenvironment of hepatocellular carcinoma

Oncotarget ◽  
2021 ◽  
Vol 12 (4) ◽  
pp. 333-343
Author(s):  
Kazunori Tokuda ◽  
Yuji Morine ◽  
Katsuki Miyazaki ◽  
Shinichiro Yamada ◽  
Yu Saito ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Cancer Associated Fibroblasts ◽  
Tumor Associated Macrophages

scholarly journals The Inflammatory Microenvironment in Hepatocellular Carcinoma: A Pivotal Role for Tumor-Associated Macrophages

2013 ◽  
Vol 2013 ◽  
pp. 1-15 ◽  
Author(s):  
Daria Capece ◽  
Mariafausta Fischietti ◽  
Daniela Verzella ◽  
Agata Gaggiano ◽  
Germana Cicciarelli ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Growth Factors ◽  
Tumor Microenvironment ◽  
Cancer Cells ◽  
Signaling Pathways ◽  
Matrix Metalloproteases ◽  
Pivotal Role ◽  
M2 Macrophage ◽  
Tumor Associated Macrophages

Hepatocellular carcinoma (HCC) is one of the most common and aggressive human cancers worldwide. HCC is an example of inflammation-related cancer and represents a paradigm of the relation occurring between tumor microenvironment and tumor development. Tumor-associated macrophages (TAMs) are a major component of leukocyte infiltrate of tumors and play a pivotal role in tumor progression of inflammation-related cancer, including HCC. Several studies indicate that, in the tumor microenvironment, TAMs acquire an M2-polarized phenotype and promote angiogenesis, metastasis, and suppression of adaptive immunity through the expression of cytokines, chemokines, growth factors, and matrix metalloproteases. Indeed, an established M2 macrophage population has been associated with poor prognosis in HCC. The molecular links that connect cancer cells and TAMs are not completely known, but recent studies have demonstrated that NF-κB, STAT-3, and HIF-1 signaling pathways play key roles in this crosstalk. In this paper, we discuss the current knowledge about the role of TAMs in HCC development, highlighting the role of TAM-derived cytokines, chemokines, and growth factors in the initiation and progression of liver cancer and outlining the signaling pathways involved in the interplay between cancer cells and TAMs.

scholarly journals Potential therapeutic targets in the tumor microenvironment of hepatocellular carcinoma: reversing the protumor effect of tumor-associated macrophages

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Jingyi Zhou ◽  
Weiyu Wang ◽  
Qi Li
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Therapeutic Targets ◽  
Interaction Network ◽  
Cell Interaction ◽  
Macrophage Phenotype ◽  
Tumor Associated Macrophages ◽  
Dynamic Interactions ◽  
Immune Modulators

AbstractIn hepatocellular carcinoma patients, due to the microenvironmental specificity of liver, the tumor microenvironment exhibits high immunosuppression and drug resistance, resulting in excessive or insufficient responses to immunotherapy. The dynamic interactions between tumor cells and immune modulators in the TME significantly impact the occurrence and development of tumors, efficacy, and drug resistance, which can create a much more positive response to immunotherapy. Moreover, with the wide application of single-cell sequencing technology in the TME, increasing evidence shows an interaction network among cells. Sequencing results suggest that specific tumor-associated macrophages are a hub node, connecting different cell populations in the cell interaction network, and can could regulate tumor generation and antitumor immunity. This review focused on therapeutic targets that could be targeted to remodel the tumor microenvironment and reprogram the tumor-associated macrophage phenotype in hepatocellular carcinoma patients, thereby improving immunotherapeutic efficacy.

scholarly journals Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma

2021 ◽  
Vol 22 (9) ◽  
pp. 4710
Author(s):  
Dong-Jun Park ◽  
Pil-Soo Sung ◽  
Gil-Won Lee ◽  
Sungwoo Cho ◽  
Sung-Min Kim ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Tumor Microenvironment ◽  
Cd8 T Cells ◽  
M2 Macrophages ◽  
Tumor Associated Macrophages ◽  
Activation Markers ◽  
Programmed Death Ligand 1 ◽  
Programmed Death ◽  
Syngeneic Mouse Model

A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68+ macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (P < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8+ T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4+ and CD8+ T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8+ T cells in HCC.

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.

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