Modulating the Crosstalk between the Tumor and Its Microenvironment Using RNA Interference: A Treatment Strategy for Hepatocellular Carcinoma

Mroweh, Mariam; Decaens, Thomas; Marche, Patrice N.; Jilkova, Zuzana Macek; Clément, Flora

doi:10.3390/ijms21155250

Cited by 15 publications

(15 citation statements)

References 152 publications

(169 reference statements)

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“…The modulations in the status of TME affect an array of cells that include immune cells (resident and migratory), endothelial cells, hepatic stellate cells, and others. This leads to the differentiation of cells into those that support tumor development and progression: tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), and cancer-associated fibroblasts (CAFs) [ 3 ]. The changes in the phenotypic and secretory profile of cells of TME result from the change in the transcriptome and/or an altered protein function in the cells accompanied by dysregulation of the complex signaling pathways in the cells.…”

Section: Introductionmentioning

confidence: 99%

Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment

Mroweh

Roth

Decaens

et al. 2021

IJMS

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Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related deaths worldwide, and its incidence is rising. HCC develops almost exclusively on the background of chronic liver inflammation, which can be caused by chronic alcohol consumption, viral hepatitis, or an unhealthy diet. The key role of chronic inflammation in the process of hepatocarcinogenesis, including in the deregulation of innate and adaptive immune responses, has been demonstrated. The inhibition of Akt (also known as Protein Kinase B) directly affects cancer cells, but this therapeutic strategy also exhibits indirect anti-tumor activity mediated by the modulation of the tumor microenvironment, as demonstrated by using Akt inhibitors AZD5363, MK-2206, or ARQ 092. Moreover, the isoforms of Akt converge and diverge in their designated roles, but the currently available Akt inhibitors fail to display an isoform specificity. Thus, selective Akt inhibition needs to be better explored in the context of HCC and its possible combination with immunotherapy. This review presents a compact overview of the current knowledge concerning the role of Akt in HCC and the effect of Akt inhibition on the HCC and liver tumor microenvironment.

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Section: Introductionmentioning

confidence: 99%

Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment

Mroweh

Roth

Decaens

et al. 2021

IJMS

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“…In recent years, more and more research has focused on the importance of the tumor microenvironment in driving malignancy, including in digestive system tumors ( 9 – 12 ). Most of the previous studies have only focused on tumor cells themselves and their internal mechanisms, but mutual communication and regulation exist between tumor cells and other components of their microenvironment ( 13 – 15 ). Through paracrine mechanisms, tumor cells could reprogram their surrounding immune and stromal microenvironments into a “pro-tumor” microenvironment.…”

Section: Introductionmentioning

confidence: 99%

Re-Clustering and Profiling of Digestive System Tumors According to Microenvironment Components

Wang¹,

Guo²,

Chen³

et al. 2021

Front. Oncol.

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BackgroundImmunotherapy has become the most promising therapy in digestive system tumors besides conventional chemotherapy and radiotherapy. But only a few patients can benefit from different types of immunotherapies, such as immune checkpoint blockade (ICB). To identify these ICB-susceptible patients, methods are urgently needed to screen and profile subgroups of patients with different responsiveness to ICB.MethodsThis study carried out analysis on patients with digestive system tumors that were obtained from Cancer Genome Atlas (TCGA) cohorts. The analyses were mainly performed using GraphPad Prism 7 and R language.ResultsWe have quantified the microenvironmental components of eight digestive system tumor patients in TCGA cohorts and evaluated their clinical value. We re-clustered patients based on their microenvironment composition and divided these patients into six clusters. The differences between these six clusters were profiled, including survival conditions, enriched biological processes, genomic mutations, and microenvironment traits. Cluster 3 was the most immune-related cluster, exhibiting a high infiltration of non-tumor components and poor survival status, along with an inhibitory immune status, and we found that patients with high stromal score indicated a poor response in ICB cohort.ConclusionsOur research provides a new strategy based on the microenvironment components for the reclassification of digestive system tumors, which could provide guidance for prognosis judgment and treatment response prediction like ICB.

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“…RNAi technology has gained wide acceptance as a tool for knocking down specific cellular transcripts; hence it has been valuable for elucidation of molecular pathways, factors involved in diseases, and potential treatments [ 1 , 2 , 3 , 4 ]. However, many issues must be addressed before this technology can be used in clinical practice, including off-target effects, the requirement for multiple rounds of transfection to achieve effective knockdown, the limited ability to target nuclear transcripts, and the costs associated with making chemical modifications in siRNA or generating viral vectors for shRNA [ 1 , 5 , 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Effective RNA Knockdown Using CRISPR-Cas13a and Molecular Targeting of the EML4-ALK Transcript in H3122 Lung Cancer Cells

Saifullah

Sakari

Suzuki

et al. 2020

IJMS

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RNAi technology has significant potential as a future therapeutic and could theoretically be used to knock down disease-specific RNAs. However, due to frequent off-target effects, low efficiency, and limited accessibility of nuclear transcripts, the clinical application of the technology remains challenging. In this study, we first assessed the stability of Cas13a mRNA and guide RNA. Next, we titrated Cas13a and guide RNA vectors to achieve effective knockdown of firefly luciferase (FLuc) RNA, used as a target transcript. The interference specificity of Cas13a on guide RNA design was next explored. Subsequently, we targeted the EML4-ALK v1 transcript in H3122 lung cancer cells. As determined by FLuc assay, Cas13a exhibited activity only toward the orientation of the crRNA–guide RNA complex residing at the 5′ of the crRNA. The activity of Cas13a was maximal for guide RNAs 24–30 bp in length, with relatively low mismatch tolerance. After knockdown of the EML4-ALK transcript, cell viability was decreased up to 50%. Cas13a could effectively knock down FLuc luminescence (70–76%), mCherry fluorescence (72%), and EML4-ALK at the protein (>80%) and transcript levels (26%). Thus, Cas13a has strong potential for use in RNA regulation and therapeutics, and could contribute to the development of personalized medicine.

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Modulating the Crosstalk between the Tumor and Its Microenvironment Using RNA Interference: A Treatment Strategy for Hepatocellular Carcinoma

Cited by 15 publications

References 152 publications

Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment

Targeting Akt in Hepatocellular Carcinoma and Its Tumor Microenvironment

Re-Clustering and Profiling of Digestive System Tumors According to Microenvironment Components

Effective RNA Knockdown Using CRISPR-Cas13a and Molecular Targeting of the EML4-ALK Transcript in H3122 Lung Cancer Cells

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