The Stem Cells in Liver Cancers and the Controversies

The identification of putative liver stem cells has brought closer the previously separate fields of liver development, regeneration, and carcinogenesis. Significant overlaps in the regulation of these processes are now being described. For example, studies in embryonic liver development have already provided the basis for directed differentiation of human embryonic stem cells and induced pluripotent stem cells into hepatocyte-like cells. As a result, the understanding of the cell biology of proliferation and differentiation in the liver has been improved. This knowledge can be used to improve the function of hepatocyte-like cells for drug testing, bioartificial livers, and transplantation. In parallel, the mechanisms regulating cancer cell biology are now clearer, providing fertile soil for novel therapeutic approaches. Recognition of the relationships between development, regeneration, and carcinogenesis, and the increasing evidence for the role of stem cells in all of these areas, has sparked fresh enthusiasm in understanding the underlying molecular mechanisms and has led to new targeted therapies for liver cirrhosis and primary liver cancers.

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GNS561, a new autophagy inhibitor active against cancer stem cells in hepatocellular carcinoma and hepatic metastasis from colorectal cancer

10.1101/2020.12.21.423741 ◽

2020 ◽

Author(s):

S. Brun ◽

J.M. Pascussi ◽

E.P. Gifu ◽

E. Bestion ◽

Z. Macek-Jilkova ◽

...

Keyword(s):

Colorectal Cancer ◽

Hepatocellular Carcinoma ◽

Stem Cells ◽

Cancer Stem Cells ◽

Great Promise ◽

Advanced Hepatocellular Carcinoma ◽

Significant Activity ◽

Autophagy Inhibitor ◽

Liver Cancers

ABSTRACTPatients with advanced hepatocellular carcinoma (HCC) or metastatic colorectal cancer (mCRC) have a very poor prognosis due to the lack of efficient treatments. As observed in several other tumors, the effectiveness of treatments is mainly hampered by the presence of a highly tumorigenic subpopulation of cancer cells called cancer stem cells (CSCs). Indeed, CSCs are resistant to chemotherapy and radiotherapy and have the ability to regenerate the tumor bulk. Hence, innovative drugs that are efficient against both bulk tumor cells and CSCs would likely improve cancer treatment. In this study, we demonstrated that GNS561, a new autophagy inhibitor that induces lysosomal cell death, showed significant activity against not only the whole tumor population but also a subpopulation displaying CSC features (high ALDH activity and tumorsphere formation ability) in HCC and in liver mCRC cell lines. These results were confirmed in vivo in an HCC-induced cirrhotic rat model in which GNS561 decreased tumor growth and reduced the frequency of CSCs (CD90+CD45−). Accordingly, GNS561, which was in a global phase 1b clinical trial in liver cancers that was recently successful, offers great promise for cancer therapy by exterminating both the tumor bulk and the CSC subpopulation.

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Cancer Stem Cells in Primary Liver Cancers: Pathological Concepts and Imaging Findings

Korean Journal of Radiology ◽

10.3348/kjr.2015.16.1.50 ◽

2015 ◽

Vol 16 (1) ◽

pp. 50 ◽

Cited By ~ 22

Author(s):

Ijin Joo ◽

Haeryoung Kim ◽

Jeong Min Lee

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Imaging Findings ◽

Liver Cancers

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Cancer Stem Cells Regulation with a Sublingual Nanotherapy using Ultra Low Doses of Non-Coding RNAs

International Journal of Cancer Research & Therapy ◽

10.33140/ijcrt.04.04.05 ◽

2019 ◽

Vol 4 (4) ◽

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Progression ◽

Mrna Translation ◽

Transcriptional Level ◽

Low Doses ◽

Rna Molecules ◽

Liver Cancers ◽

Non Coding Rnas ◽

Immunocompromised Mice

Tumors are heterogeneous tissues with abundant phenotypically and functionally distinct cell subpopulations, each having different capacities to grow, differentiate, develop drug resistance and form metastases. Tumors contain a functional subpopulation of cells that exhibit stem cell properties. These cells, named cancer stem cells (CSCs), play significant roles in the initiation and progression of cancer. So far, CSCs have been identified in breast, pancreatic, prostate, colon, head and neck, ovarian and liver cancers, melanoma and brain tumors. CSCs are defined by the following properties: (a) unlimited self-renewal capacities, (b) the ability to differentiate into non-CSC daughter cells, (c) high tumorigenicity upon injection in immunocompromised mice, and (d) have remarkable resistance to conventional therapies. MicroRNAs or miRNAs are short non-coding RNAs that regulate gene expression at the post-transcriptional level by leading to the degradation of target mRNA or repression of mRNA translation. Recent studies have highlighted several miRNAs to be differentially expressed in normal and cancer stem cells and established their role in targeting genes and pathways supporting cancer stemness properties. Long non-coding RNAs (lncRNAs) are a class of non-coding RNAs that have no potential to code proteins and are more than 200 nucleotides in length. LncRNAs can act at the transcriptional, posttranscriptional and translational level. As such, they may be involved in various biological processes such as DNA damage repair, inflammation, metabolism, cell survival, cell signaling, cell growth and differentiation. Accumulating evidence indicates that lncRNAs are key regulators of the CSCs subpopulation, thereby contributing to cancer progression. These non-coding RNA molecules represent, of course, particularly attractive targets for regulating CSCs; for this purpose, we have developed a sublingual nanotherapy delivered without any undesirable side effects thanks to the use of ultra-low doses.

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Umbilical Cord Blood-Derived Mesenchymal Stem Cells Transplantation Decreases Incidence of Liver Cancer in End-Stage Liver Disease Patients: A Retrospective Analysis Over 5 Years

10.21203/rs.3.rs-749694/v1 ◽

2021 ◽

Author(s):

Le Luo ◽

Cun-You Lai ◽

Tian-Hang Feng ◽

Yu-Tong Yao ◽

Hua Xue ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Liver Cirrhosis ◽

Liver Disease ◽

Liver Cancer ◽

Umbilical Cord Blood ◽

End Stage Liver Disease ◽

Liver Cancers ◽

End Stage

Abstract Background: End-stage liver disease (ESLD) is the final stage of a liver disease, which is characterized by liver cirrhosis. ESLD largely increases possibility of liver cancers in the world. The stem cell transplantation has become an emerging therapy to treat various liver diseases including ESLD, while whether it causes liver cancer remains unclear. The study aims to analysis the long-term therapeutic effect of umbilical cord blood-derived mesenchymal stem cells (UC-MSCs) transplantation in ESLD patients. Patients and Methods: 50 ELSD patients of non-UC-MSCs transplantation and 45 ELSD patients of UC-MSCs transplantation were retrospectively analyzed. The clinical outcomes in clinical and biochemical data, complications, and quality of life were recorded at 3, 6, 12, 36, and 60 months. Results: It was found that the incidence of liver cancer was much lower in ESLD patients with UC-MSCs transplantation than in ESLD patients without UC-MSCs transplantation (12% VS 2.2%). The survival percentage was improved by treatment with UC-MSCs transplantation compared with non-UC-MSCs transplantation in ESLD patients during the five years follow-up. The inflammation and fibrosis scores were decreased in the ESLD patients with UC-MSCs transplantation. The liver cirrhosis was largely improved, and Child-Pugh scores were decreased. Conclusions: UC-MSCs transplantation is able to decrease the risks of liver cancers in ELSD patients. The reduction of liver cancer incidence might be related to decrease of inflammation by UC-MSCs transplantation. More efforts should be investigated towards increasing the number of patients and follow-up time to further verify the therapeutic benefits of UC-MSCs translations in treating liver cancers.

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