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1
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Zhang Q, Zhang M. Recent advances in lung cancer organoid (tumoroid) research (Review). Exp Ther Med 2024; 28:383. [PMID: 39161616 PMCID: PMC11332118 DOI: 10.3892/etm.2024.12672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Accepted: 02/01/2024] [Indexed: 08/21/2024] Open
Abstract
Lung cancer is the most critical type of malignant tumor that threatens human health. Traditional preclinical models have certain defects; for example, they cannot accurately reflect the characteristics of lung cancer and their development is costly and time-consuming. Through self-organization, cancer stem cells (CSCs) generate cancer organoids that have a structure similar to that of lung cancer tissues, overcoming to some extent the aforementioned challenges, thus enabling them to have broader application prospects. Lung cancer organoid (LCO) development methods can be divided into three broad categories based on the source of cells, which include cell lines, patient-derived xenografts and patient tumor tissue/pleural effusion. There are 17 different methods that have been described for the development of LCOs. These methods can be further merged into six categories based on the source of cells, the pre-treatment method used, the composition of the medium and the culture scaffold. These categories are: i) CSCs induced by defined transcription factors; ii) suspension culture; iii) relative optimal culture medium; iv) suboptimal culture medium; v) mechanical digestion and suboptimal culture medium; and vi) hydrogel scaffold. In the current review, the advantages and disadvantages of each of the aforementioned methods are summarized, and references for supporting studies are cited.
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Affiliation(s)
- Qiang Zhang
- Department of Clinical Laboratory, Longgang District People's Hospital of Shenzhen, Shenzhen, Guangdong 518172, P.R. China
| | - Mingyang Zhang
- School of Basic Medical Sciences, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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2
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Hassani I, Anbiah B, Moore AL, Abraham PT, Odeniyi IA, Habbit NL, Greene MW, Lipke EA. Establishment of a tissue-engineered colon cancer model for comparative analysis of cancer cell lines. J Biomed Mater Res A 2024; 112:231-249. [PMID: 37927200 PMCID: PMC12083550 DOI: 10.1002/jbm.a.37611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 08/13/2023] [Accepted: 08/30/2023] [Indexed: 11/07/2023]
Abstract
To overcome the limitations of in vitro two-dimensional (2D) cancer models in mimicking the complexities of the native tumor milieu, three-dimensional (3D) engineered cancer models using biomimetic materials have been introduced to more closely recapitulate the key attributes of the tumor microenvironment. Specifically, for colorectal cancer (CRC), a few studies have developed 3D engineered tumor models to investigate cell-cell interactions or efficacy of anti-cancer drugs. However, recapitulation of CRC cell line phenotypic differences within a 3D engineered matrix has not been systematically investigated. Here, we developed an in vitro 3D engineered CRC (3D-eCRC) tissue model using the natural-synthetic hybrid biomaterial PEG-fibrinogen and three CRC cell lines, HCT 116, HT-29, and SW480. To better recapitulate native tumor conditions, our 3D-eCRC model supported higher cell density encapsulation (20 × 106 cells/mL) and enabled longer term maintenance (29 days) as compared to previously reported in vitro CRC models. The 3D-eCRCs formed using each cell line demonstrated line-dependent differences in cellular and tissue properties, including cellular growth and morphology, cell subpopulations, cell size, cell granularity, migration patterns, tissue growth, gene expression, and tissue stiffness. Importantly, these differences were found to be most prominent from Day 22 to Day 29, thereby indicating the importance of long-term culture of engineered CRC tissues for recapitulation and investigation of mechanistic differences and drug response. Our 3D-eCRC tissue model showed high potential for supporting future in vitro comparative studies of disease progression, metastatic mechanisms, and anti-cancer drug candidate response in a CRC cell line-dependent manner.
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Affiliation(s)
- Iman Hassani
- Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA
- Department of Chemical Engineering, Tuskegee University, Tuskegee, AL 36088, USA
| | - Benjamin Anbiah
- Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA
| | - Andrew L. Moore
- Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA
| | - Peter T. Abraham
- Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA
| | - Ifeoluwa A. Odeniyi
- Department of Nutritional Sciences, Auburn University, Auburn, AL 36849, USA
| | - Nicole L. Habbit
- Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA
| | - Michael W. Greene
- Department of Nutritional Sciences, Auburn University, Auburn, AL 36849, USA
| | - Elizabeth A. Lipke
- Department of Chemical Engineering, Auburn University, Auburn, AL 36849, USA
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3
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Sarker DB, Xue Y, Mahmud F, Jocelyn JA, Sang QXA. Interconversion of Cancer Cells and Induced Pluripotent Stem Cells. Cells 2024; 13:125. [PMID: 38247819 PMCID: PMC10814385 DOI: 10.3390/cells13020125] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/07/2024] [Accepted: 01/08/2024] [Indexed: 01/23/2024] Open
Abstract
Cancer cells, especially cancer stem cells (CSCs), share many molecular features with induced pluripotent stem cells (iPSCs) that enable the derivation of induced pluripotent cancer cells by reprogramming malignant cells. Conversely, normal iPSCs can be converted into cancer stem-like cells with the help of tumor microenvironment components and genetic manipulation. These CSC models can be utilized in oncogenic initiation and progression studies, understanding drug resistance, and developing novel therapeutic strategies. This review summarizes the role of pluripotency factors in the stemness, tumorigenicity, and therapeutic resistance of cancer cells. Different methods to obtain iPSC-derived CSC models are described with an emphasis on exposure-based approaches. Culture in cancer cell-conditioned media or cocultures with cancer cells can convert normal iPSCs into cancer stem-like cells, aiding the examination of processes of oncogenesis. We further explored the potential of reprogramming cancer cells into cancer-iPSCs for mechanistic studies and cancer dependencies. The contributions of genetic, epigenetic, and tumor microenvironment factors can be evaluated using these models. Overall, integrating iPSC technology into cancer stem cell research holds significant promise for advancing our knowledge of cancer biology and accelerating the development of innovative and tailored therapeutic interventions.
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Affiliation(s)
- Drishty B. Sarker
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Yu Xue
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Faiza Mahmud
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Jonathan A. Jocelyn
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
| | - Qing-Xiang Amy Sang
- Department of Chemistry and Biochemistry, Florida State University, Tallahassee, FL 32306-4390, USA; (D.B.S.); (Y.X.); (F.M.); (J.A.J.)
- Institute of Molecular Biophysics, Florida State University, Tallahassee, FL 32306-4380, USA
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Sarhan MO, Haffez H, Elsayed NA, El-Haggar RS, Zaghary WA. New phenothiazine conjugates as apoptosis inducing agents: Design, synthesis, In-vitro anti-cancer screening and 131I-radiolabeling for in-vivo evaluation. Bioorg Chem 2023; 141:106924. [PMID: 37871390 DOI: 10.1016/j.bioorg.2023.106924] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Revised: 10/06/2023] [Accepted: 10/16/2023] [Indexed: 10/25/2023]
Abstract
Phenothiazines (PTZs) are a group of compounds characterized by the presence of the 10H-dibenzo-[b,e]-1,4-thiazine system. PTZs used in clinics as antipsychotic drugs with other diverse biological activities. The current aim of the study is to investigate and understand the effect of potent PTZs compounds using a group of In-vitro and In-vivo assays. A total of seventeen novel phenothiazine derivatives have been designed, synthesized, and evaluated primarily in-vitro for their ability to inhibit proliferation activity against NCI-60 cancer cell lines, including several multi-drug resistant (MDR) tumor cell lines. Almost all compounds were active and displayed promising cellular activities with GI50 values in the sub-micromolar range. Four of the most promising derivatives (4b, 4h, 4g and 6e) have been further tested against two selected sensitive cancer cell lines (colon cancer; HCT-116 and breast cancer; MDA-MB231). The apoptosis assay showed that all the selected compounds were able to induce early apoptosis and compound 6e was able to induce additional cellular necrosis. Cell cycle assay showed all selected compounds were able to induce cell cycle arrest at sub-molecular phase of G0-G1 with compound 6e induced cell cycle arrest at G2M in HCT-116 cells. Accordingly, the apoptotic effect of the selected compounds was extensively investigated on genetic level and Casp-3, Casp-9 and Bax gene were up-regulated with down-regulation of Bcl-2 gene suggesting the activation of both intrinsic and extrinsic pathways. In-vivo evaluation of the antitumor activity of compound 4b in solid tumor bearing mice showed promising therapeutic effect with manifestation of dose and time dependent toxic effects at higher doses. For better evaluation of the degree of localization of 4b, its 131I-congener (131I-4b) was injected intravenously in Ehrlich solid tumor bearing mice that showed good localization at tumor site with rapid distribution and clearance from the blood. In-silico study suggested NADPH oxidases (NOXs) as potential molecular target. The compounds introduced in the current study work provided a cutting-edge phenothiazine hybrid scaffold with promising anti-proliferation action that may suggest their anti-cancer activity.
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Affiliation(s)
- Mona O Sarhan
- Labelled Compounds Department, Hot Lab Centre, Egyptian Atomic Energy Authority, Egypt
| | - Hesham Haffez
- Biochemistry and Molecular Biology Department, Faculty of Pharmacy, Helwan University, 11795 Cairo, Egypt; Center of Scientific Excellence "Helwan Structural Biology Research, (HSBR)", Helwan University, 11795 Cairo, Egypt.
| | - Nosaiba A Elsayed
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, 11795 Cairo, Egypt
| | - Radwan S El-Haggar
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, 11795 Cairo, Egypt
| | - Wafaa A Zaghary
- Pharmaceutical Chemistry Department, Faculty of Pharmacy, Helwan University, 11795 Cairo, Egypt.
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Lama Tamang R, Kumar B, Patel SM, Thapa I, Ahmad A, Kumar V, Ahmad R, Becker DF, Bastola D(K, Dhawan P, Singh AB. Pyrroline-5-Carboxylate Reductase-2 Promotes Colorectal Carcinogenesis by Modulating Microtubule-Associated Serine/Threonine Kinase-like/Wnt/β-Catenin Signaling. Cells 2023; 12:1883. [PMID: 37508547 PMCID: PMC10377831 DOI: 10.3390/cells12141883] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 07/03/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
BACKGROUND Despite significant progress in clinical management, colorectal cancer (CRC) remains the third most common cause of cancer-related deaths. A positive association between PYCR2 (pyrroline-5-carboxylate reductase-2), a terminal enzyme of proline metabolism, and CRC aggressiveness was recently reported. However, how PYCR2 promotes colon carcinogenesis remains ill understood. METHODS A comprehensive analysis was performed using publicly available cancer databases and CRC patient cohorts. Proteomics and biochemical evaluations were performed along with genetic manipulations and in vivo tumor growth assays to gain a mechanistic understanding. RESULTS PYCR2 expression was significantly upregulated in CRC and associated with poor patient survival, specifically among PYCR isoforms (PYCR1, 2, and 3). The genetic inhibition of PYCR2 inhibited the tumorigenic abilities of CRC cells and in vivo tumor growth. Coinciding with these observations was a significant decrease in cellular proline content. PYCR2 overexpression promoted the tumorigenic abilities of CRC cells. Proteomics (LC-MS/MS) analysis further demonstrated that PYCR2 loss of expression in CRC cells inhibits survival and cell cycle pathways. A subsequent biochemical analysis supported the causal role of PYCR2 in regulating CRC cell survival and the cell cycle, potentially by regulating the expression of MASTL, a cell-cycle-regulating protein upregulated in CRC. Further studies revealed that PYCR2 regulates Wnt/β-catenin-signaling in manners dependent on the expression of MASTL and the cancer stem cell niche. CONCLUSIONS PYCR2 promotes MASTL/Wnt/β-catenin signaling that, in turn, promotes cancer stem cell populations and, thus, colon carcinogenesis. Taken together, our data highlight the significance of PYCR2 as a novel therapeutic target for effectively treating aggressive colon cancer.
