start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=1 article-no= start-page=15628 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220917 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cancer stem cells induced by chronic stimulation with prostaglandin E2 exhibited constitutively activated PI3K axis en-subtitle= kn-subtitle= en-abstract= kn-abstract=Previously, our group has demonstrated establishment of Cancer Stem Cell (CSC) models from stem cells in the presence of conditioned medium of cancer cell lines. In this study, we tried to identify the factors responsible for the induction of CSCs. Since we found the lipid composition could be traced to arachidonic acid cascade in the CSC model, we assessed prostaglandin E2 (PGE2) as a candidate for the ability to induce CSCs from induced pluripotent stem cells (iPSCs). Mouse iPSCs acquired the characteristics of CSCs in the presence of 10 ng/mL of PGE2 after 4 weeks. Since constitutive Akt activation and pik3cg overexpression were found in the resultant CSCs, of which growth was found independent of PGE2, chronic stimulation of the receptors EP-2/4 by PGE2 was supposed to induce CSCs from iPSCs through epigenetic effect. The bioinformatics analysis of the next generation sequence data of the obtained CSCs proposed not only receptor tyrosine kinase activation by growth factors but also extracellular matrix and focal adhesion enhanced PI3K pathway. Collectively, chronic stimulation of stem cells with PGE2 was implied responsible for cancer initiation enhancing PI3K/Akt axis. en-copyright= kn-copyright= en-aut-name=MinematsuHideki en-aut-sei=Minematsu en-aut-mei=Hideki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SugiharaYuki en-aut-sei=Sugihara en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=AdachiMasaki en-aut-sei=Adachi en-aut-mei=Masaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Laboratory of Nao?Biotechnology, Division of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Division of Biochemistry, Chemistry Department, Faculty of Science, Menoufa University kn-affil= affil-num=3 en-affil=R&D Center, Katayama Chemicals Ind., Co. Ltd, Ina, Minoh kn-affil= affil-num=4 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=R&D Center, Katayama Chemicals Ind., Co. Ltd, Ina, Minoh kn-affil= affil-num=8 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=1 article-no= start-page=347 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220110 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=The efficacy of PI3K gamma and EGFR inhibitors on the suppression of the characteristics of cancer stem cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cancer stem cells (CSCs) are capable of continuous proliferation, self-renewal and are proposed to play significant roles in oncogenesis, tumor growth, metastasis and cancer recurrence. We have established a model of CSCs that was originally developed from mouse induced pluripotent stem cells (miPSCs) by proposing miPSCs to the conditioned medium (CM) of cancer derived cells, which is a mimic of carcinoma microenvironment. Further research found that not only PI3K-Akt but also EGFR signaling pathway was activated during converting miPSCs into CSCs. In this study, we tried to observe both of PI3K gamma inhibitor Eganelisib and EGFR inhibitor Gefitinib antitumor effects on the models of CSCs derived from miPSCs (miPS-CSC) in vitro and in vivo. As the results, targeting these two pathways exhibited significant inhibition of cell proliferation, self-renewal, migration and invasion abilities in vitro. Both Eganelisib and Gefitinib showed antitumor effects in vivo while Eganelisib displayed more significant therapeutic efficacy and less side effects than Gefitinib on all miPS-CSC models. Thus, these data suggest that the inhibitiors of PI3K and EGFR, especially PI3K gamma, might be a promising therapeutic strategy against CSCs defeating cancer in the near future. en-copyright= kn-copyright= en-aut-name=XuYanning en-aut-sei=Xu en-aut-mei=Yanning kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=DuJuan en-aut-sei=Du en-aut-mei=Juan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=LiuBingbing en-aut-sei=Liu en-aut-mei=Bingbing kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=WangQing en-aut-sei=Wang en-aut-mei=Qing kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=LiHanbo en-aut-sei=Li en-aut-mei=Hanbo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=LiuYixin en-aut-sei=Liu en-aut-mei=Yixin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FuXiaoying en-aut-sei=Fu en-aut-mei=Xiaoying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=ZhuZhengmao en-aut-sei=Zhu en-aut-mei=Zhengmao kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ChenLing en-aut-sei=Chen en-aut-mei=Ling kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= affil-num=1 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Department of Etiology, Shanxi Provincial Cancer Hospital kn-affil= affil-num=4 en-affil=Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Maternity Hospital, Tianjin Key Laboratory of Human Development and Reproductive Regulation kn-affil= affil-num=5 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Department of Genetics and Cell Biology, College of Life Sciences, Nankai University kn-affil= affil-num=7 en-affil=Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Maternity Hospital, Tianjin Key Laboratory of Human Development and Reproductive Regulation kn-affil= affil-num=8 en-affil=Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Maternity Hospital, Tianjin Key Laboratory of Human Development and Reproductive Regulation kn-affil= affil-num=9 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=10 en-affil=Department of Genetics and Cell Biology, College of Life Sciences, Nankai University kn-affil= affil-num=11 en-affil=Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Maternity Hospital, Tianjin Key Laboratory of Human Development and Reproductive Regulation kn-affil= affil-num=12 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=41 cd-vols= no-issue=1 article-no= start-page=29 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2022 dt-pub=20220121 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Different pancreatic cancer microenvironments convert iPSCs into cancer stem cells exhibiting distinct plasticity with altered gene expression of metabolic pathways en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background
Cancer stem cells (CSCs) are generated under irregular microenvironment in vivo, of which mimic is quite difficult due to the lack of enough information of the factors responsible for cancer initiation. Here, we demonstrated that mouse induced pluripotent cells (miPSCs) reprogrammed from normal embryonic fibroblasts were susceptible to the microenvironment affected by cancer cells to convert into CSCs in vivo.
