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Biggs MA, Das A, Goncalves BG, Murray ME, Frantzeskos SA, Hunt HL, Phan CAN, Banerjee IA. Developing New Peptides and Peptide-Drug Conjugates for Targeting the FGFR2 Receptor-Expressing Tumor Cells and 3D Spheroids. Biomimetics (Basel) 2024; 9:515. [PMID: 39329537 PMCID: PMC11429203 DOI: 10.3390/biomimetics9090515] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/11/2024] [Accepted: 08/23/2024] [Indexed: 09/28/2024] Open
Abstract
In this work, we utilized a biomimetic approach for targeting KATO (III) tumor cells and 3D tumoroids. Specifically, the binding interactions of the bioactive short peptide sequences ACSAG (A-pep) and LPHVLTPEAGAT (L-pep) with the fibroblast growth factor receptor (FGFR2) kinase domain was investigated for the first time. Both peptides have been shown to be derived from natural resources previously. We then created a new fusion trimer peptide ACSAG-LPHVLTPEAGAT-GASCA (Trimer-pep) and investigated its binding interactions with the FGFR2 kinase domain in order to target the fibroblast growth factor receptor 2 (FGFR2), which is many overexpressed in tumor cells. Molecular docking and molecular dynamics simulation studies revealed critical interactions with the activation loop, hinge and glycine-rich loop regions of the FGFR2 kinase domain. To develop these peptides for drug delivery, DOX (Doxorubicin) conjugates of the peptides were created. Furthermore, the binding of the peptides with the kinase domain was further confirmed through surface plasmon resonance studies. Cell studies with gastric cancer cells (KATO III) revealed that the conjugates and the peptides induced higher cytotoxicity in the tumor cells compared to normal cells. Following confirmation of cytotoxicity against tumor cells, the ability of the conjugates and the peptides to penetrate 3D spheroids was investigated by evaluating their permeation in co-cultured spheroids grown with KATO (III) and colon tumor-associated fibroblasts (CAFs). Results demonstrated that Trimer-pep conjugated with DOX showed the highest permeation, while the ACSAG conjugate also demonstrated reasonable permeation of the drug. These results indicate that these peptides may be further explored and potentially utilized to create drug conjugates for targeting tumor cells expressing FGFR2 for developing therapeutics.
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Affiliation(s)
- Mary A Biggs
- Department of Chemistry and Biochemistry, Fordham University, 441 East Fordham Road, Bronx, NY 10458, USA
| | - Amrita Das
- Department of Chemistry and Biochemistry, Fordham University, 441 East Fordham Road, Bronx, NY 10458, USA
| | - Beatriz G Goncalves
- Department of Chemistry and Biochemistry, Fordham University, 441 East Fordham Road, Bronx, NY 10458, USA
| | - Molly E Murray
- Department of Chemistry and Biochemistry, Fordham University, 441 East Fordham Road, Bronx, NY 10458, USA
| | - Sophia A Frantzeskos
- Department of Chemistry and Biochemistry, Fordham University, 441 East Fordham Road, Bronx, NY 10458, USA
| | - Hannah L Hunt
- Department of Chemistry and Biochemistry, Fordham University, 441 East Fordham Road, Bronx, NY 10458, USA
| | - Chau Ahn N Phan
- Department of Chemistry and Biochemistry, Fordham University, 441 East Fordham Road, Bronx, NY 10458, USA
| | - Ipsita A Banerjee
- Department of Chemistry and Biochemistry, Fordham University, 441 East Fordham Road, Bronx, NY 10458, USA
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Otaegi-Ugartemendia M, Matheu A, Carrasco-Garcia E. Impact of Cancer Stem Cells on Therapy Resistance in Gastric Cancer. Cancers (Basel) 2022; 14:cancers14061457. [PMID: 35326607 PMCID: PMC8946717 DOI: 10.3390/cancers14061457] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2022] [Revised: 03/06/2022] [Accepted: 03/09/2022] [Indexed: 12/04/2022] Open
Abstract
Gastric cancer (GC) is the fourth leading cause of cancer death worldwide, with an average 5-year survival rate of 32%, being of 6% for patients presenting distant metastasis. Despite the advances made in the treatment of GC, chemoresistance phenomena arise and promote recurrence, dissemination and dismal prognosis. In this context, gastric cancer stem cells (gCSCs), a small subset of cancer cells that exhibit unique characteristics, are decisive in therapy failure. gCSCs develop different protective mechanisms, such as the maintenance in a quiescent state as well as enhanced detoxification procedures and drug efflux activity, that make them insusceptible to current treatments. This, together with their self-renewal capacity and differentiation ability, represents major obstacles for the eradication of this disease. Different gCSC regulators have been described and used to isolate and characterize these cell populations. However, at the moment, no therapeutic strategy has achieved the effective targeting of gCSCs. This review will focus on the properties of cancer stem cells in the context of therapy resistance and will summarize current knowledge regarding the impact of the gCSC regulators that have been associated with GC chemoradioresistance.