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Affiliation(s)
- Raju Lama Tamang
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Balawant Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Sagar M. Patel
- Department of Biochemistry and Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Ishwor Thapa
- School of Interdisciplinary Informatics, College of Information Science & Technology, University of Nebraska at Omaha, Omaha, NE 68182, USA
| | - Alshomrani Ahmad
- Department of Pathology and Microbiology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Vikas Kumar
- Department of Genetics, Cell Biology, and Anatomy, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Rizwan Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
| | - Donald F. Becker
- Department of Biochemistry and Redox Biology Center, University of Nebraska-Lincoln, Lincoln, NE 68588, USA
| | - Dundy (Kiran) Bastola
- School of Interdisciplinary Informatics, College of Information Science & Technology, University of Nebraska at Omaha, Omaha, NE 68182, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105-1850, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-65870, USA
| | - Amar B. Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE 68198-6125, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, NE 68105-1850, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198-65870, USA
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Lee E, Cheung J, Bialkowska AB. Krüppel-like Factors 4 and 5 in Colorectal Tumorigenesis. Cancers (Basel) 2023; 15:cancers15092430. [PMID: 37173904 PMCID: PMC10177156 DOI: 10.3390/cancers15092430] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 04/17/2023] [Accepted: 04/18/2023] [Indexed: 05/15/2023] Open
Abstract
Krüppel-like factors (KLFs) are transcription factors regulating various biological processes such as proliferation, differentiation, migration, invasion, and homeostasis. Importantly, they participate in disease development and progression. KLFs are expressed in multiple tissues, and their role is tissue- and context-dependent. KLF4 and KLF5 are two fascinating members of this family that regulate crucial stages of cellular identity from embryogenesis through differentiation and, finally, during tumorigenesis. They maintain homeostasis of various tissues and regulate inflammation, response to injury, regeneration, and development and progression of multiple cancers such as colorectal, breast, ovarian, pancreatic, lung, and prostate, to name a few. Recent studies broaden our understanding of their function and demonstrate their opposing roles in regulating gene expression, cellular function, and tumorigenesis. This review will focus on the roles KLF4 and KLF5 play in colorectal cancer. Understanding the context-dependent functions of KLF4 and KLF5 and the mechanisms through which they exert their effects will be extremely helpful in developing targeted cancer therapy.
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Affiliation(s)
- Esther Lee
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Jacky Cheung
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Agnieszka B Bialkowska
- Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
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7
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Correnti M, Binatti E, Gammella E, Invernizzi P, Recalcati S. The Emerging Role of Tumor Microenvironmental Stimuli in Regulating Metabolic Rewiring of Liver Cancer Stem Cells. Cancers (Basel) 2022; 15:5. [PMID: 36612000 PMCID: PMC9817521 DOI: 10.3390/cancers15010005] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/14/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
Primary liver cancer (PLC) is one of the most devastating cancers worldwide. Extensive phenotypical and functional heterogeneity is a cardinal hallmark of cancer, including PLC, and is related to the cancer stem cell (CSC) concept. CSCs are responsible for tumor growth, progression, relapse and resistance to conventional therapies. Metabolic reprogramming represents an emerging hallmark of cancer. Cancer cells, including CSCs, are very plastic and possess the dynamic ability to constantly shift between different metabolic states depending on various intrinsic and extrinsic stimuli, therefore amplifying the complexity of understanding tumor heterogeneity. Besides the well-known Warburg effect, several other metabolic pathways including lipids and iron metabolism are altered in PLC. An increasing number of studies supports the role of the surrounding tumor microenvironment (TME) in the metabolic control of liver CSCs. In this review, we discuss the complex metabolic rewiring affecting liver cancer cells and, in particular, liver CSCs. Moreover, we highlight the role of TME cellular and noncellular components in regulating liver CSC metabolic plasticity. Deciphering the specific mechanisms regulating liver CSC-TME metabolic interplay could be very helpful with respect to the development of more effective and innovative combinatorial therapies for PLC treatment.
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Affiliation(s)
- Margherita Correnti
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milano, Italy
| | - Eleonora Binatti
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Elena Gammella
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milano, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Stefania Recalcati
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milano, Italy
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8
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Cancer cells as a new source of induced pluripotent stem cells. Stem Cell Res Ther 2022; 13:459. [PMID: 36064437 PMCID: PMC9446809 DOI: 10.1186/s13287-022-03145-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 08/17/2022] [Indexed: 11/10/2022] Open
Abstract
Over the last 2 decades, induced pluripotent stem cells (iPSCs) have had various potential applications in various medical research areas, from personalized medicine to disease treatment. Different cellular resources are accessible for iPSC generation, such as keratinocytes, skin fibroblasts, and blood or urine cells. However, all these sources are somatic cells, and we must make several changes in a somatic cell's transcriptome and chromatin state to become a pluripotent cell. It has recently been revealed that cancer cells can be a new source of iPSCs production. Cancer cells show similarities with iPSCs in self-renewal capacity, reprogramming potency, and signaling pathways. Although genetic abnormalities and potential tumor formation in cancer cells pose a severe risk, reprogrammed cancer-induced pluripotent stem cells (cancer-iPSCs) indicate that pluripotency can transiently overcome the cancer phenotype. This review discusses whether cancer cells can be a preferable source to generate iPSCs.
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Wuputra K, Ku CC, Pan JB, Liu CJ, Liu YC, Saito S, Kato K, Lin YC, Kuo KK, Chan TF, Chong IW, Lin CS, Wu DC, Yokoyama KK. Stem Cell Biomarkers and Tumorigenesis in Gastric Cancer. J Pers Med 2022; 12:jpm12060929. [PMID: 35743714 PMCID: PMC9224738 DOI: 10.3390/jpm12060929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Revised: 05/25/2022] [Accepted: 05/31/2022] [Indexed: 02/01/2023] Open
Abstract
Stomach cancer has a high mortality, which is partially caused by an absence of suitable biomarkers to allow detection of the initiation stages of cancer progression. Thus, identification of critical biomarkers associated with gastric cancer (GC) is required to advance its clinical diagnoses and treatment. Recent studies using tracing models for lineage analysis of GC stem cells indicate that the cell fate decision of the gastric stem cells might be an important issue for stem cell plasticity. They include leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5+), Cholecystokinin receptor 2 (Cckr2+), and axis inhibition protein 2 (Axin2+) as the stem cell markers in the antrum, Trefoil Factor 2 (TFF2+), Mist1+ stem cells, and Troy+ chief cells in the corpus. By contrast, Estrogen receptor 1 (eR1), Leucine-rich repeats and immunoglobulin-like domains 1 (Lrig1), SRY (sex determining region Y)-box 2 (Sox2), and B lymphoma Mo-MLV insertion region 1 homolog (Bmi1) are rich in both the antrum and corpus regions. These markers might help to identify the cell-lineage identity and analyze the plasticity of each stem cell population. Thus, identification of marker genes for the development of GC and its environment is critical for the clinical application of cancer stem cells in the prevention of stomach cancers.
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Affiliation(s)
- Kenly Wuputra
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (K.W.); (C.-C.K.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-J.L.); (K.-K.K.); (D.-C.W.)
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
| | - Chia-Chen Ku
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (K.W.); (C.-C.K.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-J.L.); (K.-K.K.); (D.-C.W.)
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
| | - Jia-Bin Pan
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (K.W.); (C.-C.K.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-J.L.); (K.-K.K.); (D.-C.W.)
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
| | - Chung-Jung Liu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-J.L.); (K.-K.K.); (D.-C.W.)
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
- Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Yi-Chang Liu
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
| | - Shigeo Saito
- Saito Laboratory of Cell Technology, Yaita 329-2192, Japan;
- Horus Co., Ltd., Nakano, Tokyo 164-0001, Japan
| | - Kohsuke Kato
- Department of Infection Biology, Graduate School of Comprehensive Human Sciences, The University of Tsukuba, Tsukuba 305-8577, Japan;
| | - Ying-Chu Lin
- School of Dentistry, Kaohsiung Medical University, Kaohsiung 80708, Taiwan;
| | - Kung-Kai Kuo
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-J.L.); (K.-K.K.); (D.-C.W.)
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
- Division of General & Digestive Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
| | - Te-Fu Chan
- Department of Obstetrics and Genecology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
| | - Inn-Wen Chong
- Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
| | - Chang-Shen Lin
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (K.W.); (C.-C.K.); (J.-B.P.); (C.-S.L.)
| | - Deng-Chyang Wu
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-J.L.); (K.-K.K.); (D.-C.W.)
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
- Division of Gastroenterology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan
- Department of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Department of Obstetrics and Genecology, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
| | - Kazunari K. Yokoyama
- Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (K.W.); (C.-C.K.); (J.-B.P.); (C.-S.L.)
- Regenerative Medicine and Cell Therapy Research Center, Kaohsiung Medical University, Kaohsiung 80708, Taiwan; (C.-J.L.); (K.-K.K.); (D.-C.W.)
- Cell Therapy and Research Center, Kaohsiung Medical University Hospital, Kaohsiung 80756, Taiwan;
- Correspondence: ; Tel.: +886-7312-1101 (ext. 2729); Fax: +886-7313-3849
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10
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Arai H, Millstein J, Loupakis F, Stintzing S, Wang J, Battaglin F, Kawanishi N, Jayachandran P, Soni S, Zhang W, Mumenthaler SM, Cremolini C, Heinemann V, Falcone A, Lenz HJ. Germ line polymorphisms of genes involved in pluripotency transcription factors predict efficacy of cetuximab in metastatic colorectal cancer. Eur J Cancer 2021; 150:133-142. [PMID: 33901792 PMCID: PMC12047410 DOI: 10.1016/j.ejca.2021.03.048] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 03/17/2021] [Accepted: 03/25/2021] [Indexed: 01/01/2023]
Abstract
BACKGROUND Cancer stem cells (CSCs) are primarily maintained by a network of pluripotency transcription factors (PTFs). Given a close relationship of CSC regulation with epidermal growth factor receptor and vascular endothelial growth factor signalling, we investigated whether single-nucleotide polymorphisms (SNPs) in PTF genes are related to the efficacy of cetuximab and/or bevacizumab in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Genomic and clinical data from three independent clinical trial cohorts were tested: cetuximab cohort (FOLFIRI/cetuximab arm in FIRE-3, n = 129), bevacizumab cohort 1 (FOLFIRI/bevacizumab arm in FIRE-3, n = 107) and bevacizumab cohort 2 (FOLFIRI/bevacizumab arm in TRIBE, n = 215). Genomic DNA extracted from blood samples was genotyped, and ten SNPs were tested for association with clinical outcomes. RESULTS In the cetuximab cohort, four SNPs were significantly associated with progression-free survival in univariate analysis: NANOG rs11055767 (any A allele vs C/C, hazard ratio [HR] = 0.62, 95% confidence interval [CI] = 0.42-0.94, p = 0.02), NANOG rs10744044 (any A allele vs G/G, HR = 0.59, 95% CI = 0.39-0.90, p = 0.01), NANOGP8 rs2168958 (any C allele vs A/A, HR = 2.12, 95% CI = 1.36-3.29, p < 0.001) and NANOGP8 rs2279066 (any C allele vs T/T, HR = 1.80, 95% CI = 1.06-1.68, p = 0.03). Multivariate analysis confirmed the significant associations for NANOGP8 rs2168958 and NANOGP8 rs2279066. In either bevacizumab cohort, no significant associations were observed in univariate analysis. CONCLUSIONS Germ line polymorphisms in the PTF genes could be predictive markers for cetuximab in mCRC.
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Affiliation(s)
- Hiroyuki Arai
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Joshua Millstein
- Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Fotios Loupakis
- Clinical and Experimental Oncology Department, Medical Oncology Unit 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
| | - Sebastian Stintzing
- Medical Department, Division of Hematology, Oncology, and Tumour Immunology (CCM), Charité - Universitaetsmedizin, Berlin, Germany
| | - Jingyuan Wang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Francesca Battaglin
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Natsuko Kawanishi
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Priya Jayachandran
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Shivani Soni
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Wu Zhang
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Shannon M Mumenthaler
- Lawrence J. Ellison Institute for Transformative Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA
| | - Chiara Cremolini
- Department of Translational Medicine, Division of Medical Oncology, University of Pisa, Pisa, Italy
| | - Volker Heinemann
- Department of Medicine III, University Hospital, LMU Munich, Munich, Germany
| | - Alfredo Falcone
- Department of Translational Medicine, Division of Medical Oncology, University of Pisa, Pisa, Italy
| | - Heinz-Josef Lenz
- Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, USA.
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11
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Klepinina L, Klepinin A, Truu L, Chekulayev V, Vija H, Kuus K, Teino I, Pook M, Maimets T, Kaambre T. Colon cancer cell differentiation by sodium butyrate modulates metabolic plasticity of Caco-2 cells via alteration of phosphotransfer network. PLoS One 2021; 16:e0245348. [PMID: 33471801 PMCID: PMC7817017 DOI: 10.1371/journal.pone.0245348] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 12/28/2020] [Indexed: 12/12/2022] Open
Abstract
The ability of butyrate to promote differentiation of cancer cells has important implication for colorectal cancer (CRC) prevention and therapy. In this study, we examined the effect of sodium butyrate (NaBT) on the energy metabolism of colon adenocarcinoma Caco-2 cells coupled with their differentiation. NaBT increased the activity of alkaline phosphatase indicating differentiation of Caco-2 cells. Changes in the expression of pluripotency-associated markers OCT4, NANOG and SOX2 were characterized during the induced differentiation at mRNA level along with the measures that allowed distinguishing the expression of different transcript variants. The functional activity of mitochondria was studied by high-resolution respirometry. Glycolytic pathway and phosphotransfer network were analyzed using enzymatical assays. The treatment of Caco-2 cells with NaBT increased production of ATP by oxidative phosphorylation, enhanced mitochondrial spare respiratory capacity and caused rearrangement of the cellular phosphotransfer networks. The flexibility of phosphotransfer networks depended on the availability of glutamine, but not glucose in the cell growth medium. These changes were accompanied by suppressed cell proliferation and altered gene expression of the main pluripotency-associated transcription factors. This study supports the view that modulating cell metabolism through NaBT can be an effective strategy for treating CRC. Our data indicate a close relationship between the phosphotransfer performance and metabolic plasticity of CRC, which is associated with the cell differentiation state.