Methods Three different pancreatic cancer line cells, BxPC3, PANC1, and PK8 cells were mixed with miPSCs and subcutaneously injected into immunodeficient mice. Tumors were evaluated by histological analysis and cells derived from iPSCs were isolated and selected from tumors. The isolated cells were characterized for cancer stem cell characters in vitro and in vivo as well as their responses to anticancer drugs. The impact of co-injection of iPSCs with cancer cells on transcriptome and signaling pathways of iPSCs was investigated.
Results The injection of miPSCs mixed with human pancreatic cancer cells into immunodeficient mice maintained the stemness of miPSCs and changed their phenotype. The miPSCs acquired CSC characteristics of tumorigenicity and self-renewal. The drug responses and the metastatic ability of CSCs converted from miPSCs varied depending on the microenvironment of cancer cells. Interestingly, transcriptome profiles of these cells indicated that the pathways related with aggressiveness and energy production were upregulated from the levels of miPSCs.
Conclusions
Our result suggests that cancer-inducing microenvironment in vivo could rewire the cell signaling and metabolic pathways to convert normal stem cells into CSCs. en-copyright= kn-copyright= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=OharaToshiaki en-aut-sei=Ohara en-aut-mei=Toshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KumonKazuki en-aut-sei=Kumon en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=FuXiaoying en-aut-sei=Fu en-aut-mei=Xiaoying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=Al KadiMohamad en-aut-sei=Al Kadi en-aut-mei=Mohamad kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=SalomonDavid S. en-aut-sei=Salomon en-aut-mei=David S. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= affil-num=1 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Department of Pathology and Experimental Medicine, Medical School, Okayama University kn-affil= affil-num=3 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=Department of Bacterial Infections, Research Institute for Microbial Diseases, Osaka University kn-affil= affil-num=8 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=9 en-affil=Mouse genetics program, Center for Cancer Research, National Cancer Institute kn-affil= affil-num=10 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=Cancer stem cells kn-keyword=Cancer stem cells en-keyword=iPSCs kn-keyword=iPSCs en-keyword=Conversion kn-keyword=Conversion en-keyword=Plasticity kn-keyword=Plasticity en-keyword=Tumorigenesis kn-keyword=Tumorigenesis en-keyword=Pancreatic cancer microenvironments kn-keyword=Pancreatic cancer microenvironments END start-ver=1.4 cd-journal=joma no-vol=11 cd-vols= no-issue=1 article-no= start-page=23977 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20211214 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Differentiation of cancer stem cells into erythroblasts in the presence of CoCl2 en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cancer 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-1 alpha 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. en-copyright= kn-copyright= en-aut-name=KumonKazuki en-aut-sei=Kumon en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=UenoShunsuke en-aut-sei=Ueno en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=MonzurSadia en-aut-sei=Monzur en-aut-mei=Sadia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=NawaraHend M. en-aut-sei=Nawara en-aut-mei=Hend M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=Abu QuoraHagar A. en-aut-sei=Abu Quora en-aut-mei=Hagar A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShetaMona en-aut-sei=Sheta en-aut-mei=Mona kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=XuYanning en-aut-sei=Xu en-aut-mei=Yanning kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FuXiaoying en-aut-sei=Fu en-aut-mei=Xiaoying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=8 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=9 en-affil=Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics, Nankai University Affiliated Maternity Hospital, Tianjin Key Laboratory of Human Development and Reproductive Regulation kn-affil= affil-num=10 en-affil=Department of Pathology, Tianjin University of Traditional Chinese Medicine kn-affil= affil-num=11 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=12 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=13 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= END start-ver=1.4 cd-journal=joma no-vol=521 cd-vols= no-issue=28 article-no= start-page=142 end-page=154 dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=202111 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Chronic exposure to FGF2 converts iPSCs into cancer stem cells with an enhanced integrin/focal adhesion/PI3K/AKT axis en-subtitle= kn-subtitle= en-abstract= kn-abstract=We previously demonstrated the conversion of normal stem cells, including induced pluripotent stem cells (iPSCs), into cancer stem cells (CSCs) without genetic manipulation. Herein, we designed a meta-analysis to assess gene expression profiles in different breast cancer cell lines focusing on the secretory factors responsible for conversion. As a result, fibroblast growth factor 2 (FGF2) was found to be the best candidate in T47D and BT549 cells, of which conditioned medium was previously successful in inducing CSCs. When treated with 3.1 ƒĘg/ml FGF2, mouse iPSCs not only maintained survival without LIF for three weeks but also acquired growth ability independent of FGF2. The resultant cells exhibited expression of stemness and cancer stem cell markers, sphere-forming ability, differentiation, and tumorigenicity with malignancy. The primary cultures of the tumor confirmed the signatures of CSCs with two different phenotypes with or without GFP expression under control of the Nanog promoter. Bioinformatic analysis of gene expression profiles suggested constitutive autocrine activation of the FGF receptor, integrins, focal adhesions, and PI3K/AKT