GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer

Brun, Sonia; Pascussi, Jean‐Marc; Gifu, Elena Patricia; Bestion, Eloïne; Jilkova, Zuzana Macek; Wang, Guanxiong; Bassissi, Firas; Mezouar, Soraya; Courcambeck, Jérôme; Merle, Philippe; Decaens, Thomas; Pannequin, Julie; Halfon, Philippe; Fromentel, Claude Caron de

doi:10.7150/jca.58533

Cited by 9 publications

(9 citation statements)

References 48 publications

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“…By contrast, a classical rat model of DEN-induced HCC is based on chronic exposure to DEN which, by itself, leads to chronic inflammation and fibrosis, followed by HCC after 14–20 weeks [ 5 , 6 , 30 ]. However, while the DEN-induced mouse model of HCC is well described and characterized, there is still limited information about the DEN-induced rat model, despite this model being widely used in preclinical testing to target liver fibrosis and HCC [ 5 , 6 , 30 , 31 , 32 , 33 ]. Here, we performed a characterization, including an RNA-seq analysis, to identify the molecular signatures associated with DEN-induced liver cancer development in rats and compared them with the expression profiles of human HCC.…”

Section: Discussionmentioning

confidence: 99%

DEN-Induced Rat Model Reproduces Key Features of Human Hepatocellular Carcinoma

Kurma

Manches

Chuffart

et al. 2021

Cancers

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Hepatocellular carcinoma (HCC) is the most common type of liver cancer. The majority of HCC cases are associated with liver fibrosis or cirrhosis developing from chronic liver injuries. The immune system of the liver contributes to the severity of tissue damage, the establishment of fibrosis and the disease’s progression towards HCC. Herein, we provide a detailed characterization of the DEN-induced HCC rat model during fibrosis progression and HCC development with a special focus on the liver’s inflammatory microenvironment. Fischer 344 male rats were treated weekly for 14 weeks with intra-peritoneal injections of 50 mg/kg DEN. The rats were sacrificed before starting DEN-injections at 0 weeks, after 8 weeks, 14 weeks and 20 weeks after the start of DEN-injections. We performed histopathological, immunohistochemical, RT-qPCR, RNA-seq and flow cytometry analysis. Data were compared between tumor and non-tumor samples from the DEN-treated versus untreated rats, as well as versus human HCCs. Chronic DEN injections lead to liver damage, hepatocytes proliferation, liver fibrosis and cirrhosis, disorganized vasculature, and a modulated immune microenvironment that mimics the usual events observed during human HCC development. The RNA-seq results showed that DEN-induced liver tumors in the rat model shared remarkable molecular characteristics with human HCC, especially with HCC associated with high proliferation. In conclusion, our study provides detailed insight into hepatocarcinogenesis in a commonly used model of HCC, facilitating the future use of this model for preclinical testing.

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Section: Discussionmentioning

confidence: 99%

DEN-Induced Rat Model Reproduces Key Features of Human Hepatocellular Carcinoma

Kurma

Manches

Chuffart

et al. 2021

Cancers

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“…Numerous cellular processes contribute to the maintenance of the specific functions of CSCs, including autophagy and EVs secretion [ 282 ], with autophagy contributing to the transport of cellular proteins as well as the secretion of EVs [ 282 , 283 ]. Targeting EV secretion could become a possible therapeutic strategy for anti-tumor therapy [ 282 , 284 ]. EV-mediated communication between non-CSCs and CSCs are essential for adaptation to the ecological niches [ 285 , 286 ].…”

Section: Secretome-targeted Immunotherapy For Cscsmentioning

confidence: 99%

Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment

Xiang

Jiang

et al. 2023

Mol Cancer

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Ongoing research has revealed that the existence of cancer stem cells (CSCs) is one of the biggest obstacles in the current cancer therapy. CSCs make an influential function in tumor progression, recurrence and chemoresistance due to their typical stemness characteristics. CSCs are preferentially distributed in niches, and those niche sites exhibit characteristics typical of the tumor microenvironment (TME). The complex interactions between CSCs and TME illustrate these synergistic effects. The phenotypic heterogeneity within CSCs and the spatial interactions with the surrounding tumor microenvironment led to increased therapeutic challenges. CSCs interact with immune cells to protect themselves against immune clearance by exploiting the immunosuppressive function of multiple immune checkpoint molecules. CSCs also can protect themselves against immune surveillance by excreting extracellular vesicles (EVs), growth factors, metabolites and cytokines into the TME, thereby modulating the composition of the TME. Therefore, these interactions are also being considered for the therapeutic development of anti-tumor agents. We discuss here the immune molecular mechanisms of CSCs and comprehensively review the interplay between CSCs and the immune system. Thus, studies on this topic seem to provide novel ideas for reinvigorating therapeutic approaches to cancer.