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Affiliation(s)
- Ljudmila Klepinina
- Laboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia
- * E-mail:
| | - Aleksandr Klepinin
- Laboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia
| | - Laura Truu
- Laboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia
| | - Vladimir Chekulayev
- Laboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia
| | - Heiki Vija
- Laboratory of Environmental Toxicology, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia
| | - Kaisa Kuus
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Indrek Teino
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Martin Pook
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Toivo Maimets
- Department of Cell Biology, Institute of Molecular and Cell Biology, University of Tartu, Tartu, Estonia
| | - Tuuli Kaambre
- Laboratory of Chemical Biology, National Institute of Chemical Physics and Biophysics, Tallinn, Estonia
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12
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Richard V, Kumar TRS, Pillai RM. Transitional dynamics of cancer stem cells in invasion and metastasis. Transl Oncol 2021; 14:100909. [PMID: 33049522 PMCID: PMC7557893 DOI: 10.1016/j.tranon.2020.100909] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 09/15/2020] [Accepted: 09/30/2020] [Indexed: 02/07/2023] Open
Abstract
At the onset, few cancer cells amidst the tumor bulk, identified as cancer stem cells (CSCs) or early disseminated cancer cells (eDCCs) are capable of survival post conventional therapy and persist as minimal residual disease (MRD). Metastatic subclones emerge both early and late in the life of primary tumor ensuing an ongoing regional clonal evolution of progenitor cells in metastatic and primary tumors. In the last decade, multiple studies proposed various identities of stem-like cells that undergo transitions to adapt to the changing microenvironment as the disease progresses. This review advocates with substantial evidence the dynamic model of tumor propagation by exploring the specific cell types, reversible phenotypic plasticity between the tumorigenic leader seeds and the supporting follower cancer cells both in circulation and in solid tissue to accurately decipher tumor promoting clones and its role in metastatic dissemination and tumor re-growth. (142 words).
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Affiliation(s)
- Vinitha Richard
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala State, India
| | - T R Santhosh Kumar
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala State, India
| | - Radhakrishna M Pillai
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram 695014, Kerala State, India.
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13
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Reprogramming and Differentiation of Cutaneous Squamous Cell Carcinoma Cells in Recessive Dystrophic Epidermolysis Bullosa. Int J Mol Sci 2020; 22:ijms22010245. [PMID: 33383666 PMCID: PMC7795642 DOI: 10.3390/ijms22010245] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/13/2020] [Accepted: 12/24/2020] [Indexed: 02/04/2023] Open
Abstract
The early onset and rapid progression of cutaneous squamous cell carcinoma (cSCC) leads to high mortality rates in individuals with recessive dystrophic epidermolysis bullosa (RDEB). Currently, the molecular mechanisms underlying cSCC development in RDEB are not well understood and there are limited therapeutic options. RDEB-cSCC arises through the accumulation of genetic mutations; however, previous work analyzing gene expression profiles have not been able to explain its aggressive nature. Therefore, we generated a model to study RDEB-cSCC development using cellular reprograming and re-differentiation technology. We compared RDEB-cSCC to cSCC that were first reprogrammed into induced pluripotent stem cells (RDEB-cSCC-iPSC) and then differentiated back to keratinocytes (RDEB-cSCC-iKC). The RDEB-cSCC-iKC cell population had reduced proliferative capacities in vitro and in vivo, suggesting that reprogramming and re-differentiation leads to functional changes. Finally, we performed RNA-seq analysis for RDEB-cSCC, RDEB-cSCC-iPSC, and RDEB-cSCC-iKC and identified different gene expression signatures between these cell populations. Taken together, this cell culture model offers a valuable tool to study cSCC and provides a novel way to identify potential therapeutic targets for RDEB-cSCC.
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14
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Hass R, von der Ohe J, Ungefroren H. The Intimate Relationship Among EMT, MET and TME: A T(ransdifferentiation) E(nhancing) M(ix) to Be Exploited for Therapeutic Purposes. Cancers (Basel) 2020; 12:3674. [PMID: 33297508 PMCID: PMC7762343 DOI: 10.3390/cancers12123674] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 12/03/2020] [Accepted: 12/03/2020] [Indexed: 12/12/2022] Open
Abstract
Intratumoral heterogeneity is considered the major cause of drug unresponsiveness in cancer and accumulating evidence implicates non-mutational resistance mechanisms rather than genetic mutations in its development. These non-mutational processes are largely driven by phenotypic plasticity, which is defined as the ability of a cell to reprogram and change its identity (phenotype switching). Tumor cell plasticity is characterized by the reactivation of developmental programs that are closely correlated with the acquisition of cancer stem cell properties and an enhanced potential for retrodifferentiation or transdifferentiation. A well-studied mechanism of phenotypic plasticity is the epithelial-mesenchymal transition (EMT). Current evidence suggests a complex interplay between EMT, genetic and epigenetic alterations, and clues from the tumor microenvironment in cell reprogramming. A deeper understanding of the connections between stem cell, epithelial-mesenchymal, and tumor-associated reprogramming events is crucial to develop novel therapies that mitigate cell plasticity and minimize the evolution of tumor heterogeneity, and hence drug resistance. Alternatively, vulnerabilities exposed by tumor cells when residing in a plastic or stem-like state may be exploited therapeutically, i.e., by converting them into less aggressive or even postmitotic cells. Tumor cell plasticity thus presents a new paradigm for understanding a cancer's resistance to therapy and deciphering its underlying mechanisms.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany;
| | - Hendrik Ungefroren
- First Department of Medicine, UKSH, Campus Lübeck, 23538 Lübeck, Germany;
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, UKSH, Campus Kiel, 24105 Kiel, Germany
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15
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Eslahi M, Dana PM, Asemi Z, Hallajzadeh J, Mansournia MA, Yousefi B. The effects of chitosan-based materials on glioma: Recent advances in its applications for diagnosis and treatment. Int J Biol Macromol 2020; 168:124-129. [PMID: 33275978 DOI: 10.1016/j.ijbiomac.2020.11.180] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 07/05/2020] [Accepted: 11/25/2020] [Indexed: 12/20/2022]
Abstract
Glioma is known as the most common primary brain tumor occurring in adolescents and is considered as a lethal disease worldwide. Despite the advancements in presently available therapeutic approaches (i.e. radiation therapy and chemotherapy), the rate of amelioration in glioma patients is still low. In this regard, it seems that there is a need for reconsidering and enhancing current therapies and/or discovering novel therapeutic platforms. Chitosan is a natural polysaccharide with several beneficial characteristics, including biocompatibility, biodegradability, and low toxicity. Without causing toxic effects on healthy cells, chitosan nanoparticles are attractive targets in cancer therapy which lead to the sustained release and enhanced internalization of chemotherapeutic drugs as well as higher cytotoxicity for cancer cells. Hence, these properties turn it into a suitable candidate for the treatment of various cancers, including glioma. In the viewpoint of glioma, cancer inhibition is possible through targeting glioma-associated signaling pathways and molecules such as MMP-9, VEGF, TRAIL and nuclear factor-κB by chitosan and its derivatives. Moreover, it has been acknowledged that chitosan and its derivatives can be applied as a delivery system for carrying a diverse range of therapeutic agents to the tumor site. Besides the anti-glioma effects of chitosan and its derivatives, these molecules can be utilized for culturing glioma cancer cells; providing a better understanding of glioma pathogenesis. Furthermore, it is documented that 3D chitosan scaffolds are potential targets that offer advantageous drug screening platforms. Herein, we summarized the anti-glioma effects of chitosan and also its utilization as drug delivery systems in the treatment of glioma.
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Affiliation(s)
- Masoumeh Eslahi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Parisa Maleki Dana
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran
| | - Jamal Hallajzadeh
- Department of Biochemistry and Nutrition, Research Center for Evidence-Based Health Management, Maragheh University of Medical Sciences, Maragheh, Iran.
| | - Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Bahman Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran and Department of Biochemistry and Nutrition, Research Center for Evidence-Based Health Management, Maragheh University of Medical Sciences, Maragheh, Iran.
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16
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Fujiwara S, Kawamoto T, Kawakami Y, Koterazawa Y, Hara H, Takemori T, Kitayama K, Yahiro S, Kakutani K, Matsumoto T, Matsushita T, Niikura T, Koyanagi-Aoi M, Aoi T, Kuroda R, Akisue T. Acquisition of cancer stem cell properties in osteosarcoma cells by defined factors. Stem Cell Res Ther 2020; 11:429. [PMID: 33008481 PMCID: PMC7532109 DOI: 10.1186/s13287-020-01944-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Accepted: 09/20/2020] [Indexed: 12/18/2022] Open
Abstract
Background Cancer stem cells (CSCs) are considered to be responsible for tumor initiation, formation, and poor prognosis of cancer patients. However, the rarity of CSCs in clinical samples makes it difficult to elucidate characteristics of CSCs, especially in osteosarcoma (OS). The aim of this study is to verify whether it is possible to generate CSC-like cells by transducing defined factors into an OS cell line. Methods We retrovirally transduced the Octamer-binding transcription factor 3/4 (OCT3/4), Kruppel-like factor 4 (KLF4), and SRY-box transcription factor 2 (SOX2) genes into the MG-63 human OS cell line (MG-OKS). Parental and GFP-transduced MG-63 cells were used as negative control. We assessed the properties of the generated cells in vitro and in vivo. Multiple comparisons among groups were made using a one-way analysis of variance (ANOVA) followed by post hoc testing with Tukey’s procedure. Results MG-OKS cells in vitro exhibited the significantly increased mRNA expression levels of CSC markers (CD24, CD26, and CD133), decreased cell growth, increased chemoresistance and cell migration, and enhanced sphere formation. Notably, MG-OKS cells cultured under osteogenic differentiation conditions showed strongly positive staining for both Alizarin Red S and alkaline phosphatase, indicating osteogenesis of the cells. Gene ontology analysis of microarray data revealed significant upregulation of epidermal-related genes. Tumors derived from MG-OKS cells in vivo were significantly larger than those from other cells in μCT analysis, and immunohistochemical staining showed that Ki-67, osteocalcin, and HIF-1α-positive cells were more frequently detected in the MG-OKS-derived tumors. Conclusions In this study, we successfully generated OS CSC-like cells with significantly enhanced CSC properties following transduction of defined factors.
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Affiliation(s)
- Shuichi Fujiwara
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Teruya Kawamoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan. .,Division of Orthopaedic Surgery, Kobe University Hospital International Clinical Cancer Research Center, Kobe, Japan.
| | - Yohei Kawakami
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yasufumi Koterazawa
- Department of iPS Cell Applications, Kobe University Graduate School of Medicine, Kobe, Japan.,Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan.,Division of Gastrointestinal Surgery, Kobe University Graduate School of Medicine, Kobe, Japan
| | - Hitomi Hara
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Toshiyuki Takemori
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Kazumichi Kitayama
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Shunsuke Yahiro
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Kenichiro Kakutani
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tomoyuki Matsumoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Takehiko Matsushita
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Takahiro Niikura
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Michiyo Koyanagi-Aoi
- Department of iPS Cell Applications, Kobe University Graduate School of Medicine, Kobe, Japan.,Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan.,Center for Human Resource development for Regenerative Medicine, Kobe University Hospital, Kobe, Japan
| | - Takashi Aoi
- Department of iPS Cell Applications, Kobe University Graduate School of Medicine, Kobe, Japan.,Division of Advanced Medical Science, Graduate School of Science, Technology and Innovation, Kobe University, Kobe, Japan.,Center for Human Resource development for Regenerative Medicine, Kobe University Hospital, Kobe, Japan
| | - Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Toshihiro Akisue
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.,Department of Rehabilitation Science, Kobe University Graduate School of Health Sciences, Kobe, Japan
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17
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Chu HY, Chen YJ, Hsu CJ, Liu YW, Chiou JF, Lu LS, Tseng FG. Physical Cues in the Microenvironment Regulate Stemness-Dependent Homing of Breast Cancer Cells. Cancers (Basel) 2020; 12:E2176. [PMID: 32764400 PMCID: PMC7464848 DOI: 10.3390/cancers12082176] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 12/24/2022] Open
Abstract
Tissue-specific microenvironmental factors contribute to the targeting preferences of metastatic cancers. However, the physical attributes of the premetastatic microenvironment are not yet fully characterized. In this research, we develop a transwell-based alginate hydrogel (TAH) model to study how permeability, stiffness, and roughness of a hanging alginate hydrogel regulate breast cancer cell homing. In this model, a layer of physically characterized alginate hydrogel is formed at the bottom of a transwell insert, which is placed into a matching culture well with an adherent monolayer of breast cancer cells. We found that breast cancer cells dissociate from the monolayer and home to the TAH for continual growth. The process is facilitated by the presence of rich serum in the upper chamber, the increased stiffness of the gel, as well as its surface roughness. This model is able to support the homing ability of MCF-7 and MDA-MB-231 cells drifting across the vertical distance in the culture medium. Cells homing to the TAH display stemness phenotype morphologically and biochemically. Taken together, these findings suggest that permeability, stiffness, and roughness are important physical factors to regulate breast cancer homing to a premetastatic microenvironment.