pathways. FGF2 could potently initiate cancer as a component of the inflammatory microenvironment. en-copyright= kn-copyright= en-aut-name=ShetaMona en-aut-sei=Sheta en-aut-mei=Mona kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=MonzurSadia en-aut-sei=Monzur en-aut-mei=Sadia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=KumonKazuki en-aut-sei=Kumon en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=Abu QuoraHagar A. en-aut-sei=Abu Quora en-aut-mei=Hagar A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=FarahatMahmoud en-aut-sei=Farahat en-aut-mei=Mahmoud kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=FuXiaoying en-aut-sei=Fu en-aut-mei=Xiaoying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= affil-num=1 en-affil=Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=2 en-affil=Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=3 en-affil=Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=4 en-affil=Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=5 en-affil=Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=6 en-affil=Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=7 en-affil=Department of Biomaterials, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University kn-affil= affil-num=8 en-affil=Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=9 en-affil=Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=10 en-affil=Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= affil-num=11 en-affil=Department of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems kn-affil= en-keyword=Cancer initiation kn-keyword=Cancer initiation en-keyword=Cancer stem cells kn-keyword=Cancer stem cells en-keyword=iPSCs kn-keyword=iPSCs en-keyword=FGF2 kn-keyword=FGF2 en-keyword=Chronic inflammation kn-keyword=Chronic inflammation END start-ver=1.4 cd-journal=joma no-vol=3 cd-vols= no-issue=3 article-no= start-page=60 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200821 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Metastasis Model of Cancer Stem Cell-Derived Tumors en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=MansourHager en-aut-sei=Mansour en-aut-mei=Hager kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=YanTing en-aut-sei=Yan en-aut-mei=Ting kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Department of Pathology, Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University kn-affil= affil-num=5 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= en-keyword=metastasis kn-keyword=metastasis en-keyword=cancer stem cells kn-keyword=cancer stem cells en-keyword=transplantation kn-keyword=transplantation en-keyword=surgery kn-keyword=surgery END start-ver=1.4 cd-journal=joma no-vol=11 cd-vols= no-issue=7 article-no= start-page=3475 end-page=3495 dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=2021 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Microenvironment of mammary fat pads affected the characteristics of the tumors derived from the induced cancer stem cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Breast cancer is the first common cause of cancer-related death in women worldwide. Since the malignancy and aggressiveness of breast cancer have been correlated with the presence of breast cancer stem cells, the establishment of a disease model with cancer stem cells is required for the development of a novel therapeutic strategy. Here, we aimed to evaluate the availability of cancer stem cell models developed from mouse induced pluripotent stem cells with the conditioned medium of different subtypes of breast cancer cell lines, the hormonal-responsive T47D cell line and the triple-negative breast cancer BT549 cell line, to generate in vivo tumor models. When transplanted into the mammary fat pads of BALB/c nude mice, these two model cells formed malignant tumors exhibiting pronounced histopathological characteristics similar to breast cancers. Serial transplantation of the primary cultured cells into mammary fat pads evoked the same features of breast cancer, while this result was perturbed following subcutaneous transplantation. The tumors formed in the mammary fat pads exhibited immune reactivities to prolactin receptor, progesterone receptor, green florescent protein, Ki67, CD44, estrogen receptor alpha/beta and cytokeratin 8, while all of the tumors and their derived primary cells exhibited immunoreactivity to estrogen receptor alpha/beta and cytokeratin 8. Cancer stem cells can be developed from pluripotent stem cells via the secretory factors of cancer-derived cells with the capacity to inherit tissue specificity. However, cancer stem cells should be plastic enough to be affected by the microenvironment of specific tissues. In summary, we successfully established a breast cancer tumor model using mouse induced pluripotent stem cells developed from normal fibroblasts without genetic manipulation. en-copyright= kn-copyright= en-aut-name=Abu QuoraHagar A. en-aut-sei=Abu Quora en-aut-mei=Hagar A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=El-GhlbanSamah en-aut-sei=El-Ghlban en-aut-mei=Samah kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=NairNeha en-aut-sei=Nair en-aut-mei=Neha kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=NawaraHend M. en-aut-sei=Nawara en-aut-mei=Hend M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=ShetaMona en-aut-sei=Sheta en-aut-mei=Mona kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=MonzurSadia en-aut-sei=Monzur en-aut-mei=Sadia kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=FuXiaoying en-aut-sei=Fu en-aut-mei=Xiaoying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=OsmanAmira en-aut-sei=Osman en-aut-mei=Amira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Division of Biochemistry, Faculty of Science, Menoufia University kn-affil= affil-num=4 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=8 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=9 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=10 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=11 en-affil=Department of Histology, Faculty