The Role of the Tumor Microenvironment in the Development and Progression of Hepatocellular Carcinoma

Sevic, Ina; Spinelli, Fiorella Mercedes; Cantero, María José; Reszegi, Andrea; Kovalszky, Ilona; Garcı́a, Mariana; Alaniz, Laura

doi:10.15586/hepatocellularcarcinoma.2019.ch2

Cited by 14 publications

(23 citation statements)

References 106 publications

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“…To date, pharmacological approaches in search for new drugs have focused mainly on oncogenic signaling pathways, while the tumor microenvironment (TME), in which tumors develop, has only recently become an important target for anti-cancer therapies. The TME contributes to three key mechanisms of cancers to evade immune recognition—(1) allowing the (epithelial) cancer cells to thrive in a chronically inflamed environment by shifting the micromilieu towards immunosuppression; (2) promoting cancer growth via inducing angiogenesis in a hypoxic environment; (3) facilitating active immune evasion of the cancer cells [ 10 ]. The cellular TME has been best studied and first successful therapies have emerged based on the development of checkpoint inhibitors that block immune suppressive signaling between myeloid and T cells [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

“…In each case the ECM supports the growth of tumor nodules and forms the interface between the cancer and the nontumorous tissues of the body. In advanced cancer, the TME usually mediates immunosuppression and transcriptional alterations in the TME were found to be more predictive for the survival of HCC patients than in the tumor epithelia themselves, underlining a key role of the TME in cancer progression [ 10 ]. Importantly, apart from the immune cells in the tumor connective tissue that are skewed towards immunosuppression, the tumor myofibroblasts, that is, the cancer associated fibroblasts (CAF), support cancer growth by secreting pro-cancerous, immunosuppressive and pro-angiogenic ECM components and growth factors.…”

Section: Introductionmentioning

confidence: 99%

“…Importantly, apart from the immune cells in the tumor connective tissue that are skewed towards immunosuppression, the tumor myofibroblasts, that is, the cancer associated fibroblasts (CAF), support cancer growth by secreting pro-cancerous, immunosuppressive and pro-angiogenic ECM components and growth factors. In this vein, analysis of the connective tissue of HCC has revealed several immune- and ECM-related transcriptome signatures derived from CAF that can be correlated with tumor growth and aggressiveness and patient survival [ 10 , 16 , 17 , 18 , 19 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers

Kaps

Schuppan

2020

Cells

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Cancer associated fibroblasts (CAF) and the extracellular matrix (ECM) produced by them have been recognized as key players in cancer biology and emerged as important targets for cancer treatment and drug discovery. Apart from their presence in stroma rich tumors, such as biliary, pancreatic and subtypes of hepatocellular cancer (HCC), both CAF and certain ECM components are also present in cancers without an overt intra-tumoral desmoplastic reaction. They support cancer development, growth, metastasis and resistance to chemo- or checkpoint inhibitor therapy by a multitude of mechanisms, including angiogenesis, ECM remodeling and active immunosuppression by secretion of tumor promoting and immune suppressive cytokines, chemokines and growth factors. CAF resemble activated hepatic stellate cells (HSC)/myofibroblasts, expressing α-smooth muscle actin and especially fibroblast activation protein (FAP). Apart from FAP, CAF also upregulate other functional cell surface proteins like platelet-derived growth factor receptor β (PDGFRβ) or the insulin-like growth factor receptor II (IGFRII). Notably, if formulated with adequate size and zeta potential, injected nanoparticles home preferentially to the liver. Several nanoparticular formulations were tested successfully to deliver dugs to activated HSC/myofibroblasts. Thus, surface modified nanocarriers with a cyclic peptide binding to the PDGFRβ or with mannose-6-phosphate binding to the IGFRII, effectively directed drug delivery to activated HSC/CAF in vivo. Even unguided nanohydrogel particles and lipoplexes loaded with siRNA demonstrated a high in vivo uptake and functional siRNA delivery in activated HSC, indicating that liver CAF/HSC are also addressed specifically by well-devised nanocarriers with optimized physicochemical properties. Therefore, CAF have become an attractive target for the development of stroma-based cancer therapies, especially in the liver.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers

Kaps

Schuppan

2020

Cells

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“…Conventional treatment does not meet the requirements for longer survival time and higher quality of life. An increasing number of studies revealed that the tumor microenvironment and the expression of immune checkpoint molecules accelerated the progression of cancers ( 8 – 10 ). The use of immune checkpoint inhibitors markedly improved the prognosis of cancers (e.g., melanoma) ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