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Affiliation(s)
- Hsueh-Yao Chu
- Department of Engineering and System Science, National Tsing Hua University, Hsinchu 30013, Taiwan; (H.-Y.C.); (C.-J.H.); (Y.-W.L.)
| | - Yin-Ju Chen
- Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 11031, Taiwan; (Y.-J.C.); (J.-F.C.)
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
- International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
| | - Chun-Jieh Hsu
- Department of Engineering and System Science, National Tsing Hua University, Hsinchu 30013, Taiwan; (H.-Y.C.); (C.-J.H.); (Y.-W.L.)
| | - Yang-Wei Liu
- Department of Engineering and System Science, National Tsing Hua University, Hsinchu 30013, Taiwan; (H.-Y.C.); (C.-J.H.); (Y.-W.L.)
| | - Jeng-Fong Chiou
- Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 11031, Taiwan; (Y.-J.C.); (J.-F.C.)
- Department of Radiology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan
| | - Long-Sheng Lu
- Department of Radiation Oncology, Taipei Medical University Hospital, Taipei 11031, Taiwan; (Y.-J.C.); (J.-F.C.)
- Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
- International Ph.D. Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
- International Ph.D. Program for Cell Therapy and Regeneration Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Fan-Gang Tseng
- Department of Engineering and System Science, National Tsing Hua University, Hsinchu 30013, Taiwan; (H.-Y.C.); (C.-J.H.); (Y.-W.L.)
- Department of Engineering and System Science, Frontier Research Center on Fundamental and Applied Sciences of Matters, National Tsing-Hua University, Hsinchu 30013, Taiwan
- Research Center for Applied Sciences, Academia Sinica, No. 128, Sec. 2, Academia Rd., Nankang, Taipei 11529, Taiwan
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18
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Thankamony AP, Saxena K, Murali R, Jolly MK, Nair R. Cancer Stem Cell Plasticity - A Deadly Deal. Front Mol Biosci 2020; 7:79. [PMID: 32426371 PMCID: PMC7203492 DOI: 10.3389/fmolb.2020.00079] [Citation(s) in RCA: 96] [Impact Index Per Article: 19.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Accepted: 04/06/2020] [Indexed: 12/12/2022] Open
Abstract
Intratumoral heterogeneity is a major ongoing challenge in the effective therapeutic targeting of cancer. Accumulating evidence suggests that a fraction of cells within a tumor termed Cancer Stem Cells (CSCs) are primarily responsible for this diversity resulting in therapeutic resistance and metastasis. Adding to this complexity, recent studies have shown that there can be different subpopulations of CSCs with varying biochemical and biophysical traits resulting in varied dissemination and drug-resistance potential. Moreover, cancer cells can exhibit a high level of plasticity or the ability to dynamically switch between CSC and non-CSC states or among different subsets of CSCs. In addition, CSCs also display extensive metabolic plasticity. The molecular mechanisms underlying these different interconnected axes of plasticity has been under extensive investigation and the trans-differentiation process of Epithelial to Mesenchymal transition (EMT) has been identified as a major contributing factor. Besides genetic and epigenetic factors, CSC plasticity is also shaped by non-cell-autonomous effects such as the tumor microenvironment (TME). In this review, we discuss the latest developments in decoding mechanisms and implications of CSC plasticity in tumor progression at biochemical and biophysical levels, and the latest in silico approaches being taken for characterizing cancer cell plasticity. These efforts can help improve existing therapeutic approaches by taking into consideration the contribution of cellular plasticity/heterogeneity in enabling drug resistance.
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Affiliation(s)
- Archana P. Thankamony
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
- Manipal Academy of Higher Education (MAHE), Manipal, India
| | - Kritika Saxena
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
| | - Reshma Murali
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Mohit Kumar Jolly
- Centre for BioSystems Science and Engineering, Indian Institute of Science, Bengaluru, India
| | - Radhika Nair
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
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19
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Reprogramming of chimpanzee fibroblasts into a multipotent cancerous but not fully pluripotent state by transducing iPSC factors in 2i/LIF culture. Differentiation 2020; 112:67-76. [DOI: 10.1016/j.diff.2020.01.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2019] [Revised: 10/23/2019] [Accepted: 01/06/2020] [Indexed: 02/07/2023]
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20
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Li H, Piao L, Liu S, Cui Y, Xuan Y. B7-H4 is a potential prognostic biomarker of prostate cancer. Exp Mol Pathol 2020; 114:104406. [PMID: 32088189 DOI: 10.1016/j.yexmp.2020.104406] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 02/14/2020] [Accepted: 02/17/2020] [Indexed: 12/17/2022]
Abstract
B7-H4 is a member of B7 family which regulates immune responses by delivering costimulatory signals. However, it negatively regulates T cell-mediated immunity and may play an important role in tumor immune evasion. Although several studies have been reported that expression of B7-H4 is elevated in the several types of human cancer with a poor clinical outcome, its clinical significance in the prostate cancer (PCa) has not been well studied. In this study, we investigated the clinical significance of B7-H4 in human PCa and determined if B7-H4 expression is associated with the cancer cell stemness in PCa. Our studies show that expression of B7-H4 is correlated with the pathologic tumor (pT) stage and the clinical stage of PCa. The Kaplan-Meier survival analysis revealed that PCa patients with high expression of B7-H4 exhibits a shorter overall survival (OS) rate. Univariate and multivariate Cox regression analysis indicated that B7-H4 is an independent poor prognostic factor of PCa. In addition, the expression of B7-H4 is correlated with the cancer cell stemness associated genes expression in PCa. Further, our studies show that B7-H4 regulates cancer cell stemness associated genes expression and effects on the cell cycle and PI3K/Akt signaling related genes expression in PCa. These results indicate that B7-H4 expression is associated with cancer cell stemness, and B7-H4 is a potential prognostic biomarker and a therapeutic target of PCa.
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Affiliation(s)
- Haoyue Li
- Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji 133002, PR China; Department of Pathology, Yanbian University College of Medicine, Yanji 133002, PR China
| | - Lihua Piao
- Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji 133002, PR China; Department of Pathology, Yanbian University College of Medicine, Yanji 133002, PR China
| | - Sicen Liu
- Department of Oncology, Affiliated Hospital of Yanbian University, Yanji 133002, PR China
| | - Yan Cui
- Department of Oncology, Affiliated Hospital of Yanbian University, Yanji 133002, PR China
| | - Yanhua Xuan
- Institute for Regenerative Medicine, Yanbian University College of Medicine, Yanji 133002, PR China; Department of Pathology, Yanbian University College of Medicine, Yanji 133002, PR China.
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21
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Aravindan N, Jain D, Somasundaram DB, Herman TS, Aravindan S. Cancer stem cells in neuroblastoma therapy resistance. CANCER DRUG RESISTANCE (ALHAMBRA, CALIF.) 2019; 2:948-967. [PMID: 31867574 PMCID: PMC6924637 DOI: 10.20517/cdr.2019.72] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Neuroblastoma (NB) is the most common cancer of infancy and accounts for nearly one tenth of pediatric cancer deaths. This mortality rate has been attributed to the > 50% frequency of relapse despite intensive, multimodal clinical therapy in patients with progressive NB. Given the disease’s heterogeneity and developed resistance, attaining a cure after relapse of progressive NB is highly challenging. A rapid decrease in the timeline between successive recurrences is likely due to the ongoing acquisition of genetic rearrangements in undifferentiated NB-cancer stem cells (CSCs). In this review, we present the current understanding of NB-CSCs, their intrinsic role in tumorigenesis, their function in disease progression, and their influence on acquired therapy resistance and tumor evolution. In particular, this review focus on the intrinsic involvement of stem cells and signaling in the genesis of NB, the function of pre-existing CSCs in NB progression and therapy response, the formation and influence of induced CSCs (iCSCs) in drug resistance and tumor evolution, and the development of a CSC-targeted therapeutic approach.
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Affiliation(s)
- Natarajan Aravindan
- Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.,Department of Pathology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.,Department of Anesthesiology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Drishti Jain
- Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Dinesh Babu Somasundaram
- Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Terence S Herman
- Department of Radiation Oncology, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA.,Stephenson Cancer Center, Oklahoma City, OK 73104, USA
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22
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Konno M, Taniguchi M, Ishii H. Significant epitranscriptomes in heterogeneous cancer. Cancer Sci 2019; 110:2318-2327. [PMID: 31187550 PMCID: PMC6676114 DOI: 10.1111/cas.14095] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 06/03/2019] [Accepted: 06/05/2019] [Indexed: 02/06/2023] Open
Abstract
Precision medicine places significant emphasis on techniques for the identification of DNA mutations and gene expression by deep sequencing of gene panels to obtain medical data. However, other diverse information that is not easily readable using bioinformatics, including RNA modifications, has emerged as a novel diagnostic and innovative therapy owing to its multifunctional aspects. It is suggested that this breakthrough innovation might open new avenues for the elucidation of uncharacterized cancer cellular functions to develop more precise medical applications. The functional characteristics and regulatory mechanisms of RNA modifications, ie, the epitranscriptome (ETR), which reflects RNA metabolism, remains unclear, mainly due to detection methods being limited. Recent studies have revealed that N6‐methyl adenosine, the most common modification in mRNA in eukaryotes, is affected in various types of cancer and, in some cases, cancer stem cells, but also affects cellular responses to viral infections. The ETR can control cancer cell fate through mRNA splicing, stability, nuclear export, and translation. Here we report on the recent progress of ETR detection methods, and biological findings regarding the significance of ETR in cancer precision medicine.
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Affiliation(s)
- Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Masateru Taniguchi
- The Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan
| | - Hideshi Ishii
- Department of Medical Data Science, Graduate School of Medicine, Osaka University, Osaka, Japan
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23
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Voutsadakis IA. The pluripotency network in colorectal cancer pathogenesis and prognosis: an update. Biomark Med 2019; 12:653-665. [PMID: 29944017 DOI: 10.2217/bmm-2017-0369] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Stemness characteristics are defining properties of cancer initiating cells and are associated with the ability to metastasize and survive in hostile environments. Establishment of the stem cell network depends on the action of a set of core transcription factors that work in concert with other ancillary proteins that are also important during embryonic development. New data consolidate the role of core pluripotency transcription factors OCT4, SOX2 and NANOG as adverse prognostic factors in colorectal cancer. mRNA-binding proteins LIN28 and Musashi, that are associated with stemness, and epigenetic modifiers such as de-acetylase SIRT1 may also have prognostic value in colorectal cancer. This paper provides an update of the stem cell factors in the pathogenesis and prognosis of colorectal cancer.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, Ontario, Canada.,Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada
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24
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Zhou Z, Feng Z, Hu D, Yang P, Gur M, Bahar I, Cristofanilli M, Gradishar WJ, Xie XQ, Wan Y. A novel small-molecule antagonizes PRMT5-mediated KLF4 methylation for targeted therapy. EBioMedicine 2019; 44:98-111. [PMID: 31101597 PMCID: PMC6604046 DOI: 10.1016/j.ebiom.2019.05.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 05/03/2019] [Accepted: 05/06/2019] [Indexed: 12/25/2022] Open
Abstract
Background Triple negative breast cancers (TNBCs) have a poor prognosis and are not amenable to endocrine- or HER2-targeted therapies. The malignant and invasive feature of TNBCs is correlated with its high cancer stem cell population. Recent results from us and others have unveiled an oncogenic role for the PRMT5-KLF4 axis in regulating tumor progression by orchestrating the stemness in mammary tumor cell as well as genome stability. Methylation of KLF4 by PRMT5 leads to KLF4 stabilization, resulting in promoting mitogenesis. Methods We have developed a small molecule inhibitor, WX2–43, that specifically intercepts the interaction between PRMT5 and KLF4, thereby enhancing KLF4 degradation. Findings Results from our characterization demonstrate that WX2–43 binds to the region between amino acids L400-M500 on PRMT5. Degradation of KLF4 down-regulates KLF4-mediated genes transcription. We have characterized the potent effect for WX2–43 in inhibiting PRMT5-KLF4 binding that, in turns, suppresses tumor progression and induces tumor cell death in both TNBC cultured-cell and animal models. Interpretation WX2–43-mediated inhibition of KLF4 methylation by PRMT5 could be a potential strategy for anti-TNBC treatment. Fund This work was supported, in whole or in part, by National Institutes of Health grants CA202963 and CA202948 (Wan), R21HL109654 (Xie), P30DA035778 (Xie and Bahar) and P41GM103712 (Bahar).