of Medicine, Kafr Elsheikh University kn-affil= affil-num=12 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=13 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=Mammary fat pad kn-keyword=Mammary fat pad en-keyword=microenvironment kn-keyword=microenvironment en-keyword=iPSCs kn-keyword=iPSCs en-keyword=CSCs kn-keyword=CSCs en-keyword=breast cancer kn-keyword=breast cancer END start-ver=1.4 cd-journal=joma no-vol=13 cd-vols= no-issue=10 article-no= start-page=2491 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210520 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cripto-1 as a Potential Target of Cancer Stem Cells for Immunotherapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Simple Summary Cancer immunotherapy is gaining attention as a potential fourth treatment following surgery, chemotherapy, and radiation therapy. Cancer stem cells have recently been recognized and validated as a key target for cancer treatment. Cripto-1, which is a GPI-anchored membrane-bound protein that functions as a co-receptor of Nodal, is a marker of cancer stem cells. Since Nodal is a member of the TGF-beta family, which performs an important role in stem cells and cancer stem cells, the inhibition of Cripto-1 could be a strategy by which to block Nodal signaling and thereby suppress cancer stem cells. We propose that Cripto-1 may be a novel target for cancer immunotherapy. The immune system has been found to be suppressed in cancer patients. Cancer cells are extremely resistant to chemotherapeutic drugs, conventional immunotherapy, or cancer antigen vaccine therapy. Cancer immunotherapy, which is mainly based on immune checkpoint inhibitors, such as those for PD-1, PD-L1, and CTLA4, is an effective treatment method. However, no immunotherapeutic target has been found that retains validity in the face of tumor diversity. The transforming growth factor (TGF)-beta cytokine family possesses broad biological activity and is involved in the induction and/or transdifferentiation of helper T cells, which are important in immunotherapy. Nodal is a member of the TGF-beta family playing important roles in tissue stem cells and cancer stem cells (CSCs), interacting with the co-receptor Cripto-1, as well as with Activin type IB (Alk4) and Activin typeIIreceptors, and maintaining stemness and Notch and Wnt/beta-catenin signaling in CSCs. In recent years, it has been reported that Cripto-1 could be a potential therapeutic target in CSCs. Here, we review the accumulated literature on the molecular mechanisms by which Cripto-1 functions in CSCs and discuss the potential of Cripto-1 as an immunotherapeutic target in CSCs. en-copyright= kn-copyright= en-aut-name=IshiiHiroko en-aut-sei=Ishii en-aut-mei=Hiroko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SalomonDavid S. en-aut-sei=Salomon en-aut-mei=David S. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= affil-num=1 en-affil=GSP Enterprise, Inc. kn-affil= affil-num=2 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute kn-affil= affil-num=5 en-affil= kn-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University en-keyword=Cripto-1 kn-keyword=Cripto-1 en-keyword=TGF-beta kn-keyword=TGF-beta en-keyword=cancer stem cells kn-keyword=cancer stem cells en-keyword=immunotherapy kn-keyword=immunotherapy en-keyword=antibody kn-keyword=antibody END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue=5 article-no= start-page=500 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=20210502 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Paclitaxel-Based Chemotherapy Targeting Cancer Stem Cells from Mono- to Combination Therapy en-subtitle= kn-subtitle= en-abstract= kn-abstract=Paclitaxel (PTX) is a chemotherapeutical agent commonly used to treat several kinds of cancer. PTX is known as a microtubule-targeting agent with a primary molecular mechanism that disrupts the dynamics of microtubules and induces mitotic arrest and cell death. Simultaneously, other mechanisms have been evaluated in many studies. Since the anticancer activity of PTX was discovered, it has been used to treat many cancer patients and has become one of the most extensively used anticancer drugs. Regrettably, the resistance of cancer to PTX is considered an extensive obstacle in clinical applications and is one of the major causes of death correlated with treatment failure. Therefore, the combination of PTX with other drugs could lead to efficient therapeutic strategies. Here, we summarize the mechanisms of PTX, and the current studies focusing on PTX and review promising combinations. en-copyright= kn-copyright= en-aut-name=NawaraHend M. en-aut-sei=Nawara en-aut-mei=Hend M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Department of Biotechnology and Drug Discovery, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=paclitaxel kn-keyword=paclitaxel en-keyword=microtubule targeting agent kn-keyword=microtubule targeting agent en-keyword=anticancer kn-keyword=anticancer en-keyword=cancer stem cells kn-keyword=cancer stem cells en-keyword=combination therapy kn-keyword=combination therapy END start-ver=1.4 cd-journal=joma no-vol=11 cd-vols= no-issue=2 article-no= start-page=441 end-page=457 dt-received= dt-revised= dt-accepted= dt-pub-year=2021 dt-pub=2021 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Isolation and characterization of cancer stem cells derived from human glioblastoma en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cancer stem cell (CSC) is considered as a cause of cancer recurrence and metastasis. Simultaneously CSCs are responsible for the heterogeneous population in tumor tissues due to their differentiation potential. However, the characterizations of CSCs are still not enough and cancer stem cell lines widely available is desired to be established for the advancement of cancer research. In this study, we tried to isolate and characterize stem like cells from human glioblastoma cell line U-251MG cells. U-251MG P1 cells, which was previously condensed in the presence of hyaluronic acid as CD44 positive population were