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“…A critical function of CSCs is immune surveillance, by which many cancers are protected by resistance to immunotherapy [ 24 , 30 , 32 ] and also to drugs [ 36 ]. Additional cellular processes that contribute to CSC function, i.e., autophagy and EV secretion, are important also for cell survival [ 21 , 37 , 38 , 39 , 40 ]. Autophagy, which contributes to the traffic, turnover, and secretion of cytoplasmic proteins and membranes, favors CSCs and their vesicles [ 37 , 38 ].…”

Section: Cscs and Their Evs Are Essential For Cancer Initiation And Its Processesmentioning

confidence: 99%

“…Autophagy, which contributes to the traffic, turnover, and secretion of cytoplasmic proteins and membranes, favors CSCs and their vesicles [ 37 , 38 ]. Inhibitors, which affect EV secretion, are now believed to be highly important and attractive for anticancer therapy [ 37 , 39 ]. Bypassing autophagy inhibition can be achieved by drugs [ 39 ], thanks to the acute adaptability and plasticity of CSCs [ 17 ].…”

Section: Cscs and Their Evs Are Essential For Cancer Initiation And Its Processesmentioning

confidence: 99%

“…Inhibitors, which affect EV secretion, are now believed to be highly important and attractive for anticancer therapy [ 37 , 39 ]. Bypassing autophagy inhibition can be achieved by drugs [ 39 ], thanks to the acute adaptability and plasticity of CSCs [ 17 ]. EVs duplicate many effects of CSCs and are essential for the communication between various types of cells concentrated in the niches [ 7 , 21 , 28 ].…”

Section: Cscs and Their Evs Are Essential For Cancer Initiation And Its Processesmentioning

confidence: 99%

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Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development

Meldolesi

2022

IJMS

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Stem cells, identified several decades ago, started to attract interest at the end of the nineties when families of mesenchymal stem cells (MSCs), concentrated in the stroma of most organs, were found to participate in the therapy of many diseases. In cancer, however, stem cells of high importance are specific to another family, the cancer stem cells (CSCs). This comprehensive review is focused on the role and the mechanisms of CSCs and of their specific extracellular vesicles (EVs), which are composed of both exosomes and ectosomes. Compared to non-stem (normal) cancer cells, CSCs exist in small populations that are preferentially distributed to the niches, such as minor specific tissue sites corresponding to the stroma of non-cancer tissues. At niches and marginal sites of other cancer masses, the tissue exhibits peculiar properties that are typical of the tumor microenvironment (TME) of cancers. The extracellular matrix (ECM) includes components different from non-cancer tissues. CSCs and their EVs, in addition to effects analogous to those of MSCs/EVs, participate in processes of key importance, specific to cancer: generation of distinct cell subtypes, proliferation, differentiation, progression, formation of metastases, immune and therapy resistance, cancer relapse. Many of these, and other, effects require CSC cooperation with surrounding cells, especially MSCs. Filtered non-cancer cells, especially macrophages and fibroblasts, contribute to collaborative cancer transition/integration processes. Therapy developments are mentioned as ongoing preclinical initiatives. The preliminary state of clinical medicine is presented in terms of both industrial development and future treatments. The latter will be administered to specific patients together with known drugs, with the aim of eradicating their tumor growth and metastases.

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GNS561, a New Autophagy Inhibitor Active against Cancer Stem Cells in Hepatocellular Carcinoma and Hepatic Metastasis from Colorectal Cancer

Cited by 9 publications

References 48 publications

DEN-Induced Rat Model Reproduces Key Features of Human Hepatocellular Carcinoma

DEN-Induced Rat Model Reproduces Key Features of Human Hepatocellular Carcinoma

Cross-talk between cancer stem cells and immune cells: potential therapeutic targets in the tumor immune microenvironment

Cancer Stem Cells and Their Vesicles, Together with Other Stem and Non-Stem Cells, Govern Critical Cancer Processes: Perspectives for Medical Development

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