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Affiliation(s)
- Zhuan Zhou
- Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, United States; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, United States
| | - Zhiwei Feng
- Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, United States
| | - Dong Hu
- Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, United States
| | - Peng Yang
- Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, United States
| | - Mert Gur
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, United States
| | - Ivet Bahar
- Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, United States
| | - Massimo Cristofanilli
- Lynn Sage Breast Cancer Program, Department of Medicine-Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, United States
| | - William J Gradishar
- Lynn Sage Breast Cancer Program, Department of Medicine-Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, United States
| | - Xiang-Qun Xie
- Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, United States.
| | - Yong Wan
- Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, United States; Department of Pharmacology, Northwestern University Feinberg School of Medicine, United States; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, United States.
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25
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Honma S, Hisamori S, Nishiuchi A, Itatani Y, Obama K, Shimono Y, Sakai Y. F-Box/WD Repeat Domain-Containing 7 Induces Chemotherapy Resistance in Colorectal Cancer Stem Cells. Cancers (Basel) 2019; 11:cancers11050635. [PMID: 31067777 PMCID: PMC6562509 DOI: 10.3390/cancers11050635] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 04/22/2019] [Accepted: 05/03/2019] [Indexed: 12/30/2022] Open
Abstract
Although the cancer stem cell (CSC) concept has provided a reasonable explanation for cancer recurrence following chemotherapy, the relationship between CSCs and chemotherapy resistance has not been thoroughly investigated, especially in solid tumors. We aimed to identify the mechanism underlying colorectal cancer (CRC) chemoresistance focusing on the cell cycle mediator F-Box/WD repeat domain-containing 7 (FBXW7). From 55 consecutive CRC cases who underwent neoadjuvant chemotherapy (NAC) or neoadjuvant chemoradiotherapy (NACRT) at Kyoto University Hospital, pre-treatment endoscopic biopsy specimens were collected and divided into two groups upon immunohistochemical (IHC) analysis: 21 cases of FBXW7 high expression (FBXW7-high group) and 34 cases of low expression (FBXW7-low group). High FBXW7 expression in pre-treatment biopsy specimen was significantly associated with poor pathological therapeutic effect (p = 0.019). The proportion of FBXW7-positive cells in surgically resected CRC specimens from patients who underwent NAC or NACRT was significantly higher than that in the pre-treatment biopsy specimens (p < 0.001). The expression of FBXW7 was inversely correlated with that of Ki67 in both pre-treatment biopsy specimens and surgically resected specimens. FBXW7 expression in the EpCAMhigh/CD44high subpopulation isolated by flow cytometry from CRC samples was significantly higher than that in the EpCAMhigh/CD44low subpopulation. Cell-cycle analysis in CRC cell lines revealed that, upon FBXW7 silencing, the proportion of G0/G1 cells was significantly lower than that in control cells. Moreover, knockdown of FBXW7 in CRC cell lines increased the sensitivity to anti-cancer drugs in vitro and in vivo. A subset of CRC stem cells possesses chemoresistance through FBXW7 expression. Cell cycle arrest induced by FBXW7 expression should be considered as a potential therapeutic target to overcome chemoresistance in CRC stem cell subsets.
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Affiliation(s)
- Shusaku Honma
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
| | - Shigeo Hisamori
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
| | - Aya Nishiuchi
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
| | - Yoshiro Itatani
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
| | - Kazutaka Obama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
| | - Yohei Shimono
- Department of Biochemistry, School of Medicine, Fujita Health University, Aichi 470-1192, Japan.
| | - Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8507, Japan.
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26
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The role of SOX family members in solid tumours and metastasis. Semin Cancer Biol 2019; 67:122-153. [PMID: 30914279 DOI: 10.1016/j.semcancer.2019.03.004] [Citation(s) in RCA: 263] [Impact Index Per Article: 43.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2018] [Revised: 03/07/2019] [Accepted: 03/21/2019] [Indexed: 02/07/2023]
Abstract
Cancer is a heavy burden for humans across the world with high morbidity and mortality. Transcription factors including sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX) proteins are thought to be involved in the regulation of specific biological processes. The deregulation of gene expression programs can lead to cancer development. Here, we review the role of the SOX family in breast cancer, prostate cancer, renal cell carcinoma, thyroid cancer, brain tumours, gastrointestinal and lung tumours as well as the entailing therapeutic implications. The SOX family consists of more than 20 members that mediate DNA binding by the HMG domain and have regulatory functions in development, cell-fate decision, and differentiation. SOX2, SOX4, SOX5, SOX8, SOX9, and SOX18 are up-regulated in different cancer types and have been found to be associated with poor prognosis, while the up-regulation of SOX11 and SOX30 appears to be favourable for the outcome in other cancer types. SOX2, SOX4, SOX5 and other SOX members are involved in tumorigenesis, e.g. SOX2 is markedly up-regulated in chemotherapy resistant cells. The SoxF family (SOX7, SOX17, SOX18) plays an important role in angio- and lymphangiogenesis, with SOX18 seemingly being an attractive target for anti-angiogenic therapy and the treatment of metastatic disease in cancer. In summary, SOX transcription factors play an important role in cancer progression, including tumorigenesis, changes in the tumour microenvironment, and metastasis. Certain SOX proteins are potential molecular markers for cancer prognosis and putative potential therapeutic targets, but further investigations are required to understand their physiological functions.
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27
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Sato Y, Yamada T, Hiroyama T, Sudo K, Hasegawa N, Hyodo I, Nakamura Y. A robust culture method for maintaining tumorigenic cancer stem cells in the hepatocellular carcinoma cell line Li-7. Cancer Sci 2019; 110:1644-1652. [PMID: 30784169 PMCID: PMC6500967 DOI: 10.1111/cas.13978] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Revised: 01/23/2019] [Accepted: 02/18/2019] [Indexed: 12/21/2022] Open
Abstract
Cancer tissues contain small populations of highly tumorigenic cells termed cancer stem cells (CSCs). Immortalized cell lines containing CSCs are valuable and powerful experimental tools for research into the characteristics of these stem cells. We previously reported that the hepatocellular carcinoma cell line Li‐7 includes abundant CD13+CD166−CSCs; however, the number of these cells decreases after long‐term culture as a result of differentiation to non‐CSC populations. To ensure consistent and reproducible results in experiments using Li‐7 cells, it is important that the CSC population is maintained stably regardless of culture duration and passage. In the present study, we found that a commercially available culture medium for maintenance of embryonic stem cells and induced pluripotent stem cells, mTeSR1, effectively prevented spontaneous differentiation by CD13+CD166− cells to CD13−CD166+ cells and therefore maintained the CSC population in Li‐7 cell cultures. CD13+CD166−CSCs maintained using this culture medium retained high tumorigenicity after transplantation into mice; they also showed the ability to differentiate in vitro into non‐CSC populations in RPMI‐1640 with 10% FBS medium. We analyzed gene expression profiles of CSC and non‐CSC populations in Li‐7 cultures using an RNA sequencing method. Genes such as FGFR, NOTCH1, and JAG1, that are associated with tumorigenicity and stemness, were upregulated in the CSC population. Our results suggest that CSCs can be maintained in immortalized cancer cell lines cultured over an extended period using a medium developed for culture of embryonic/induced pluripotent stem cells.
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Affiliation(s)
- Yukako Sato
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
| | - Takeshi Yamada
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.,Division of Clinical Research and Regional Innovation, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Takashi Hiroyama
- Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
| | - Kazuhiro Sudo
- Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
| | - Naoyuki Hasegawa
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Ichinosuke Hyodo
- Division of Gastroenterology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan
| | - Yukio Nakamura
- Cell Engineering Division, RIKEN BioResource Research Center, Tsukuba, Japan
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28
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Primitive Cancer Cell States: A Target for Drug Screening? Trends Pharmacol Sci 2019; 40:161-171. [DOI: 10.1016/j.tips.2019.01.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Revised: 12/05/2018] [Accepted: 01/07/2019] [Indexed: 12/26/2022]
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29
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Saito S, Lin YC, Nakamura Y, Eckner R, Wuputra K, Kuo KK, Lin CS, Yokoyama KK. Potential application of cell reprogramming techniques for cancer research. Cell Mol Life Sci 2019; 76:45-65. [PMID: 30283976 PMCID: PMC6326983 DOI: 10.1007/s00018-018-2924-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2018] [Revised: 09/15/2018] [Accepted: 09/19/2018] [Indexed: 02/07/2023]
Abstract
The ability to control the transition from an undifferentiated stem cell to a specific cell fate is one of the key techniques that are required for the application of interventional technologies to regenerative medicine and the treatment of tumors and metastases and of neurodegenerative diseases. Reprogramming technologies, which include somatic cell nuclear transfer, induced pluripotent stem cells, and the direct reprogramming of specific cell lineages, have the potential to alter cell plasticity in translational medicine for cancer treatment. The characterization of cancer stem cells (CSCs), the identification of oncogene and tumor suppressor genes for CSCs, and the epigenetic study of CSCs and their microenvironments are important topics. This review summarizes the application of cell reprogramming technologies to cancer modeling and treatment and discusses possible obstacles, such as genetic and epigenetic alterations in cancer cells, as well as the strategies that can be used to overcome these obstacles to cancer research.
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Affiliation(s)
- Shigeo Saito
- Saito Laboratory of Cell Technology, Yaita, Tochigi, 329-1571, Japan
- College of Engineering, Nihon University, Koriyama, Fukushima, 963-8642, Japan
| | - Ying-Chu Lin
- School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Yukio Nakamura
- Cell Engineering Division, RIKEN BioResource Center, Tsukuba, Ibaraki, 305-0074, Japan
| | - Richard Eckner
- Department of Biochemistry and Molecular Biology, Rutgers, New Jersey Medical School-Rutgers, The State University of New Jersey, Newark, NJ, 07101, USA
| | - Kenly Wuputra
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan
| | - Kung-Kai Kuo
- Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, 807, Taiwan
| | - Chang-Shen Lin
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, 804, Taiwan.
| | - Kazunari K Yokoyama
- Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, 807, Taiwan.
- Faculty of Molecular Preventive Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, 113-0033, Japan.
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30
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The Crosstalk between Cancer Stem Cells and Microenvironment Is Critical for Solid Tumor Progression: The Significant Contribution of Extracellular Vesicles. Stem Cells Int 2018; 2018:6392198. [PMID: 30532788 PMCID: PMC6247433 DOI: 10.1155/2018/6392198] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Revised: 10/02/2018] [Accepted: 10/11/2018] [Indexed: 12/12/2022] Open
Abstract
Several evidences nowadays demonstrated the critical role of the microenvironment in regulating cancer stem cells and their involvement in tumor progression. Extracellular vesicles (EVs) are considered as one of the most effective vehicles of information among cells. Accordingly, a number of studies led to the recognition of stem cell-associated EVs as new complexes able to contribute to cell fate determination of either normal or tumor cells. In this review, we aim to highlight an existing bidirectional role of EV-mediated communication—from cancer stem cells to microenvironment and also from microenvironment to cancer stem cells—in the most widespread solid cancers as prostate, breast, lung, and colon tumors.
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31
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Hirashima K, Yue F, Kobayashi M, Uchida Y, Nakamura S, Tomotsune D, Matsumoto K, Takizawa-Shirasawa S, Yokoyama T, Kanno H, Sasaki K. Cell biological profiling of reprogrammed cancer stem cell-like colon cancer cells maintained in culture. Cell Tissue Res 2018; 375:697-707. [PMID: 30284085 DOI: 10.1007/s00441-018-2933-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2018] [Accepted: 09/18/2018] [Indexed: 12/11/2022]
Abstract
Cancer stem cells (CSCs) are specific targets for therapeutic applications, but the rarity of CSCs within tumors makes the isolation of CSCs difficult. To overcome these problems, we generated CSCs in vitro using established reprogramming techniques. We transduced four previously established reprogramming factors, Oct3/4, Sox2, Klf4, and L-myc, into the colon cancer cell lines LoVo and OUMS-23, and investigated the biological characteristics of these lines. Tra-1-60+ cells were obtained from reprogrammed induced pluripotent stem (iPS) cell-like colonies and showed CSC properties, including colony formation, maintenance of colonies by repeated passages, and feeder cell dependency, as well as increased expressions of CSC markers such as CD133 and ALDH1. The CSC-like cells showed increased chemoresistance to 5-fluorouracil and elevated tumorigenicity upon transplantation into kidneys of immune-deficient mice. These tumors shifted to a poorly differentiated stage with many atypical cells, cytoplasmic mucin, and focal papillary components, with demonstrated dedifferentiation. The principal component analysis from DNA microarrays showed that though both cell lines moved to iPS cells after reprogramming, they were not completely identical to iPS cells. Significantly elevated gene expression of Decorin and CD90 was observed in CSC-like cells. Together, these results show that reprogramming of cancer cells produced not pluripotent stem cells but CSC-like cells, and these findings will provide biological information about genuine CSCs and help establish new CSC-targeted therapies.