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Affiliation(s)
| | - Ander Matheu
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (M.O.-U.); (A.M.)
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), 28029 Madrid, Spain
- IKERBASQUE, Basque Foundation for Science, 48009 Bilbao, Spain
| | - Estefania Carrasco-Garcia
- Cellular Oncology Group, Biodonostia Health Research Institute, 20014 San Sebastian, Spain; (M.O.-U.); (A.M.)
- CIBER de Fragilidad y Envejecimiento Saludable (CIBERfes), 28029 Madrid, Spain
- Correspondence: ; Tel.: +34-943-006296
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Jafari N, Abediankenari S, Hossein-Nataj H. miR-34a mimic or pre-mir-34a, which is the better option for cancer therapy? KatoIII as a model to study miRNA action in human gastric cancer cells. Cancer Cell Int 2021; 21:178. [PMID: 33740991 PMCID: PMC7980621 DOI: 10.1186/s12935-021-01872-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Accepted: 03/08/2021] [Indexed: 12/15/2022] Open
Abstract
Background Aberrantly expressed microRNAs play important roles in gastric tumorigenesis. However, use of miRNAs as a therapeutic option in gastric cancer still remains as a challenging problem. Methods We performed transient transfection of miR-34a-5p mimic and stable transfection of pre-mir-34a into KatoIII cells. Then, we evaluated the effect of transfected miRNAs on numerous cellular and molecular processes. Results Following transient transfection of miR-34a-5p mimic at 25 nM—a commonly used concentration—into KatoIII cells, inhibition of two target genes expression, namely Notch1 and β-catenin, was not observed, but a non-significant marginal increase of these genes was detected. No changes were detected in the percentage of apoptotic cells as well as in CD44 + and EpCAM + cells after 25 nM miR-34a-5p mimic transfection. Interestingly, stable transfection of pre-mir-34a into KatoIII cells (named as KatoIII-pGFPC1-34a cells) caused a significant repression in β-catenin protein and Notch1 mRNA levels (p < 0.05 and p < 0.01, respectively) relative to equivalent control (KatoIII- pGFPC1-empty cells). The percentage of CD44 + cells in the KatoIII-pGFPC1-34a cells (< 40%) was significantly lower than that in control cells (~ 95%) (p < 0.05). An increase of ~ 3.5% in apoptotic cells and a slower proliferation rate were detected in KatoIII-pGFPC1-34a cells. Conclusions Our study revealed that the effect of miR mimic in target gene repression can be dependent to its concentration as well as to the cell type. Meanwhile, our findings further support a regulatory function for pre-miRNAs in target repression and will help to develop effective therapeutic strategies in cancer treatment. Supplementary Information The online version contains supplementary material available at 10.1186/s12935-021-01872-5.