subjected to single cell isolation procedure. Although 5 clones were isolated, only one clone exhibited high expression of CD44, Nanog, OCT3/4 and SOX2, and named U-251MGSC1. The sphere forming ability of U-251MGSC1 cell was significantly higher than the parental U-251MG cells. Tumorigenicity of U-251MG-SC1 cells were higher than that of U-251MG cells. U-251MGSC1 cells exhibited higher expression of CD44, SOX2, Nestin and A2B5 than U-251MG cells in vitro and in vivo. The expression of GFAP and NF-M was enhanced when the cells were treated with the conditioned medium of U-251MG cells indicating the potential of differentiation. Sphere forming ability was more efficient than that of U-251MG cells and was enhanced in the presence of hyaluronic acid, which enhanced the cell growth as well. U-251MGSC1 cells exhibited rapid growth tumor in nude mice and efficient metastatic ability in transmembrane assay when compared with U-251MG cells. As the result, we concluded U-251MGSC1 cell was a glioblastoma CSC line derived from the parental U-251MG cells. U-251MGSC1 cells will be a good tool to develop effective therapeutic agents against CSCs and to elucidate the properties of glioma derived CSCs and the mechanism of tumor development in brain. en-copyright= kn-copyright= en-aut-name=IshiiHiroko en-aut-sei=Ishii en-aut-mei=Hiroko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=MimuraYuki en-aut-sei=Mimura en-aut-mei=Yuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KatayamaShota en-aut-sei=Katayama en-aut-mei=Shota kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= affil-num=1 en-affil=GSP Enterprise, Inc. kn-affil= affil-num=2 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=Cancer stem cell kn-keyword=Cancer stem cell en-keyword=glioblastoma kn-keyword=glioblastoma en-keyword=sphere formation kn-keyword=sphere formation en-keyword=CD44 kn-keyword=CD44 en-keyword=SOX2 kn-keyword=SOX2 en-keyword=GFAP kn-keyword=GFAP END start-ver=1.4 cd-journal=joma no-vol=9 cd-vols= no-issue=1 article-no= start-page=45 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20201228 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Cancer Stem Cell Microenvironment Models with Biomaterial Scaffolds In Vitro en-subtitle= kn-subtitle= en-abstract= kn-abstract=Defined by its potential for self-renewal, differentiation and tumorigenicity, cancer stem cells (CSCs) are considered responsible for drug resistance and relapse. To understand the behavior of CSC, the effects of the microenvironment in each tissue are a matter of great concerns for scientists in cancer biology. However, there are many complicated obstacles in the mimicking the microenvironment of CSCs even with current advanced technology. In this context, novel biomaterials have widely been assessed as in vitro platforms for their ability to mimic cancer microenvironment. These efforts should be successful to identify and characterize various CSCs specific in each type of cancer. Therefore, extracellular matrix scaffolds made of biomaterial will modulate the interactions and facilitate the investigation of CSC associated with biological phenomena simplifying the complexity of the microenvironment. In this review, we summarize latest advances in biomaterial scaffolds, which are exploited to mimic CSC microenvironment, and their chemical and biological requirements with discussion. The discussion includes the possible effects on both cells in tumors and microenvironment to propose what the critical factors are in controlling the CSC microenvironment focusing the future investigation. Our insights on their availability in drug screening will also follow the discussion. en-copyright= kn-copyright= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=KitanoShiro en-aut-sei=Kitano en-aut-mei=Shiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=IshiiHiroko en-aut-sei=Ishii en-aut-mei=Hiroko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ShangYucheng en-aut-sei=Shang en-aut-mei=Yucheng kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MatsusakiMichiya en-aut-sei=Matsusaki en-aut-mei=Michiya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= affil-num=1 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Technical Research Institute, Toppan Printing Co., Ltd. kn-affil= affil-num=4 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=GSP Enterprise, Inc. kn-affil= affil-num=6 en-affil=Department of Applied Chemistry, Graduate School of Engineering, Osaka University kn-affil= affil-num=7 en-affil=Department of Applied Chemistry, Graduate School of Engineering, Osaka University kn-affil= affil-num=8 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=cancer stem cells kn-keyword=cancer stem cells en-keyword=biomaterial scaffolds kn-keyword=biomaterial scaffolds en-keyword=tumor microenvironment kn-keyword=tumor microenvironment en-keyword=drug screening kn-keyword=drug screening END start-ver=1.4 cd-journal=joma no-vol=122 cd-vols= no-issue=9 article-no= start-page=1378 end-page=1390 dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200317 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=A novel model of liver cancer stem cells developed from induced pluripotent stem cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background
Liver cancer is the second most common cause of cancer-related death. Every type of tumours including liver cancer contains cancer stem cells (CSCs). To date, the molecular mechanism regulating the development of liver CSCs remains unknown.
Methods
In this study, we tried to generate a new model of liver CSCs by converting mouse induced pluripotent stem cells (miPSCs) with hepatocellular carcinoma (HCC) cell line Huh7 cells conditioned medium (CM). miPSCs treated with CM were injected into the liver of BALB/c nude mice. The developed tumours were then excised and analysed.
Results
The primary cultured cells from the malignant tumour possessed self-renewal capacity, differentiation potential and tumorigenicity in vivo, which were found rich in liver cancer-associated markers as well as CSC markers.
