scholarly journals Metastasis of Cancer Stem Cells Developed in the Microenvironment of Hepatocellular Carcinoma

2019 ◽  
Vol 6 (3) ◽  
pp. 73 ◽  
Author(s):  
Said M. Afify ◽  
Ghmkin Hassan ◽  
Amira Osman ◽  
Anna Sanchez Calle ◽  
Hend M Nawara ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Cultured Cells ◽  
Malignant Tumors ◽  
Metastatic Potential ◽  
Metastatic Cells ◽  
Huh7 Cells ◽  
Induced Pluripotent

Metastasis develops when cancer cells spread from the primary site of a malignant tumor to the surrounding and distant tissues, and it is the most critical problem in cancer treatment. Our group developed cancer stem cells (CSCs) from induced pluripotent stem cells (iPSCs) in the presence of a conditioned medium (CM) of cancer-derived cells. The CSCs were characterized by the formation of malignant tumors in vivo, followed by metastasis. In this study, CSCs converted from mouse iPSCs in the presence of CM from hepatocellular carcinoma (HCC) cell line Huh7 cells. These converted cells (miPS-Huh7cm cells) were established as the metastatic cells. The generated CSCs were injected into the liver or spleen of nude mice. Almost one month after transplantation, the tumors were excised, and the primary cultured cells derived from the malignant tumors and metastatic nodules were evaluated by stemness and metastatic markers to compare their differences. The miPS-Huh7cm cells exhibited metastatic potential, and efficiently formed malignant tumors with lung and/or liver lesions in vivo, whereas the injected miPS formed teratoma. The primary cultured cells derived from the malignant tumors and metastatic nodules sustained the expression of stemness markers, such as Nanog, Klf4 and c-Myc, and acquired cancer stem markers, such as CD90, CD44 and ALDH1. Simultaneously, the expression of metastatic markers, such as Slug, Twist1 and vimentin, in primary cells derived from the malignant tumors, was higher than in metastatic nodules. The CSCs derived from iPSCs, forming malignant tumors and displaying high metastasis, will provide a good animal model to study the mechanisms of metastasis.

scholarly journals Metastasis Model of Cancer Stem Cell-Derived Tumors

2020 ◽  
Vol 3 (3) ◽  
pp. 60 ◽  
Author(s):  
Hager Mansour ◽  
Ghmkin Hassan ◽  
Said M. Afify ◽  
Ting Yan ◽  
Akimasa Seno ◽  
...  
Keyword(s):  
Stem Cells ◽  
Malignant Tumors ◽  
Metastatic Potential ◽  
The Body ◽  
Tumor Initiating Cells ◽  
Secondary Tumors ◽  
Metastatic Cells ◽  
Metastasis Model ◽  
Induced Pluripotent ◽  
Cell Conditioned Medium

Metastasis includes the dissemination of cancer cells from a malignant tumor and seed in distant sites inside the body forming secondary tumors. Metastatic cells from the primary tumor can move even before the cancer is detected. Therefore, metastases are responsible for more than 90% of cancer-related deaths. Over recent decades there has been adequate evidence suggesting the existence of CSCs with self-renewing and drug-resistant potency within heterogeneous tumors. Cancer stem cells (CSCs) act as a tumor initiating cells and have roles in tumor retrieve and metastasis. Our group recently developed a unique CSC model from mouse induced pluripotent stem cells cultured in the presence of cancer cell-conditioned medium that mimics tumors microenvironment. Using this model, we demonstrated a new method for studying metastasis by intraperitoneal transplantation of tumors and investigate the metastasis ability of cells from these segments. First of all, CSCs were injected subcutaneously in nude mice. The developed malignant tumors were minimized then transplanted into the peritoneal cavity. Following this, the developed tumor in addition to lung, pancreas and liver were then excised and analyzed. Our method showed the metastatic potential of CSCs with the ability of disseminated and moving to blood circulation and seeding in distant organs such as lung and pancreas. This method could provide a good model to study the mechanisms of metastasis according to CSC theory.

