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 Key Factor Regulating Inflammatory Microenvironment, Metastasis, and Resistance in Breast Cancer: Interleukin-1 Signaling

2021 ◽  
Vol 2021 ◽  
pp. 1-18
Author(s):  
Fengjie Liu ◽  
Lihong Li ◽  
Meng Lan ◽  
Tengteng Zou ◽  
Zhaodi Kong ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Interleukin 1 ◽  
Therapeutic Targets ◽  
Metastatic Breast ◽  
Receptor System ◽  
Inflammatory Infiltration ◽  
Inflammatory Microenvironment ◽  
Incidence And Mortality

Breast cancer is one of the top-ranked cancers for incidence and mortality worldwide. The biggest challenges in breast cancer treatment are metastasis and drug resistance, for which work on molecular evaluation, mechanism studies, and screening of therapeutic targets is ongoing. Factors that lead to inflammatory infiltration and immune system suppression in the tumor microenvironment are potential therapeutic targets. Interleukin-1 is known as a proinflammatory and immunostimulatory cytokine, which plays important roles in inflammatory diseases. Recent studies have shown that interleukin-1 cytokines drive the formation and maintenance of an inflammatory/immunosuppressive microenvironment through complex intercellular signal crosstalk and tight intracellular signal transduction, which were found to be potentially involved in the mechanism of metastasis and drug resistance of breast cancer. Some preclinical and clinical treatments or interventions to block the interleukin-1/interleukin-1 receptor system and its up- and downstream signaling cascades have also been proven effective. This study provides an overview of IL-1-mediated signal communication in breast cancer and discusses the potential of IL-1 as a therapeutic target especially for metastatic breast cancer and combination therapy and current problems, aiming at enlightening new ideas in the study of inflammatory cytokines and immune networks in the tumor microenvironment.

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 Agent-Based Learning Model for the Obesity Paradox in RCC

2021 ◽  
Vol 9 ◽  
Author(s):  
Matteo Belenchia ◽  
Giacomo Rocchetti ◽  
Stefano Maestri ◽  
Alessia Cimadamore ◽  
Rodolfo Montironi ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Environmental Changes ◽  
Interaction Network ◽  
Obesity Paradox ◽  
Cell Interaction ◽  
Computational Framework ◽  
Agent Based ◽  
Medical Needs ◽  
Starting Model ◽  
Cell Cell

A recent study on the immunotherapy treatment of renal cell carcinoma reveals better outcomes in obese patients compared to lean subjects. This enigmatic contradiction has been explained, in the context of the debated obesity paradox, as the effect produced by the cell-cell interaction network on the tumor microenvironment during the immune response. To better understand this hypothesis, we provide a computational framework for the in silico study of the tumor behavior. The starting model of the tumor, based on the cell-cell interaction network, has been described as a multiagent system, whose simulation generates the hypothesized effects on the tumor microenvironment. The medical needs in the immunotherapy design meet the capabilities of a multiagent simulator to reproduce the dynamics of the cell-cell interaction network, meaning a reaction to environmental changes introduced through the experimental data.

scholarly journals Bioinformatic Evidence Reveals that Cell Cycle Correlated Genes Drive the Communication between Tumor Cells and the Tumor Microenvironment and Impact the Outcomes of Hepatocellular Carcinoma

2021 ◽  
Vol 2021 ◽  
pp. 1-25
Author(s):  
Dongdong Chen ◽  
Zhijun Feng ◽  
Mingzhen Zhou ◽  
Zhijian Ren ◽  
Fan Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Poor Prognosis ◽  
Interaction Network ◽  
Prognostic Biomarkers ◽  
Cancer Type ◽  
Hematopoietic Stem ◽  
Key Genes

Hepatocellular carcinoma (HCC) is an aggressive cancer type with poor prognosis; thus, there is especially necessary and urgent to screen potential prognostic biomarkers for early diagnosis and novel therapeutic targets. In this study, we downloaded target data sets from the GEO database, and obtained codifferentially expressed genes using the limma R package and identified key genes through the protein–protein interaction network and molecular modules, and performed GO and KEGG pathway analyses for key genes via the clusterProfiler package and further determined their correlations with clinicopathological features using the Oncomine database. Survival analysis was completed in the GEPIA and the Kaplan–Meier plotter database. Finally, correlations between key genes, cell types infiltrated in the tumor microenvironment (TME), and hypoxic signatures were explored based on the TIMER database. From the results, 11 key genes related to the cell cycle were determined, and high levels of these key genes’ expression were focused on advanced and higher grade status HCC patients, as well as in samples of TP53 mutation and vascular invasion. Besides, the 11 key genes were significantly associated with poor prognosis of HCC and also were positively related to the infiltration level of MDSCs in the TME and the HIF1A and VEGFA of hypoxic signatures, but a negative correlation was found with endothelial cells (ECs) and hematopoietic stem cells. The result determined that 11 key genes (RRM2, NDC80, ECT2, CCNB1, ASPM, CDK1, PRC1, KIF20A, DTL, TOP2A, and PBK) could play a vital role in the pathogenesis of HCC, drive the communication between tumor cells and the TME, and act as probably promising diagnostic, therapeutic, and prognostic biomarkers in HCC patients.