Conclusions
We established a model of liver CSCs converting from miPS and showed different stages of stemness during conversion process. Our CSC model will be important to assess the molecular mechanisms necessary to develop liver CSCs and could help in defeating liver cancer. en-copyright= kn-copyright= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=CalleAnna Sanchez en-aut-sei=Calle en-aut-mei=Anna Sanchez kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KumonKazuki en-aut-sei=Kumon en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=NawaraHend M. en-aut-sei=Nawara en-aut-mei=Hend M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MansourHager M. en-aut-sei=Mansour en-aut-mei=Hager M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=KhayraniApriliana Cahya en-aut-sei=Khayrani en-aut-mei=Apriliana Cahya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=AlamMd Jahangir en-aut-sei=Alam en-aut-mei=Md Jahangir kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=DuJuan en-aut-sei=Du en-aut-mei=Juan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=IwasakiYoshiaki en-aut-sei=Iwasaki en-aut-mei=Yoshiaki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Division of Molecular and Cellular Medicine, National Cancer Center Research Institute kn-affil= affil-num=3 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=7 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=8 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=9 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=10 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=11 en-affil=Okayama University Research Laboratory of Stem Cell Engineering in Detroit, IBio, Wayne State University kn-affil= affil-num=12 en-affil=Department of Gastroenterology and Hepatology, Graduate School of Medicine, Okayama University kn-affil= affil-num=13 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= en-keyword=Cancer models kn-keyword=Cancer models en-keyword=Cancer stem cells kn-keyword=Cancer stem cells END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=6 article-no= start-page=1360 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200526 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Paclitaxel and Sorafenib: The Effective Combination of Suppressing the Self-Renewal of Cancer Stem Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Combination therapy, which is a treatment modality combining two or more therapeutic agents, is considered a cornerstone of cancer therapy. The combination of anticancer drugs, of which functions are different from the other, enhances the efficiency compared to the monotherapy because it targets cancer cells in a synergistic or an additive manner. In this study, the combination of paclitaxel and sorafenib in low concentration was evaluated to target cancer stem cells, miPS-BT549cmP and miPS-Huh7cmP cells, developed from mouse induced pluripotent stem cells. The synergistic effect of paclitaxel and sorafenib on cancer stem cells was assessed by the inhibition of proliferation, self-renewal, colony formation, and differentiation. While the IC(50)values of paclitaxel and sorafenib were approximately ranging between 250 and 300 nM and between 6.5 and 8 mu M, respectively, IC(50)of paclitaxel reduced to 20 and 25 nM, which was not toxic in a single dose, in the presence of 1 mu M sorafenib, which was not toxic to the cells. Then, the synergistic effect was further assessed for the potential of self-renewal of cancer stem cells by sphere formation ability. As a result, 1 mu M of sorafenib significantly enhanced the effect of paclitaxel to suppress the number of spheres. Simultaneously, paclitaxel ranging in 1 to 4 nM significantly suppressed not only the colony formation but also the tube formation of the cancer stem cells in the presence of 1 mu M sorafenib. These results suggest the combination therapy of paclitaxel and sorafenib in low doses should be an attractive approach to target cancer stem cells with fewer side effects. en-copyright= kn-copyright= en-aut-name=NawaraHend M. en-aut-sei=Nawara en-aut-mei=Hend M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=AtallahMarwa N. en-aut-sei=Atallah en-aut-mei=Marwa N. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MansourHager en-aut-sei=Mansour en-aut-mei=Hager kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=Abu QuoraHagar A. en-aut-sei=Abu Quora en-aut-mei=Hagar A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=AlamMd Jahangir en-aut-sei=Alam en-aut-mei=Md Jahangir kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=OsmanAmira en-aut-sei=Osman en-aut-mei=Amira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=KakutaHiroki en-aut-sei=Kakuta en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=HamadaHiroki en-aut-sei=Hamada en-aut-mei=Hiroki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name=–…”ö•jł kn-aut-sei=–…”ö kn-aut-mei=•jł aut-affil-num=12 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name=–…”öšŽĄ kn-aut-sei=–…”ö kn-aut-mei=šŽĄ aut-affil-num=13 ORCID= affil-num=1 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Vertebrates Embryology and Comparative Anatomy, Zoology Department, Faculty of Science, Menoufia University kn-affil= affil-num=6 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=8 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=9 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=10 en-affil=Division of Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences kn-affil= affil-num=11 en-affil=Department of Life Science, Faculty of Science, Okayama University of Science kn-affil= affil-num=12 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=13 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= en-keyword=cancer stem cells kn-keyword=cancer stem cells en-keyword=combination therapy kn-keyword=combination therapy en-keyword=paclitaxel kn-keyword=paclitaxel en-keyword=sorafenib kn-keyword=sorafenib END start-ver=1.4 cd-journal=joma no-vol=10 cd-vols= no-issue=1 article-no= start-page=9955 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200622 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Signaling Inhibitors Accelerate the Conversion of mouse iPS Cells into Cancer Stem Cells in the Tumor Microenvironment en-subtitle= kn-subtitle= en-abstract= kn-abstract=Cancer stem cells (CSCs) are a class of cancer cells characterized by self-renewal, differentiation and tumorigenic potential. We previously established a model of CSCs by culturing mouse induced pluripotent stem cells (miPSCs) for four weeks in the presence of a conditioned medium (CM) of cancer cell lines, which functioned as the tumor microenvironment. Based on this methodology of developing CSCs from miPSCs, we assessed the risk of 110 non-mutagenic chemical compounds, most of which are known as inhibitors of cytoplasmic signaling pathways, as potential carcinogens. We treated miPSCs with each compound for one week in the presence of a CM of Lewis lung carcinoma (LLC) cells. However, one-week