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Affiliation(s)
- Kanji Hirashima
- Department of Anatomy and Organ Technology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
| | - Fengming Yue
- Department of Anatomy and Organ Technology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Mikiko Kobayashi
- Department of Pathology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Yuriko Uchida
- Department of Anatomy and Organ Technology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Shunsuke Nakamura
- Department of Anatomy and Organ Technology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Daihachiro Tomotsune
- Department of Anatomy and Organ Technology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.,Department of Biotechnology and Biomedical Engineering, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Ken Matsumoto
- Nissui Pharmaceutical Co., Ltd., 1075-2 Hokunanmoro, Yuki, Ibaraki, 307-0036, Japan
| | | | - Tadayuki Yokoyama
- Bourbon Corporation, 4-2-14 Matsunami, Kashiwazaki, Niigata, 945-8611, Japan
| | - Hiroyuki Kanno
- Department of Pathology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Katsunori Sasaki
- Department of Anatomy and Organ Technology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.,Department of Biotechnology and Biomedical Engineering, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
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Exosomes Regulate the Transformation of Cancer Cells in Cancer Stem Cell Homeostasis. Stem Cells Int 2018; 2018:4837370. [PMID: 30344611 PMCID: PMC6174755 DOI: 10.1155/2018/4837370] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2018] [Accepted: 07/31/2018] [Indexed: 02/07/2023] Open
Abstract
In different biological model systems, exosomes are considered mediators of cell-cell communication between different cell populations. Exosomes, as extracellular vesicles, participate in physiological and pathological processes by transmitting signaling molecules such as proteins, nucleic acids, and lipids. The tumor's microenvironment consists of many types of cells, including cancer stem cells and mesenchymal cells. It is well known that these cells communicate with each other and thereby regulate the progression of the tumor. Recent studies have provided evidence that exosomes mediate the interactions between different types of cells in the tumor microenvironment, providing further insight into how these cells interact through exosome signaling. Cancer stem cells are a small kind of heterogeneous cells that existed in tumor tissues or cancer cell lines. These cells possess a stemness phenotype with a self-renewal ability and multipotential differentiation which was considered the reason for the failure of conventional cancer therapies and tumor recurrence. However, a highly dynamic equilibrium was found between cancer stem cells and cancer cells, and this indicates that cancer stem cells are no more special target and blocking the transformation of cancer stem cells and cancer cells seem to be a more significant therapy strategy. Whether exosomes, as an information transforming carrier between cells, regulated cancer cell transformation in cancer stem cell dynamic equilibrium and targeting exosome signaling attenuated the formation of cancer stem cells and finally cure cancers is worthy of further study.
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Chao HM, Chern E. Patient-derived induced pluripotent stem cells for models of cancer and cancer stem cell research. J Formos Med Assoc 2018; 117:1046-1057. [PMID: 30172452 DOI: 10.1016/j.jfma.2018.06.013] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2017] [Revised: 05/28/2018] [Accepted: 06/15/2018] [Indexed: 02/06/2023] Open
Abstract
Induced pluripotent stem cells (iPSCs) are embryonic stem cell-like cells reprogrammed from somatic cells by four transcription factors, OCT4, SOX2, KLF4 and c-MYC. iPSCs derived from cancer cells (cancer-iPSCs) could be a novel strategy for studying cancer. During cancer cell reprogramming, the epigenetic status of the cancer cell may be altered, such that it acquires stemness and pluripotency. The cellular behavior of the reprogrammed cells exhibits dynamic changes during the different stages of reprogramming. The cells may acquire the properties of cancer stem cells (CSCs) during the process of reprogramming, and lose their carcinogenic properties during reprogramming into a cancer-iPSCs. Differentiation of cancer-iPSCs by teratoma formation or organoid culturing could mimic the process of tumorigenesis. Some of the molecular mechanisms associated with cancer progression could be elucidated using the cancer-iPSC model. Furthermore, cancer-iPSCs could be expanded in culture system or bioreactors, and serve as cell sources for research, and as personal disease models for therapy and drug screening. This article introduces cancer studies that used the cell reprogramming strategy.
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Affiliation(s)
- Hsiao-Mei Chao
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taiwan; Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taiwan
| | - Edward Chern
- niChe Lab for Stem Cell and Regenerative Medicine, Department of Biochemical Science and Technology, National Taiwan University, Taiwan.
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Chatterji P, Hamilton KE, Liang S, Andres SF, Wijeratne HRS, Mizuno R, Simon LA, Hicks PD, Foley SW, Pitarresi JR, Klein-Szanto AJ, Mah AT, Van Landeghem L, Gregory BD, Lengner CJ, Madison BB, Shah P, Rustgi AK. The LIN28B-IMP1 post-transcriptional regulon has opposing effects on oncogenic signaling in the intestine. Genes Dev 2018; 32:1020-1034. [PMID: 30068703 PMCID: PMC6075153 DOI: 10.1101/gad.314369.118] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2018] [Accepted: 06/04/2018] [Indexed: 12/15/2022]
Abstract
RNA-binding proteins (RBPs) are expressed broadly during both development and malignant transformation, yet their mechanistic roles in epithelial homeostasis or as drivers of tumor initiation and progression are incompletely understood. Here we describe a novel interplay between RBPs LIN28B and IMP1 in intestinal epithelial cells. Ribosome profiling and RNA sequencing identified IMP1 as a principle node for gene expression regulation downstream from LIN28B In vitro and in vivo data demonstrate that epithelial IMP1 loss increases expression of WNT target genes and enhances LIN28B-mediated intestinal tumorigenesis, which was reversed when we overexpressed IMP1 independently in vivo. Furthermore, IMP1 loss in wild-type or LIN28B-overexpressing mice enhances the regenerative response to irradiation. Together, our data provide new evidence for the opposing effects of the LIN28B-IMP1 axis on post-transcriptional regulation of canonical WNT signaling, with implications in intestinal homeostasis, regeneration and tumorigenesis.
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Affiliation(s)
- Priya Chatterji
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
| | - Kathryn E Hamilton
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
- Department of Pediatrics, Division of Gastroenterology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
| | - Shun Liang
- Department of Genetics, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Sarah F Andres
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
| | - H R Sagara Wijeratne
- Department of Genetics, Rutgers University, New Brunswick, New Jersey 08901, USA
| | - Rei Mizuno
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
| | - Lauren A Simon
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
- Department of Pediatrics, Division of Gastroenterology, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
| | - Philip D Hicks
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
| | - Shawn W Foley
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA
| | - Jason R Pitarresi
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
| | - Andres J Klein-Szanto
- Department of Pathology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
| | - Amanda T Mah
- Department of Medicine, Hematology Division, Stanford University, Stanford, California 94305, USA
| | - Laurianne Van Landeghem
- Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, North Carolina 27607, USA
| | - Brian D Gregory
- Department of Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19014, USA
| | - Christopher J Lengner
- Department of Biomedical Sciences, School of Veterinary Medicine, Institute for Regenerative Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
| | - Blair B Madison
- Department of Medicine, Division of Gastroenterology, Washington University School of Medicine, St. Louis, Missouri 63110, USA
| | - Premal Shah
- Department of Genetics, Rutgers University, New Brunswick, New Jersey 08901, USA
- Human Genetics Institute of New Jersey, Piscataway, New Jersey 08854 USA
| | - Anil K Rustgi
- Department of Medicine, Division of Gastroenterology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
- Department of Genetics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
- Abramson Cancer Center, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19014, USA
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Liu M, Tu J, Gingold JA, Kong CSL, Lee DF. Cancer in a dish: progress using stem cells as a platform for cancer research. Am J Cancer Res 2018; 8:944-954. [PMID: 30034933 PMCID: PMC6048395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 05/18/2018] [Indexed: 06/08/2023] Open
Abstract
Cancer models derived from patient specimens poorly reflect early-stage cancer development because cancer cells acquire numerous additional molecular alterations before the disease is clinically detectable. Earlier studies have used differentiated cells derived from induced pluripotent cancer cells (iPCCs) to partially mirror cancer disease phenotype, but the highly heterogeneous nature of cancer cells as well as difficulties with reprogramming cancer cells has limited the application of this technique. An alternative approach to modeling cancer in a dish entails reprogramming adult differentiated cells from patients with cancer syndromes to pluripotent stem cells (PSCs), followed by directed differentiation of those PSCs. A directed reprogramming and differentiation strategy has the potential to recapitulate cancer progression and capture the earliest molecular alterations that underlie cancer initiation. The reprogrammed cells share patient-specific genetic and epigenetic traits, offering a new platform to develop personalized therapy for cancer patients. In this review, we will provide an overview of available reprogramming methods of cancer cells and describe how cancer-derived stem cells have been used to characterize effects of defined molecular alterations in specific cell types. We also describe the "disease in a dish" model developed to study genetic cancer syndromes. These approaches highlight recent contributions of stem cell technology to the cancer biology realm.
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Affiliation(s)
- Mo Liu
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at HoustonHouston, TX 77030, USA
| | - Jian Tu
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at HoustonHouston, TX 77030, USA
- Department of Musculoskeletal Oncology, The First Affiliated Hospital of Sun Yat-sen UniversityGuangzhou 510080, PR China
| | - Julian A Gingold
- Women’s Health Institute, Cleveland Clinic FoundationCleveland, OH 44195, USA
| | - Celine Shuet Lin Kong
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at HoustonHouston, TX 77030, USA
| | - Dung-Fang Lee
- Department of Integrative Biology and Pharmacology, McGovern Medical School, The University of Texas Health Science Center at HoustonHouston, TX 77030, USA
- The University of Texas MD Anderson Cancer Center UT Health Graduate School of Biomedical SciencesHouston, TX 77030, USA
- Center for Stem Cell and Regenerative Medicine, The Brown Foundation Institute of Molecular Medicine for The Prevention of Human Diseases, The University of Texas Health Science Center at HoustonHouston, TX 77030, USA
- Center for Precision Health, School of Biomedical Informatics and School of Public Health, The University of Texas Health Science Center at HoustonHouston, TX 77030, USA
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Regeneration of cervical reserve cell-like cells from human induced pluripotent stem cells (iPSCs): A new approach to finding targets for cervical cancer stem cell treatment. Oncotarget 2018; 8:40935-40945. [PMID: 28402962 PMCID: PMC5522215 DOI: 10.18632/oncotarget.16783] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2016] [Accepted: 02/27/2017] [Indexed: 12/27/2022] Open
Abstract
Cervical reserve cells are epithelial progenitor cells that are pathologically evident as the origin of cervical cancer. Thus, investigating the characteristics of cervical reserve cells could yield insight into the features of cervical cancer stem cells (CSCs). In this study, we established a method for the regeneration of cervical reserve cell-like properties from human induced pluripotent stem cells (iPSCs) and named these cells induced reserve cell-like cells (iRCs). Approximately 70% of iRCs were positive for the reserve cell markers p63, CK5 and CK8. iRCs also expressed the SC junction markers CK7, AGR2, CD63, MMP7 and GDA. While iRCs expressed neither ERα nor ERβ, they expressed CA125. These data indicated that iRCs possessed characteristics of cervical epithelial progenitor cells. iRCs secreted higher levels of several inflammatory cytokines such as macrophage migration inhibitory factor (MIF), soluble intercellular adhesion molecule 1 (sICAM-1) and C-X-C motif ligand 10 (CXCL-10) compared with normal cervical epithelial cells. iRCs also expressed human leukocyte antigen-G (HLA-G), which is an important cell-surface antigen for immune tolerance and carcinogenesis. Together with the fact that cervical CSCs can originate from reserve cells, our data suggested that iRCs were potent immune modulators that might favor cervical cancer cell survival. In conclusion, by generating reserve cell-like properties from iPSCs, we provide a new approach that may yield new insight into cervical cancer stem cells and help find new oncogenic targets.