Tropism of liver epithelial cells toward hepatocellular carcinoma in vitro and in vivo with altering gene expression of cancer stem cells

2018 ◽  
Vol 215 (4) ◽  
pp. 735-743
Author(s):  
Kuo-Shyang Jeng ◽  
Chi-Juei Jeng ◽  
Wen-Juei Jeng ◽  
I-Shyan Sheen ◽  
Shih-Yun Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Epithelial Cells ◽  
Cancer Stem Cells ◽  
Liver Epithelial Cells

scholarly journals Long noncoding RNA HULC accelerates the growth of human liver cancer stem cells by upregulating CyclinD1 through miR675-PKM2 pathway via autophagy

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Chen Wang ◽  
Xiaoxue Jiang ◽  
Xiaonan Li ◽  
Shuting Song ◽  
Qiuyu Meng ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Human Liver ◽  
Noncoding Rna ◽  
Liver Cancer Stem Cells ◽  
Huh7 Cells ◽  
Human Liver Cancer

Abstract Background The functions of HULC have been demonstrated in several cancers. However, its mechanism has not been elucidated in human liver cancer stem cells. Methods Liver cancer stem cells were isolated from Huh7 cells; gene infection and tumorigenesis test in vitro and in vivo were performed. Results We demonstrate that HULC promotes growth of liver cancer stem cells in vitro and in vivo. Mechanistically, HULC enhances the expression of Sirt1 dependent on miR675 and then induces the cellular autophagy through Sirt1. HULC enhances CyclinD1 and thereby increases pRB and inhibited P21 WAF1/CIP 1 via autophagy-miR675-PKM2 pathway in human liver cancer stem cells. Ultimately, our results demonstrate that CyclinD1 is required for the oncogenic functions of HULC in liver cancer stem cells. Conclusions It reveals the key molecular signaling pathways for HULC and provides important basic information for finding effective tumor therapeutic targets based on HULC.

scholarly journals Targeting liver cancer stem cells for the treatment of hepatocellular carcinoma

2019 ◽  
Vol 12 ◽  
pp. 175628481882156 ◽  
Author(s):  
Na Li ◽  
Ying Zhu
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Cancer Stem Cells ◽  
Liver Cancer ◽  
Malignant Tumors ◽  
Noncoding Rnas ◽  
Cellular Level ◽  
Liver Cancer Stem Cells ◽  
Oncolytic Adenoviruses ◽  
Novel Therapeutic Strategies

Liver cancer is one of the most common malignant tumors and prognosis remains poor. It has been increasingly recognized that liver cancer stem cells (LCSCs) are responsible for the carcinogenesis, recurrence, metastasis and chemoresistance of hepatocellular carcinoma (HCC). Targeting LCSCs is promising to be a new direction for the treatment of HCC. Herein, we summarize the potentially therapeutic targets in LCSCs at the level of genes, molecules and cells, such as knockout of oncogenes or oncoproteins, restoring the silent tumor suppressor genes, inhibition of the transcription factors and regulation of noncoding RNAs (including microRNAs and long noncoding RNAs) in LCSCs at the genetic level; inhibition of markers and blockade of the key signaling pathways of LCSCs at the molecular level; and inhibiting autophagy and application of oncolytic adenoviruses in LCSCs at the cellular level. Moreover, we analyze the potential targets in LCSCs to eliminate chemoresistance of HCC. Thereinto, the suppression of autophagy and Nanog by chloroquine and shRNA respectively may be the most promising targeting approaches. These targets may provide novel therapeutic strategies for the treatment of HCC by targeting LCSCs.

scholarly journals Differentiation of cancer stem cells into erythroblasts in the presence of CoCl2

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kazuki Kumon ◽  
Said M. Afify ◽  
Ghmkin Hassan ◽  
Shunsuke Ueno ◽  
Sadia Monzur ◽  
...  
Keyword(s):  
Stem Cells ◽  
Tumor Microenvironment ◽  
Cancer Stem Cells ◽  
Malignant Tumors ◽  
Multilineage Differentiation ◽  
Differentiation Potential ◽  
Hypoxic Conditions ◽  
Induced Pluripotent ◽  
Insight Into ◽  
Runx1 Expression