period was too short for the CM to convert miPSCs into CSCs. Consequently, PDO325901 (MEK inhibitor), CHIR99021 (GSK-3 beta inhibitor) and Dasatinib (Abl, Src and c-Kit inhibitor) were found to confer miPSCs with the CSC phenotype in one week. The tumor cells that survived exhibited stemness markers, spheroid formation and tumorigenesis in Balb/c nude mice. Hence, we concluded that the three signal inhibitors accelerated the conversion of miPSCs into CSCs. Similarly to our previous study, we found that the PI3K-Akt signaling pathway was upregulated in the CSCs. Herein, we focused on the expression of relative genes after the treatment with these three inhibitors. Our results demonstrated an increased expression of pik3ca, pik3cb, pik3r5 and pik3r1 genes indicating class IA PI3K as the responsible signaling pathway. Hence, AKT phosphorylation was found to be up-regulated in the obtained CSCs. Inhibition of Erk1/2, tyrosine kinase, and/or GSK-3 beta was implied to be involved in the enhancement of the PI3K-AKT signaling pathway in the undifferentiated cells, resulting in the sustained stemness, and subsequent conversion of miPSCs into CSCs in the tumor microenvironment. en-copyright= kn-copyright= en-aut-name=DuJuan en-aut-sei=Du en-aut-mei=Juan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=XuYanning en-aut-sei=Xu en-aut-mei=Yanning kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SasadaSaki en-aut-sei=Sasada en-aut-mei=Saki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=OoAung Ko Ko en-aut-sei=Oo en-aut-mei=Aung Ko Ko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=MahmudHafizah en-aut-sei=Mahmud en-aut-mei=Hafizah kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=KhayraniApriliana Cahya en-aut-sei=Khayrani en-aut-mei=Apriliana Cahya kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=AlamMd Jahangir en-aut-sei=Alam en-aut-mei=Md Jahangir kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=KumonKazuki en-aut-sei=Kumon en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=UesakiRyo en-aut-sei=Uesaki en-aut-mei=Ryo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=MansourHager M. en-aut-sei=Mansour en-aut-mei=Hager M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=NairNeha en-aut-sei=Nair en-aut-mei=Neha kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= en-aut-name=OkadaNobuhiro en-aut-sei=Okada en-aut-mei=Nobuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=16 ORCID= en-aut-name=ChenLing en-aut-sei=Chen en-aut-mei=Ling kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=17 ORCID= en-aut-name=YanTing en-aut-sei=Yan en-aut-mei=Ting kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=18 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=19 ORCID= affil-num=1 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=8 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=9 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=10 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=11 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=12 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=13 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=14 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=15 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=16 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=17 en-affil=Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics kn-affil= affil-num=18 en-affil=Department of Pathology, Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University kn-affil= affil-num=19 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= en-keyword=2020-06-22 kn-keyword=2020-06-22 END start-ver=1.4 cd-journal=joma no-vol=8 cd-vols= no-issue=1 article-no= start-page=200 end-page=207 dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=2020 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Upregulated CCL20 and CCR6 in Cancer Stem Cells Converted from Mouse iPS Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=Background: Cancer stem cells (CSCs) as a class of malignant cancer cells play an important role in tumor progression. Previous studies by our group have demonstrated the establishment of the model of CSCs converting mouse iPS cells (miPSCs) into CSCs by treating the miPSCs with a conditioned medium (CM) of Lewis Lung Carcinoma (LLC) cells with or without the nonmutagenic chemical compounds. CSCs converted from miPSCs developed highly malignant adenocarcinoma when subcutaneously transplanted into the nude mice.
Methods: The miPSCs were treated with each compound for 1 week in the presence of a CM of LLC cells. We evaluated the gene expression in the resultant CSCs comparing that in miPSCs by microarray analysis. And the expression of chemokine (C-C motif) ligand 20 (CCL20) and C-C chemokine receptor type 6 (CCR6) in converted cells were evaluated by rt-qPCR. The CCR6 expression in converted cells and primary cells were determined by flow cytometry.
Results: As the result, the expression of CCL20 was found upregulated in the presence of CM supplemented with PD0325901. Then we assessed the expression of CCR6, which was considered to be stimulated by CCL20. Then the expression of CCR6 was also found up-regulated. Interestingly, IL17A expression was also observed only in the CSCs from the primary tumor implying the effect of tumor microenvironment. Moreover, significantly high level of CCR6 was showed in flow cytometric analysis.
Conclusion: These results suggest that a model of CSCs with CCL20-CCR6 autocrine loop was obtained as the result of the conversion of iPSCs. This CSC should be a good model to study targeting CCR6 as a G protein-coupled receptor (GPCR). en-copyright= kn-copyright= en-aut-name=DuJuan en-aut-sei=Du en-aut-mei=Juan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=SasadaSaki en-aut-sei=Sasada en-aut-mei=Saki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=XuYanning en-aut-sei=Xu en-aut-mei=Yanning kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OoAung Ko Ko en-aut-sei=Oo en-aut-mei=Aung Ko Ko kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=UenoShunsuke en-aut-sei=Ueno en-aut-mei=Shunsuke kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=ZahraMaram H en-aut-sei=Zahra en-aut-mei=Maram H kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=OkadaNobuhiro en-aut-sei=Okada en-aut-mei=Nobuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ChenLing en-aut-sei=Chen en-aut-mei=Ling kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=FuXiaoying en-aut-sei=Fu en-aut-mei=Xiaoying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=TokutakaHeizo en-aut-sei=Tokutaka en-aut-mei=Heizo kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=YanTing en-aut-sei=Yan en-aut-mei=Ting kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=15 ORCID= affil-num=1 en-affil=Department of Medical Bioengineering, Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=2 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama Universityalth Systems kn-affil= affil-num=3 