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Affiliation(s)
- Narjes Jafari
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Saeid Abediankenari
- Immunogenetics Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. .,Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Science, Sari, Iran.
| | - Hadi Hossein-Nataj
- Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Science, Sari, Iran
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Azimi M, Totonchi M, Rahimi M, Firouzi J, Sahranavard P, Emami Razavi A, Memari F, Kamali F, Ebrahimi M. An integrated analysis to predict micro-RNAs targeting both stemness and metastasis in human gastric cancer. J Gastroenterol Hepatol 2021; 36:436-445. [PMID: 32633423 DOI: 10.1111/jgh.15176] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Revised: 06/06/2020] [Accepted: 07/01/2020] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Cancer stem cells (CSCs), a subpopulation of tumor cells, assess the capacity of self-renewal, metastasis, and therapeutic resistance. Regulation of CSCs and their epithelial to mesenchymal transition (EMT) potential is one of the promising strategies to eliminate cancer or to inhibit metastasis. Micro-RNAs (miRNAs) as regulators of several cell properties, such as self-renewal, metastasis, and resistance to the drug, could be proper targets in cancer diagnosis and therapy. The aim of the present study is to select common miRNAs targeting both self-renewal and metastasis in gastric cancer. METHODS Stemness-related and EMT-related genes were selected by literature mining. The common miRNAs targeting genes were chosen using different databases and r programming language. The expression pattern of selected miRNAs and genes was evaluated in gastrospheres-as a gastric CSC model-and gastric tumor biopsies. RESULTS Based on the integrated analysis, six miRNAs common to both stemness and metastasis were identified. miR-200c-3p and miR-520c-3p overexpressed in MKN-45 gastrospheres and grade III tumors. In AGS spheres, however, miR-520c-3p and miR-200c-3p upregulation and miR-34a-5p downregulation were similar to grade II tumors. Interestingly, miR-200c-3p and miR-520c-3p indicated a positive correlation with OCT4 and NOTCH1 expression in grade III tumors and MKN-45 spheres. Protein-protein network revealed that the EMT acquisition can be induced by stemness activation through intermediated core-regulatory genes, including CTNNB1, CTNND1, MAML1, KAT2A, and MAML3. CONCLUSION The upregulation of mir-200c-3p and mir-520c-3p could effect on stemness and metastasis in gastric cancer as well as gastric CSCs. Therefore, they can be used as diagnosis and prognostic factors.
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Affiliation(s)
- Mahnaz Azimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mehdi Totonchi
- Department of Genetics, Reproductive Biomedical Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran
| | - Mahsa Rahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Javad Firouzi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Parisa Sahranavard
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Amirnader Emami Razavi
- Iran National Tumor Bank, Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Fereidoon Memari
- Iran National Tumor Bank, Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Kamali
- Iran National Tumor Bank, Cancer Biology Research Center, Cancer Institute of Iran, Tehran University of Medical Sciences, Tehran, Iran
| | - Marzieh Ebrahimi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
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Peng C, Huang K, Liu G, Li Y, Yu C. MiR-876-3p regulates cisplatin resistance and stem cell-like properties of gastric cancer cells by targeting TMED3. J Gastroenterol Hepatol 2019; 34:1711-1719. [PMID: 30843262 DOI: 10.1111/jgh.14649] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2018] [Revised: 02/26/2019] [Accepted: 03/04/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND AND AIM Gastric cancer (GC), a prevalent tumor, exerts a major economic burden, and we aimed to explore miR-876-3p's effects on GC and related mechanisms. METHODS Cell viability was analyzed via CCK-8 and colony formation assay. Stem cell-like properties were examined via spheroid colony formation assay. mRNA abundance of key genes was analyzed via quantitative polymerase chain reaction. Protein level of TMED3 and stem cell markers was examined by western blot. TargetScan, luciferase, and biotin-miRNA pulldown assay were used to identify miR-876-3p's target. RESULTS MiR-876-3p was downregulated in GC, and its mRNA level had negative relationship with cisplatin resistance of GC. Moreover, decreased miR-876-3p expression level suggested poor prognosis of GC patients. MiR-876-3p inhibited drug resistance of cisplatin-resistant cell line SGC-7901/DDP and MKN-45/DDP, as shown by decreased cell viability, IC50 , and colony formation ability. MiR-876-3p inhibited stem cell-like features and downregulated the expressions of Sox-2, Oct-4, CD133, and CD44 in GC cells. Luciferase and biotin-miRNA pulldown assay confirmed that TMED3 was miR-876-3p's direct target. TMED3 siRNA inhibited miR-876-3p's effects on cisplatin resistance and stem cell-like features of SGC-7901/DDP cells. CONCLUSION MiR-876-3p enhanced cisplatin sensitivity and restricted stem cell-like features of GC through targeting TMED3.