AbstractCancer stem cells (CSCs) are subpopulations in the malignant tumors that show self-renewal and multilineage differentiation into tumor microenvironment components that drive tumor growth and heterogeneity. In previous studies, our group succeeded in producing a CSC model by treating mouse induced pluripotent stem cells. In the current study, we investigated the potential of CSC differentiation into blood cells under chemical hypoxic conditions using CoCl2. CSCs and miPS-LLCcm cells were cultured for 1 to 7 days in the presence of CoCl2, and the expression of VEGFR1/2, Runx1, c-kit, CD31, CD34, and TER-119 was assessed by RT-qPCR, Western blotting and flow cytometry together with Wright-Giemsa staining and immunocytochemistry. CoCl2 induced significant accumulation of HIF-1α changing the morphology of miPS-LLCcm cells while the morphological change was apparently not related to differentiation. The expression of VEGFR2 and CD31 was suppressed while Runx1 expression was upregulated. The population with hematopoietic markers CD34+ and c-kit+ was immunologically detected in the presence of CoCl2. Additionally, high expression of CD34 and, a marker for erythroblasts, TER-119, was observed. Therefore, CSCs were suggested to differentiate into erythroblasts and erythrocytes under hypoxia. This differentiation potential of CSCs could provide new insight into the tumor microenvironment elucidating tumor heterogenicity.

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

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.

scholarly journals Exosomal microRNA-15a from mesenchymal stem cells impedes hepatocellular carcinoma progression via downregulation of SALL4

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yu-Shui Ma ◽  
Ji-Bin Liu ◽  
Lan Lin ◽  
Hui Zhang ◽  
Jian-Jun Wu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Luciferase Reporter ◽  
Dismal Prognosis ◽  
Huh7 Cells ◽  
Gene Assay ◽  
The Impact ◽  
Hcc Cells

AbstractHepatocellular carcinoma (HCC) is a heterogeneous tumor with an increased incidence worldwide accompanied by high mortality and dismal prognosis. Emerging evidence indicates that mesenchymal stem cells (MSCs)-derived exosomes possess protective effects against various human diseases by transporting microRNAs (miRNAs or miRs). We aimed to explore the role of exosomal miR-15a derived from MSCs and its related mechanisms in HCC. Exosomes were isolated from transduced MSCs and co-incubated with Hep3B and Huh7 cells. miR-15a expression was examined by RT-qPCR in HCC cells, MSCs, and secreted exosomes. CCK-8, transwell, and flow cytometry were used to detect the effects of miR-15a or spalt-like transcription factor 4 (SALL4) on cell proliferative, migrating, invasive, and apoptotic properties. A dual-luciferase reporter gene assay was performed to validate the predicted targeting relationship of miR-15a with SALL4. Finally, in vivo experiments in nude mice were implemented to assess the impact of exosome-delivered miR-15a on HCC. The exosomes from MSCs restrained HCC cell proliferative, migrating, and invasive potentials, and accelerated their apoptosis. miR-15a was expressed at low levels in HCC cells and could bind to SALL4, thus curtailing the proliferative, migrating, and invasive abilities of HCC cells. Exosomes successfully delivered miR-15a to HCC cells. Exosomal miR-15a depressed tumorigenicity and metastasis of HCC tumors in vivo. Overall, exosomal miR-15a from MSCs can downregulate SALL4 expression and thereby retard HCC development.

scholarly journals Intracellular Autofluorescence as a New Biomarker for Cancer Stem Cells in Glioblastoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 828
Author(s):  
Joana Vieira de Castro ◽  
Céline S. Gonçalves ◽  
Eduarda P. Martins ◽  
Irene Miranda-Lorenzo ◽  
Mariana T. Cerqueira ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Malignant Tumors ◽  
Therapy Resistance ◽  
Stem Cell Markers ◽  
Intracellular Accumulation ◽  
Single Marker ◽  
Bona Fide

The identification of cancer stem cells (CSCs), which are implicated in tumor initiation, progression, therapy resistance, and relapse, is of great biological and clinical relevance. In glioblastoma (GBM), this is still a challenge, as no single marker is able to universally identify populations of GBM cancer stem cells (GSCs). Indeed, there is still controversy on whether biomarker-expressing cells fulfill the functional criteria of bona fide GSCs, despite being widely used. Here, we describe a novel subpopulation of autofluorescent (Fluo+) cells in GBM that bear all the functional characteristics of GSCs, including higher capacity to grow as neurospheres, long-term self-renewal ability, increased expression of stem cell markers, and enhanced in vivo tumorigenicity. Mechanistically, the autofluorescent phenotype is largely due to the intracellular accumulation of riboflavin, mediated by the ABC transporter ABCG2. In summary, our work identifies an intrinsic cellular autofluorescent phenotype enriched in GBM cells with functional stem cells features that can be used as a novel, simple and reliable biomarker to target these highly malignant tumors, with implications for GBM biological and clinical research.