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Olejniczak A, Szaryńska M, Kmieć Z. In vitro characterization of spheres derived from colorectal cancer cell lines. Int J Oncol 2017; 52:599-612. [PMID: 29207035 DOI: 10.3892/ijo.2017.4206] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 10/08/2017] [Indexed: 11/06/2022] Open
Abstract
Spherical cultures (SCs) can be regarded in cancer research as a link between in vitro investigations on cancer lines and in vivo studies of tumor development. SCs are believed to mimic tumor architecture and to be enriched in cancer stem cell-like cells (CSC-like cells). In the present study we characterized colonospheres derived from colorectal cancer (CRC) cell lines, and we confirmed the ability of HCT116 and HT29 cell lines to form spheres within serum-free medium, however, the detailed analysis presented the major differences concerning their characteristics including morphology, phenotype, proliferative potential, distribution in the cell cycle phases and spherogenicity. Moreover, after we magnetically separated CD133+ and CD133- cells we could conduct the analogical analysis as we performed for the original cells. We observed that all cellular fractions unveiled sphere formation capacity, even when cultured in limited number of cells per well and only SCs originated from CD133+ fraction resembled morphologically the parental spheres. Both CD133+ and CD133- subsets derived from HCT116 line were more enriched in cells in G0/G1 phase of the cell cycle in comparison to their HT29 analogues. Additionally, proliferative potential also varied amongst all studied fractions. Surprisingly, 3-D invasion assay revealed that only HCT116-derived populations were able to migrate into extended regions of Matrigel Matrix confirming their higher aggressiveness. Our results provided comprehensive characterization of CRC cell lines culture in adherent and spherical forms and, what seems to be the most advantageous, the comparison of two distinct fractions after magnetic separation. As we found the specific features of cells presented line- and expansion mode-dependency, thus, such complete description might appear crucial before CRC lines would be involved into sophisticated assays, especially focused on potentially novel therapeutic agents targeting CSC-like cells.
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Affiliation(s)
- Agata Olejniczak
- Department of Histology, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Magdalena Szaryńska
- Department of Histology, Medical University of Gdansk, 80-210 Gdansk, Poland
| | - Zbigniew Kmieć
- Department of Histology, Medical University of Gdansk, 80-210 Gdansk, Poland
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38
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Interleukin-6 blockade attenuates lung cancer tissue construction integrated by cancer stem cells. Sci Rep 2017; 7:12317. [PMID: 28951614 PMCID: PMC5615065 DOI: 10.1038/s41598-017-12017-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 09/01/2017] [Indexed: 12/23/2022] Open
Abstract
In the present study, we successfully generated lung cancer stem cell (CSC)-like cells by introducing a small set of transcription factors into a lung cancer cell line. In addition to properties that are conventionally referred to as CSC properties, the lung induced CSCs exhibited the ability to form lung cancer-like tissues in vitro with vascular cells and mesenchymal stem cells, which showed structures and immunohistological patterns that were similar to human lung cancer tissues. We named them “lung cancer organoids”. We found that interleukin-6 (IL-6), which was expressed in the lung induced CSCs, facilitates the formation of lung cancer organoids via the conversion of mesenchymal stem cells into alpha-smooth muscle actin (αSMA)-positive cells. Interestingly, the combination of anti-IL-6 antibody and cisplatin could destroy the lung cancer organoids, while cisplatin alone could not. Furthermore, IL-6 mRNA-positive cancer cells were found in clinical lung cancer samples. These results suggest that IL-6 could be a novel therapeutic target in lung cancer.
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39
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Ou C, Sun Z, Li S, Li G, Li X, Ma J. Dual roles of yes-associated protein (YAP) in colorectal cancer. Oncotarget 2017; 8:75727-75741. [PMID: 29088905 PMCID: PMC5650460 DOI: 10.18632/oncotarget.20155] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2017] [Accepted: 07/30/2017] [Indexed: 02/07/2023] Open
Abstract
Yes-associated protein (YAP) is a downstream effector molecule of a newly emerging tumour suppressor pathway called the Hippo pathway. YAP is a transcriptional co-activator and mis-expressed in various cancers, including colorectal cancer (CRC). Accumulating studies show that the high expression of nuclear YAP is linked with tumour progression and decreased survival. Nuclear YAP can interact with other transcription factors to promote cancer cell proliferation, apoptosis, metastasis and maintenance of stemness. Therefore, YAP has the potential to be a tumour biomarker or therapeutic target for CRC. However, recently, a number of studies have supported a contradictory role for YAP as a tumour suppressor, demonstrating inhibition of the tumorigenesis of CRC, involvement in promoting cell apoptosis, and inhibiting the maintenance of intestinal stem cells and inflammatory activity. In these studies, high expression of YAP was highly correlated with worse survival in CRC. In this review, we will comprehensively summarize and analyse these paradoxical reports, and discuss both the oncogenic and tumour suppressor functions of YAP in the differential status of CRC progression. Further investigation into the mechanisms responsible for the dual function of YAP will be of great value in the prevention, early diagnosis, and therapy of CRC.
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Affiliation(s)
- Chunlin Ou
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Zhenqiang Sun
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China
- Department of Anorectal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Department of Gastrointestinal Surgery, Tumor Hospital of Xinjiang Medical University, Urumqi, Xinjiang 830011, China
| | - Shen Li
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China
| | - Guiyuan Li
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China
| | - Xiayu Li
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
| | - Jian Ma
- Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, China
- Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Cancer Research Institute, Central South University, Changsha, Hunan 410078, China
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, The Third Xiangya Hospital, Central South University, Changsha, Hunan 410013, China
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40
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Sha S, Zhai Y, Lin C, Wang H, Chang Q, Song S, Ren M, Liu G. A combination of valproic acid sodium salt, CHIR99021, E-616452, tranylcypromine, and 3-Deazaneplanocin A causes stem cell-like characteristics in cancer cells. Oncotarget 2017; 8:53302-53312. [PMID: 28881812 PMCID: PMC5581111 DOI: 10.18632/oncotarget.18396] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2016] [Accepted: 05/12/2017] [Indexed: 02/07/2023] Open
Abstract
Many studies are based on the hypothesis that recurrence and drug resistance in lung carcinoma are due to a subpopulation of cancer stem-like cells (CSLCs) in solid tumors. Therefore it is crucial to screen for and recognize lung CSLCs. In this study, we stimulated non-small cell lung cancer (NSCLC) A549 cells to display stem cell-like characteristics using a combination of five small molecule compounds. The putative A549 stem cells activated an important CSLC marker, CD133 protein, as well multiple CSLC-related genes including ATP-binding cassette transporter G2 (ABCG2), C-X-C chemokine receptor type 4 (CXCR4), NESTIN, and BMI1. The A549 stem-like cells displayed resistance to the chemotherapeutic drugs etoposide and cisplatin, epithelial-to-mesenchymal transition properties, and increased protein expression levels of NOTCH1 and Hes Family bHLH Transcription Factor 1 (HES1). When A549 cells were pretreated with a NOTCH signaling pathway inhibitor before compound induction, expression of the NOTCH1 target gene HES1 was reduced. This demonstrated that the NOTCH signaling pathway in the putative A549 stem-like cells had been activated. Together, the results of our study showed that a combination of five small molecule agents could transform A549 cells into putative stem-like cells, and that these compounds could also elevate CD133 and ABCG2 protein expression levels in H460 cells. This study provides a convenient method for obtaining lung CSLCs, which may be an effective strategy for developing lung carcinoma treatments.
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Affiliation(s)
- Shuang Sha
- Tongji University School of Life Sciences and Technology, Shanghai, China.,Clinical Research Center, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Yuanfen Zhai
- Department of Immunity, Tongji University School of Medicine, Shanghai, China
| | - Chengzhao Lin
- Center for Translational Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Heyong Wang
- Center for Translational Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qing Chang
- Clinical Research Center, Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences, Shanghai, China
| | - Shuang Song
- Center for Translational Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Mingqiang Ren
- Center for Translational Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China
| | - Gentao Liu
- Center for Translational Medicine, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.,Center for Cancer Immunotherapy, Shanghai Biomed-Union Biotechnology Co. Ltd, Shanghai International Medical Zone, Shanghai, China
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41
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Chen X, Liao R, Li D, Sun J. Induced cancer stem cells generated by radiochemotherapy and their therapeutic implications. Oncotarget 2017; 8:17301-17312. [PMID: 28038467 PMCID: PMC5370042 DOI: 10.18632/oncotarget.14230] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2016] [Accepted: 12/13/2016] [Indexed: 12/26/2022] Open
Abstract
Local and distant recurrence of malignant tumors following radio- and/or chemotherapy correlates with poor prognosis of patients. Among the reasons for cancer recurrence, preexisting cancer stem cells (CSCs) are considered the most likely cause due to their properties of self-renewal, pluripotency, plasticity and tumorigenicity. It has been demonstrated that preexisting cancer stem cells derive from normal stem cells and differentiated somatic cells that undergo transformation and dedifferentiation respectively under certain conditions. However, recent studies have revealed that cancer stem cells can also be induced from non-stem cancer cells by radiochemotherapy, constituting the subpopulation of induced cancer stem cells (iCSCs). These findings suggest that radiochemotherapy has the side effect of directly transforming non-stem cancer cells into induced cancer stem cells, possibly contributing to tumor recurrence and metastasis. Therefore, drugs targeting cancer stem cells or preventing dedifferentiation of non-stem cancer cells can be combined with radiochemotherapy to improve its antitumor efficacy. The current review is to investigate the mechanisms by which induced cancer stem cells are generated by radiochemotherapy and hence provide new strategies for cancer treatment.
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Affiliation(s)
- Xiewan Chen
- Medical English Department, College of Basic Medicine, Third Military Medical University, Chongqing, China.,Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Rongxia Liao
- Medical English Department, College of Basic Medicine, Third Military Medical University, Chongqing, China
| | - Dezhi Li
- Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Jianguo Sun
- Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing, China
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42
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Ishida R, Koyanagi-Aoi M, Oshima N, Kakeji Y, Aoi T. The Tissue-Reconstructing Ability of Colon CSCs Is Enhanced by FK506 and Suppressed by GSK3 Inhibition. Mol Cancer Res 2017; 15:1455-1466. [DOI: 10.1158/1541-7786.mcr-17-0071] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2017] [Revised: 06/06/2017] [Accepted: 07/11/2017] [Indexed: 11/16/2022]
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43
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Lourenço AR, Coffer PJ. SOX4: Joining the Master Regulators of Epithelial-to-Mesenchymal Transition? Trends Cancer 2017; 3:571-582. [PMID: 28780934 DOI: 10.1016/j.trecan.2017.06.002] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 06/07/2017] [Accepted: 06/09/2017] [Indexed: 01/03/2023]
Abstract
The epithelial-to-mesenchymal transition (EMT) is an important developmental program exploited by cancer cells to gain mesenchymal features. Transcription factors globally regulating processes during EMT are often referred as 'master regulators' of EMT, and include members of the Snail and ZEB transcription factor families. The SRY-related HMG box (SOX) 4 transcription factor can promote tumorigenesis by endowing cells with migratory and invasive properties, stemness, and resistance to apoptosis, thereby regulating key aspects of the EMT program. We propose here that SOX4 should also be considered as a master regulator of EMT, and we review the molecular mechanisms underlying its function.
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Affiliation(s)
- Ana Rita Lourenço
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Uppsalalaan 6, Utrecht, The Netherlands
| | - Paul J Coffer
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands; Regenerative Medicine Center, University Medical Center Utrecht, Uppsalalaan 6, Utrecht, The Netherlands.
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44
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Teixeira G, Szyndralewiez C, Molango S, Carnesecchi S, Heitz F, Wiesel P, Wood JM. Therapeutic potential of NADPH oxidase 1/4 inhibitors. Br J Pharmacol 2017; 174:1647-1669. [PMID: 27273790 PMCID: PMC5446584 DOI: 10.1111/bph.13532] [Citation(s) in RCA: 123] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 05/23/2016] [Accepted: 05/23/2016] [Indexed: 12/16/2022] Open
Abstract
The NADPH oxidase (NOX) family of enzymes produces ROS as their sole function and is becoming recognized as key modulators of signal transduction pathways with a physiological role under acute stress and a pathological role after excessive activation under chronic stress. The seven isoforms differ in their regulation, tissue and subcellular localization and ROS products. The most studied are NOX1, 2 and 4. Genetic deletion of NOX1 and 4, in contrast to NOX2, has revealed no significant spontaneous pathologies and a pathogenic relevance of both NOX1 and 4 across multiple organs in a wide range of diseases and in particular inflammatory and fibrotic diseases. This has stimulated interest in NOX inhibitors for therapeutic application. GKT136901 and GKT137831 are two structurally related compounds demonstrating a preferential inhibition of NOX1 and 4 that have suitable properties for in vivo studies and have consequently been evaluated across a range of disease models and compared with gene deletion. In contrast to gene deletion, these inhibitors do not completely suppress ROS production, maintaining some basal level of ROS. Despite this and consistent with most gene deletion studies, these inhibitors are well tolerated and slow or prevent disease progression in a range of models of chronic inflammatory and fibrotic diseases by modulating common signal transduction pathways. Clinical trials in patients with GKT137831 have demonstrated excellent tolerability and reduction of various markers of chronic inflammation. NOX1/4 inhibition may provide a safe and effective therapeutic strategy for a range of inflammatory and fibrotic diseases. LINKED ARTICLES This article is part of a themed section on Redox Biology and Oxidative Stress in Health and Disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.12/issuetoc.