scholarly journals Comprehensive Pan-Cancer Genomic Analysis Reveals PHF19 as a Carcinogenic Indicator Related to Immune Infiltration and Prognosis of Hepatocellular Carcinoma

2022 ◽  
Vol 12 ◽  
Author(s):  
Zheng-yi Zhu ◽  
Ning Tang ◽  
Ming-fu Wang ◽  
Jing-chao Zhou ◽  
Jing-lin Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Microenvironment ◽  
Expression Patterns ◽  
Genomic Analysis ◽  
Interaction Network ◽  
Suppressor Cells ◽  
Cell Receptor ◽  
Phd Finger ◽  
Immune Infiltration ◽  
Pan Cancer

BackgroundAs a crucial constituent part of Polycomb repressive complex 2, PHD finger protein 19 (PHF19) plays a pivotal role in epigenetic regulation, and acts as a critical regulator of multiple pathophysiological processes. However, the exact roles of PHF19 in cancers remain enigmatic. The present research was primarily designed to provide the prognostic landscape visualizations of PHF19 in cancers, and study the correlations between PHF19 expression and immune infiltration characteristics in tumor microenvironment.MethodsRaw data in regard to PHF19 expression were extracted from TCGA and GEO data portals. We examined the expression patterns, prognostic values, mutation landscapes, and protein-protein interaction network of PHF19 in pan-cancer utilizing multiple databases, and investigated the relationship of PHF19 expression with immune infiltrates across TCGA-sequenced cancers. The R language was used to conduct KEGG and GO enrichment analyses. Besides, we built a risk-score model of hepatocellular carcinoma (HCC) and validated its prognostic classification efficiency.ResultsOn balance, PHF19 expression was significantly higher in cancers in comparison with that in noncancerous samples. Increased expression of PHF19 was detrimental to the clinical prognoses of cancer patients, especially HCC. There were significant correlations between PHF19 expression and TMB or MSI in several cancers. High PHF19 levels were critically associated with the infiltration of myeloid-derived suppressor cells (MDSCs) and Th2 subsets of CD4+ T cells in most cancers. Enrichment analyses revealed that PHF19 participated in regulating carcinogenic processes including cell cycle and DNA replication, and was correlated with the progression of HCC. Intriguingly, GSEA suggested that PHF19 was correlated with the cellular components including immunoglobulin complex and T cell receptor complex in HCC. Based on PHF19-associated functional gene sets, an eleven-gene prognostic signature was constructed to predict HCC prognosis. Finally, we validated pan-cancer PHF19 expression, and its impacts on immune infiltrates in HCC.ConclusionThe epigenetic related regulator PHF19 participates in the carcinogenic progression of multiple cancers, and may contribute to the immune infiltration in tumor microenvironment. Our study suggests that PHF19 can serve as a carcinogenic indicator related to prognosis in pan-cancer, especially HCC, and shed new light on therapeutics of cancers for clinicians.

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 circRNAs: Insight Into Their Role in Tumor-Associated Macrophages

2021 ◽  
Vol 11 ◽  
Author(s):  
Saili Duan ◽  
Shan Wang ◽  
Tao Huang ◽  
Junpu Wang ◽  
Xiaoqing Yuan
Keyword(s):  
Drug Resistance ◽  
Tumor Microenvironment ◽  
Immune Cells ◽  
Circular Rna ◽  
Vital Role ◽  
Stable Form ◽  
Tumor Associated Macrophages ◽  
Non Coding Rna ◽  
Insight Into

Currently, it is well known that the tumor microenvironment not only provides energy support for tumor growth but also regulates tumor signaling pathways and promotes the proliferation, invasion, metastasis, and drug resistance of tumor cells. The tumor microenvironment, especially the function and mechanism of tumor-associated macrophages (TAMs), has attracted great attention. TAMs are the most common immune cells in the tumor microenvironment and play a vital role in the occurrence and development of tumors. circular RNA (circRNA) is a unique, widespread, and stable form of non-coding RNA (ncRNA), but little is known about the role of circRNAs in TAMs or how TAMs affect circRNAs. In this review, we summarize the specific manifestations of circRNAs that affect the tumor-associated macrophages and play a significant role in tumor progression. This review helps improve our understanding of the association between circRNAs and TAMs, thereby promoting the development and progress of potential clinical targeted therapies.

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