scholarly journals Hypoxia, Inflammation and Necrosis as Determinants of Glioblastoma Cancer Stem Cells Progression

2020 ◽  
Vol 21 (8) ◽  
pp. 2660
Author(s):  
Marco Papale ◽  
Mariachiara Buccarelli ◽  
Cristiana Mollinari ◽  
Matteo A. Russo ◽  
Roberto Pallini ◽  
...  
Keyword(s):  
Stem Cells ◽  
Cancer Stem Cells ◽  
Hypoxia Inducible Factor ◽  
Human Tumor ◽  
Metastatic Potential ◽  
Cellular Adhesion ◽  
Brain Invasion ◽  
Hypoxia Inducible Factor 1 ◽  
Tumor Tissues

Tumor hypoxic microenvironment causes hypoxia inducible factor 1 alpha (HIF-1α) activation and necrosis with alarmins release. Importantly, HIF-1α also controls the expression of alarmin receptors in tumor cells that can bind to and be activated by alarmins. Human tumor tissues possess 1–2% of cancer stem cells (CSCs) residing in hypoxic niches and responsible for the metastatic potential of tumors. Our hypothesis is that hypoxic CSCs express alarmin receptors that can bind alarmins released during necrosis, an event favoring CSCs migration. To investigate this aspect, glioblastoma stem-like cell (GSC) lines were kept under hypoxia to determine the expression of hypoxic markers as well as receptor for advanced glycation end products (RAGE). The presence of necrotic extracts increased migration, invasion and cellular adhesion. Importantly, HIF-1α inhibition by digoxin or acriflavine prevented the response of GSCs to hypoxia alone or plus necrotic extracts. In vivo, GSCs injected in one brain hemisphere of NOD/SCID mice were induced to migrate to the other one in which a necrotic extract was previously injected. In conclusion, our results show that hypoxia is important not only for GSCs maintenance but also for guiding their response to external necrosis. Inhibition of hypoxic pathway may therefore represent a target for preventing brain invasion by glioblastoma stem cells (GSCs).

scholarly journals Hematopoietic Cells Derived from Cancer Stem Cells Generated from Mouse Induced Pluripotent Stem Cells

Cancers ◽  
2019 ◽  
Vol 12 (1) ◽  
pp. 82 ◽  
Author(s):  
Ghmkin Hassan ◽  
Said M. Afify ◽  
Neha Nair ◽  
Kazuki Kumon ◽  
Amira Osman ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Cancer Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Pluripotent Stem Cells ◽  
Malignant Tumors ◽  
White Blood Cells ◽  
Hematopoietic Cells ◽  
Adherent Cells ◽  
Induced Pluripotent

Cancer stem cells (CSCs) represent the subpopulation of cancer cells with the ability to differentiate into other cell phenotypes and initiated tumorigenesis. Previously, we reported generating CSCs from mouse induced pluripotent stem cells (miPSCs). Here, we investigated the ability of the CSCs to differentiate into hematopoietic cells. First, the primary cells were isolated from malignant tumors that were formed by the CSCs. Non-adherent cells (NACs) that arose from adherent cells were collected and their viability, as well as the morphology and expression of hematopoietic cell markers, were analyzed. Moreover, NACs were injected into the tail vein of busulfan conditioned Balb/c nude mice. Finally, CSCs were induced to differentiate to macrophages while using IL3 and SCF. The round nucleated NACs were found to be viable, positive for hematopoietic lineage markers and CD34, and expressed hematopoietic markers, just like homing to the bone marrow. When NACs were injected into mice, Wright–Giemsa staining showed that the number of white blood cells got higher than those in the control mice after four weeks. CSCs also showed the ability to differentiate toward macrophages. CSCs were demonstrated to have the potential to provide progenies with hematopoietic markers, morphology, and homing ability to the bone marrow, which could give new insight into the tumor microenvironment according to the plasticity of CSCs.

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