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Affiliation(s)
- G Teixeira
- Evotec International GmbHGoettingenGermany
| | | | - S Molango
- Genkyotex SAPlan les OuatesSwitzerland
| | | | - F Heitz
- Genkyotex SAPlan les OuatesSwitzerland
| | - P Wiesel
- Genkyotex SAPlan les OuatesSwitzerland
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Chitosan promotes cancer progression and stem cell properties in association with Wnt signaling in colon and hepatocellular carcinoma cells. Sci Rep 2017; 8:45751. [PMID: 28367998 PMCID: PMC5377948 DOI: 10.1038/srep45751] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Accepted: 03/06/2017] [Indexed: 12/14/2022] Open
Abstract
Cancer stem cells (CSCs), a small population of cancer cells, have been considered to be the origin of cancer initiation, recurrence, and metastasis. Tumor microenvironment provides crucial signals for CSCs to maintain stem cell properties and promotes tumorigenesis. Therefore, establishment of an appropriate cell culture system to mimic the microenvironment for CSC studies is an important issue. In this study, we grew colon and hepatocellular carcinoma (HCC) cells on chitosan membranes and evaluated the tumor progression and the CSC properties. Experimental results showed that culturing cancer cells on chitosan increased cell motility, drug resistance, quiescent population, self-renewal capacity, and the expression levels of stemness and CSC marker genes, such as OCT4, NANOG, CD133, CD44, and EpCAM. Furthermore, we demonstrated that chitosan might activate canonical Wnt/β-catenin-CD44 axis signaling in CD44positive colon cancer cells and noncanonical Wnt-STAT3 signaling in CD44negative HCC cells. In conclusion, chitosan as culture substrates activated the essential signaling of CSCs and promoted CSC properties. The chitosan culture system provides a convenient platform for the research of CSC biology and screening of anticancer drugs.
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Induction of intestinal stemness and tumorigenicity by aberrant internalization of commensal non-pathogenic E. coli. Cell Death Dis 2017; 8:e2667. [PMID: 28300841 PMCID: PMC5386548 DOI: 10.1038/cddis.2017.27] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 12/09/2016] [Accepted: 12/27/2016] [Indexed: 02/06/2023]
Abstract
Commensal Escherichia coli has been identified as a major protagonist of microbe-induced colorectal oncogenesis. Its tumour-promoting attribute is linked to the expression of DNA-damaging genotoxins. Using a constitutively invasive variant of non-pathogenic E. coli, we demonstrate that chronic presence of internalized E. coli leads to enhanced oncogenicity in colon cancer cells. Instead of genomic damage, the tumorigenic effect is mediated through an expansion of the cancer stem cell (CSC) population, likely through dedifferentiation of lineage-committed intestinal epithelial cells. Stemness-linked intestinal tumorigenicity is directly correlated to absence of microbial virulence factor expression and is specific for intestinal cells. The enriched CSC fraction remains stable in the absence of the instigating bacteria and can foster stemness traits in unexposed cells through secreted factors. Mechanistically, aberrant host invasion leads to realignment of multiple host signal transduction cascades, notably mutually re-enforcing NF-κB and β-catenin activation, through reciprocal modulation of microbe sensing pathways Nod1/Rip2 and TLR/MyD88. The expanded tumorigenic CSC population is marked by enhanced malignancy traits, long-term self-renewal capacity and robust tumorigenic ability, both in vitro and in vivo. Our study shows that microbe-induced oncogenicity is not a strict correlate of commensal virulence and can be invoked by even non-pathogenic E. coli by engendering tumorigenic stemness in host cells.
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Izgi K, Canatan H, Iskender B. Current status in cancer cell reprogramming and its clinical implications. J Cancer Res Clin Oncol 2017; 143:371-383. [PMID: 27620745 DOI: 10.1007/s00432-016-2258-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2016] [Accepted: 09/02/2016] [Indexed: 12/26/2022]
Abstract
PURPOSE The technology of reprogramming a terminally differentiated cell to an embryonic-like state uncovered the possibility of reprogramming a malignant cell back to a more manageable stem cell-like state. Since the current cancer models suffer from reflecting heterogeneous tumour structure and limited to express the late-stage markers, the induced pluripotent stem cell (iPSC) technology could provide an alternative model to recapitulate the early stages of cancer. Generation of iPSCs from cancer cells could offer a tool for understanding the mechanisms of tumour initiation-progression in vitro, a platform for studying tumour heterogeneity and origin of cancer stem cells and a source for cancer type-specific drug discovery studies. METHODS In this review, we discussed the recent findings in reprogramming cancer cells with a special emphasis on similarities between cancer cells and pluripotent cells. We presented the basis of challenges in cancer cell reprogramming including the current problems in reprogramming, cancer-specific epigenetic state and chromosomal aberrations. RESULTS Cancer epigenetics represent the major hurdle before the prospective use of cancer iPSCs as a model system and for biomarker research. When the reprogramming process is optimised for cancer cell types, it might serve for two purposes: identification of the specific epigenetic state of cancer as well as reversion of the malignant phenotype to a potentially malignant but manageable state. CONCLUSIONS Reprogramming cancer cells would serve for our understanding of cancer-specific epigenome and elucidation of overlapping mechanisms shared by cancer-initiating cells and pluripotent cells.
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Affiliation(s)
- Kenan Izgi
- Department of Medical Biochemistry, Faculty of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey
- Betul-Ziya Eren Genome and Stem Cell Centre, Erciyes University, 38039, Melikgazi, Kayseri, Turkey
| | - Halit Canatan
- Department of Medical Biology, Faculty of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey
- Betul-Ziya Eren Genome and Stem Cell Centre, Erciyes University, 38039, Melikgazi, Kayseri, Turkey
| | - Banu Iskender
- Department of Medical Biology, Faculty of Medicine, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.
- Betul-Ziya Eren Genome and Stem Cell Centre, Erciyes University, 38039, Melikgazi, Kayseri, Turkey.
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Oxidative stress induces the acquisition of cancer stem-like phenotype in breast cancer detectable by using a Sox2 regulatory region-2 (SRR2) reporter. Oncotarget 2016; 7:3111-27. [PMID: 26683522 PMCID: PMC4823094 DOI: 10.18632/oncotarget.6630] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 11/14/2015] [Indexed: 12/20/2022] Open
Abstract
We have previously identified a novel intra-tumoral dichotomy in breast cancer based on the differential responsiveness to a Sox2 reporter (SRR2), with cells responsive to SRR2 (RR) being more stem-like than unresponsive cells (RU). Here, we report that RR cells derived from MCF7 and ZR751 displayed a higher tolerance to oxidative stress than their RU counterparts, supporting the concept that the RR phenotype correlates with cancer stemness. Sox2 is directly implicated in this differential H2O2 tolerance, since siRNA knockdown of Sox2 in RR cells leveled this difference. Interestingly, H2O2 converted a proportion of RU cells into RR cells, as evidenced by their expression of luciferase and GFP, markers of SRR2 activity. Compared to RU cells, converted RR cells showed a significant increase in mammosphere formation and tolerance to H2O2. Converted RR cells also adopted the biochemical features of RR cells, as evidenced by their substantial increase in Sox2-SRR2 binding and the expression of 3 signature genes of RR cells (CD133, GPR49 and MUC15). Lastly, the H2O2-induced RU/RR conversion was detectable in a SCID mouse xenograft model and primary tumor cells. To conclude, the H2O2-induced RU/RR conversion has provided a novel model to study the acquisition of cancer stemness and plasticity.
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Yue F, Hirashima K, Tomotsune D, Takizawa-Shirasawa S, Yokoyama T, Sasaki K. Reprogramming of retinoblastoma cancer cells into cancer stem cells. Biochem Biophys Res Commun 2016; 482:549-555. [PMID: 27856246 DOI: 10.1016/j.bbrc.2016.11.072] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2016] [Accepted: 11/12/2016] [Indexed: 12/16/2022]
Abstract
Retinoblastoma is the most common intraocular malignancy in pediatric patients. It develops rapidly in the retina and can be fatal if not treated promptly. It has been proposed that a small population of cancer cells, termed cancer stem cells (CSCs), initiate tumorigenesis from immature tissue stem cells or progenitor cells. Reprogramming technology, which can convert mature cells into pluripotent stem cells (iPS), provides the possibility of transducing malignant cancer cells back to CSCs, a type of early stage of cancer. We herein took advantage of reprogramming technology to induce CSCs from retinoblastoma cancer cells. In the present study, the 4 Yamanaka transcription factors, Oct4, Sox2, Klf4 and c-myc, were transduced into retinoblastoma cells (Rbc51). iPS-like colonies were observed 15 days after transduction and showed significantly enhanced CSC properties. The gene and protein expression levels of pluripotent stem cell markers (Tra-1-60, Oct4, Nanog) and cancer stem cell markers (CD133, CD44) were up-regulated in transduced Rbc51 cells compared to control cells. Moreover, iPS-like CSCs could be sorted using the Magnetic-activated cell sorting (MACS) method. A sphere formation assay demonstrated spheroid formation in transduced Rbc51 cells cultured in serum free media, and these spheroids could be differentiated into Pax6-, Nestin-positive neural progenitors and rhodopsin- and recoverin-positive mature retinal cells. The cell viability after 5-Fu exposure was higher in transduced Rbc51 cells. In conclusion, CSCs were generated from retinoblastoma cancer cells using reprogramming technology. Our novel method can generate CSCs, the study of which can lead to better understanding of cancer-specific initiation, cancer epigenetics, and the overlapping mechanisms of cancer development and pluripotent stem cell behavior.
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Affiliation(s)
- Fengming Yue
- Department of Histology and Embryology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan.
| | - Kanji Hirashima
- Department of Histology and Embryology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan
| | - Daihachiro Tomotsune
- Department of Biotechnology and Biomedical Engineering, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University Matsumoto, 3-1-1 Asahi, Matsumoto 390-8621, Japan
| | | | - Tadayuki Yokoyama
- Bourbon Corporation, 4-2-14 Matsunami, Kashiwazaki, Niigata 945-8611, Japan
| | - Katsunori Sasaki
- Department of Histology and Embryology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto 390-8621, Japan; Department of Biotechnology and Biomedical Engineering, Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University Matsumoto, 3-1-1 Asahi, Matsumoto 390-8621, Japan
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50
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Wang T, Shigdar S, Gantier MP, Hou Y, Wang L, Li Y, Shamaileh HA, Yin W, Zhou SF, Zhao X, Duan W. Cancer stem cell targeted therapy: progress amid controversies. Oncotarget 2016; 6:44191-206. [PMID: 26496035 PMCID: PMC4792551 DOI: 10.18632/oncotarget.6176] [Citation(s) in RCA: 119] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Accepted: 10/06/2015] [Indexed: 12/12/2022] Open
Abstract
Although cancer stem cells have been well characterized in numerous malignancies, the fundamental characteristics of this group of cells, however, have been challenged by some recent observations: cancer stem cells may not necessary to be rare within tumors; cancer stem cells and non-cancer stem cells may undergo reversible phenotypic changes; and the cancer stem cells phenotype can vary substantially between patients. Here the current status and progresses of cancer stem cells theory is illustrated and via providing a panoramic view of cancer therapy, we addressed the recent controversies regarding the feasibility of cancer stem cells targeted anti-cancer therapy.
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Affiliation(s)
- Tao Wang
- School of Nursing, Zhengzhou University, Zhengzhou, China.,School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Sarah Shigdar
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Michael P Gantier
- Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, Victoria, Australia.,Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia
| | - Yingchun Hou
- Co-Innovation Center for Qinba Region's Sustainable Development, Shaanxi Normal University, Xi'an, China
| | - Li Wang
- Department of Gynecologic Oncology, Henan Cancer Hospital, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou, China
| | - Yong Li
- Cancer Care Centre, St George Hospital and St George Clinical School, University of New South Wales (UNSW), Kensington, Australia
| | - Hadi Al Shamaileh
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Wang Yin
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
| | - Shu-Feng Zhou
- Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA
| | - Xinhan Zhao
- Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University School of Medicine, Xi'an, China
| | - Wei Duan
- School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia
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