The Potential of Five Immune-Related Prognostic Genes to Predict Survival and Response to Immune Checkpoint Inhibitors for Soft Tissue Sarcomas Based on Multi-Omic Study

et al. 2020

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Low response rates to immunotherapy have been reported in soft tissue sarcoma (STS). There are few predictive biomarkers of response, and the tumor immune microenvironment associated with progression and prognosis remains unclear in STS. Gene expression data from the Cancer Genome Atlas were used to identify the immune-related prognostic genes (IRPGs) and construct the immune gene-related prognostic model (IGRPM). The tumor immune microenvironment was characterized to reveal differences between patients with different prognoses. Furthermore, somatic mutation data and DNA methylation data were analyzed to understand the underlying mechanism leading to different prognoses. The IGRPM was constructed using five IRPGs (IFIH1, CTSG, STC2, SECTM1, and BIRC5). Two groups (high-and low-risk patients) were identified based on the risk score. Low-risk patients with higher overall survival time had higher immune scores, more immune cell infiltration (e.g., CD8 T cell and activated natural killer cells), higher expression of immune-stimulating molecules, higher stimulating cytokines and corresponding receptors, higher innate immunity molecules, and stronger antigen-presenting capacity. However, inhibition of immunity was observed in low-risk patients owing to the higher expression of immune checkpoint molecules and inhibiting cytokines. High-risk patients had high tumor mutation burden, which did not significantly influence survival. Gene set enrichment analysis further revealed that pathways of cell cycle and cancers were activated in high-risk patients. DNA methylation analysis indicated that relative high methylation was associated with better overall survival. Finally, the age, mitotic counts, and risk scores were independent prognostic factors for STS. Five IRPGs performed well in risk stratification of patients and are candidate biomarkers for predicting response to immunotherapy. Differences observed through the multi-omic Gu et al. Immune Characterization of STS study of patients with different prognoses may reveal the underlying mechanism of the development and progression of STS, and thereby improve treatment.

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“…The following studies investigate these dual roles in relation to the activation of HSCs in the hepatic TME. Budhu and Wang, 2006;Fu et al, 2007;Hoechst et al, 2008;Jeong et al, 2011 Cytokines (IL-6, IL-8, IL-22): small proteins involved in a range of cell signaling that help drive fibrosis, HSC activation, and contribute to angiogenesis Chiu et al, 2014;Sevic et al, 2019 Cancer associated fibroblasts: type of cancer stromal cell critical to tumorigenesis regulation by possessing the ability to remodel the ECM and secrete proteins such as cytokines and VEGF Yin et al, 2019 Both cellular and non-cellular components cooperate in the hepatic TME to aid in hepatocarcinogenesis.…”

Section: Micro-rna Involvement In Hsc Activation In the Hepatic Tmementioning

confidence: 99%

Hepatic Stellate Cells and Hepatocarcinogenesis

Barry

Baldeosingh

Lamm

et al. 2020

Front. Cell Dev. Biol.

104

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Hepatic stellate cells (HSCs) are a significant component of the hepatocellular carcinoma (HCC) tumor microenvironment (TME). Activated HSCs transform into myofibroblastlike cells to promote fibrosis in response to liver injury or chronic inflammation, leading to cirrhosis and HCC. The hepatic TME is comprised of cellular components, including activated HSCs, tumor-associated macrophages, endothelial cells, immune cells, and non-cellular components, such as growth factors, proteolytic enzymes and their inhibitors, and other extracellular matrix (ECM) proteins. Interactions between HCC cells and their microenvironment have become topics under active investigation. These interactions within the hepatic TME have the potential to drive carcinogenesis and create challenges in generating effective therapies. Current studies reveal potential mechanisms through which activated HSCs drive hepatocarcinogenesis utilizing matricellular proteins and paracrine crosstalk within the TME. Since activated HSCs are primary secretors of ECM proteins during liver injury and inflammation, they help promote fibrogenesis, infiltrate the HCC stroma, and contribute to HCC development. In this review, we examine several recent studies revealing the roles of HSCs and their clinical implications in the development of fibrosis and cirrhosis within the hepatic TME.

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The Role of the Tumor Microenvironment in the Development and Progression of Hepatocellular Carcinoma

Cited by 14 publications

References 106 publications

Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers

Targeting Cancer Associated Fibroblasts in Liver Fibrosis and Liver Cancer Using Nanocarriers

The Potential of Five Immune-Related Prognostic Genes to Predict Survival and Response to Immune Checkpoint Inhibitors for Soft Tissue Sarcomas Based on Multi-Omic Study

Hepatic Stellate Cells and Hepatocarcinogenesis

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