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics kn-affil= affil-num=5 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=8 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=9 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=10 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=11 en-affil=Department of Pathology, Tianjin Central Hospital of Gynecology Obstetrics kn-affil= affil-num=12 en-affil=School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine kn-affil= affil-num=13 en-affil=SOM Japan kn-affil= affil-num=14 en-affil=The Hong Kong University of Science and Technology Medical Center, Shenzhen Peking University kn-affil= affil-num=15 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= en-keyword=miPSCs kn-keyword=miPSCs en-keyword=CSCs kn-keyword=CSCs en-keyword=CCR6 kn-keyword=CCR6 en-keyword=CCL20 kn-keyword=CCL20 END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=4 article-no= start-page=879 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2020 dt-pub=20200404 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Revisiting Cancer Stem Cells as the Origin of Cancer-Associated Cells in the Tumor Microenvironment: A Hypothetical View from the Potential of iPSCs en-subtitle= kn-subtitle= en-abstract= kn-abstract=The tumor microenvironment (TME) has an essential role in tumor initiation and development. Tumor cells are considered to actively create their microenvironment during tumorigenesis and tumor development. The TME contains multiple types of stromal cells, cancer-associated fibroblasts (CAFs), Tumor endothelial cells (TECs), tumor-associated adipocytes (TAAs), tumor-associated macrophages (TAMs) and others. These cells work together and with the extracellular matrix (ECM) and many other factors to coordinately contribute to tumor growth and maintenance. Although the types and functions of TME cells are well understood, the origin of these cells is still obscure. Many scientists have tried to demonstrate the origin of these cells. Some researchers postulated that TME cells originated from surrounding normal tissues, and others demonstrated that the origin is cancer cells. Recent evidence demonstrates that cancer stem cells (CSCs) have differentiation abilities to generate the original lineage cells for promoting tumor growth and metastasis. The differentiation of CSCs into tumor stromal cells provides a new dimension that explains tumor heterogeneity. Using induced pluripotent stem cells (iPSCs), our group postulates that CSCs could be one of the key sources of CAFs, TECs, TAAs, and TAMs as well as the descendants, which support the self-renewal potential of the cells and exhibit heterogeneity. In this review, we summarize TME components, their interactions within the TME and their insight into cancer therapy. Especially, we focus on the TME cells and their possible origin and also discuss the multi-lineage differentiation potentials of CSCs exploiting iPSCs to create a society of cells in cancer tissues including TME. en-copyright= kn-copyright= en-aut-name=OsmanAmira en-aut-sei=Osman en-aut-mei=Amira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=FuXiaoying en-aut-sei=Fu en-aut-mei=Xiaoying kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= affil-num=1 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=4 en-affil=Laboratory of Nano-Biotechnology, Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=CAFs kn-keyword=CAFs en-keyword=TECs kn-keyword=TECs en-keyword=TAAs kn-keyword=TAAs en-keyword=TAMs kn-keyword=TAMs en-keyword=CSCs kn-keyword=CSCs END start-ver=1.4 cd-journal=joma no-vol=12 cd-vols= no-issue=1 article-no= start-page=82 end-page= dt-received= dt-revised= dt-accepted= dt-pub-year=2019 dt-pub=20191229 dt-online= en-article= kn-article= en-subject= kn-subject= en-title= kn-title=Hematopoietic Cells Derived from Cancer Stem Cells Generated from Mouse Induced Pluripotent Stem Cells en-subtitle= kn-subtitle= en-abstract= kn-abstract=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. en-copyright= kn-copyright= en-aut-name=HassanGhmkin en-aut-sei=Hassan en-aut-mei=Ghmkin kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=1 ORCID= en-aut-name=AfifySaid M. en-aut-sei=Afify en-aut-mei=Said M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=2 ORCID= en-aut-name=NairNeha en-aut-sei=Nair en-aut-mei=Neha kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=3 ORCID= en-aut-name=KumonKazuki en-aut-sei=Kumon en-aut-mei=Kazuki kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=4 ORCID= en-aut-name=OsmanAmira en-aut-sei=Osman en-aut-mei=Amira kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=5 ORCID= en-aut-name=DuJuan en-aut-sei=Du en-aut-mei=Juan kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=6 ORCID= en-aut-name=MansourHager en-aut-sei=Mansour en-aut-mei=Hager kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=7 ORCID= en-aut-name=Abu QuoraHagar A. en-aut-sei=Abu Quora en-aut-mei=Hagar A. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=8 ORCID= en-aut-name=NawaraHend M. en-aut-sei=Nawara en-aut-mei=Hend M. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=9 ORCID= en-aut-name=SatohAyano en-aut-sei=Satoh en-aut-mei=Ayano kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=10 ORCID= en-aut-name=ZahraMaram H. en-aut-sei=Zahra en-aut-mei=Maram H. kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=11 ORCID= en-aut-name=OkadaNobuhiro en-aut-sei=Okada en-aut-mei=Nobuhiro kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=12 ORCID= en-aut-name=SenoAkimasa en-aut-sei=Seno en-aut-mei=Akimasa kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=13 ORCID= en-aut-name=SenoMasaharu en-aut-sei=Seno en-aut-mei=Masaharu kn-aut-name= kn-aut-sei= kn-aut-mei= aut-affil-num=14 ORCID= affil-num=1 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=2 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=3 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=4 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=5 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=6 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=7 en-affil= kn-affil=Graduate School of Natural Science and Technology, Okayama University affil-num=8 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=9 en-affil=Graduate School of Natural Science and Technology, Okayama University kn-affil= affil-num=10 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=11 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=12 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=13 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= affil-num=14 en-affil=Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama University kn-affil= en-keyword=Induced pluripotent stem cells kn-keyword=Induced pluripotent stem cells en-keyword=Cancer stem cells differentiation kn-keyword=Cancer stem cells differentiation en-keyword=tumor microenvironment kn-keyword=tumor microenvironment en-keyword=hematopoietic cells kn-keyword=hematopoietic cells END