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Affiliation(s)
- Chunwei Peng
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Kai Huang
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Guangjie Liu
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Yunsong Li
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Changjun Yu
- Department of Gastrointestinal Surgery, Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Shah S, Pocard M, Mirshahi M. Targeting the differentiation of gastric cancer cells (KATO‑III) downregulates epithelial‑mesenchymal and cancer stem cell markers. Oncol Rep 2019; 42:670-678. [PMID: 31233198 PMCID: PMC6609315 DOI: 10.3892/or.2019.7198] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 05/17/2019] [Indexed: 12/13/2022] Open
Abstract
The aim of the present study was to analyze the acquisition of the differentiated phenotype in the human gastric signet ring cell adenoma cancer KATO-III cell line in vitro. The morphology of KATO-III cells was explored by microcinematography. Different cytokines secreted by both adherent and non-adherent KATO-III cells into medium were observed. The cancer stem cell phenotypes were identified by reverse transcription-quantitative polymerase chain reaction using primers (E-Cad, Slug, Snail, vimentin, NANOG, NESTIN, OCT3/4 and C-X-C motif chemokine receptor 4) or antibodies [cluster of differentiation (CD)90 and CD117] by flow cytometry (FACS). The influence of the induction media for the differentiation of mesenchymal cells was studied through viability and proliferation assays, by evaluating gene expression and the expression of markers via FACS. Cell viability and cell cycle distribution were evaluated following the treatment of KATO-III with acetyl salicylic acid and using the induction media as an inhibitor of epithelial-mesenchymal transition (EMT) and heparanase. A total of 3 phenotypes of KATO-III were observed (adherent, non-adherent and cell cluster), which have internal potential for cell transition into one of the other phenotypes. KATO-III was differentiated into adipocyte-, chondrocyte-, osteocyte- and neurocyte-like cells by the induction media. Identification of the induced cells was conducted using cell dyes. Reduced mRNA expression of EMT-associated molecules, stem cell markers and heparanase was observed with acetyl salicylic acid and induction media. An inhibitory effect of acetyl salicylic acid and the induction media was also noted in regard to cell proliferation. In addition, acetyl salicylic acid induced G0/G1 phase cell cycle arrest in KATO-III cells. In conclusion, the induction of the differentiation of cancer stem cells into non-proliferating cells offers the possibility for novel drug design to overcome the issues associated with metastasis, drug resistance and systemic toxicity with improved therapeutic efficacy.
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Affiliation(s)
- Shahid Shah
- University of Sorbonne Paris Cité‑Paris 7, Lariboisière Hospital, INSERM U965, 75010 Paris, France
| | - Marc Pocard
- University of Sorbonne Paris Cité‑Paris 7, Lariboisière Hospital, INSERM U965, 75010 Paris, France
| | - Massoud Mirshahi
- University of Sorbonne Paris Cité‑Paris 7, Lariboisière Hospital, INSERM U965, 75010 Paris, France
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Shah S, Fourgeaud C, Derieux S, Mirshahi S, Contant G, Pimpie C, Lo Dico R, Soria J, Pocard M, Mirshahi M. The close relationship between heparanase and epithelial mesenchymal transition in gastric signet-ring cell adenocarcinoma. Oncotarget 2018; 9:33778-33787. [PMID: 30333909 PMCID: PMC6173471 DOI: 10.18632/oncotarget.26042] [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: 07/05/2018] [Accepted: 08/16/2018] [Indexed: 01/30/2023] Open
Abstract
Heparanase (HPSE), a heparan sulfate-specific endo-β-D-glucuronidase, plays an important role in tumor cell metastasis through the degradation of extracellular matrix heparan sulfate proteoglycans. Suramin, a polysulfonated naphthylurea, is an inhibitor of HPSE with suramin analogues. Our objective was to analyze the HPSE involvement in gastric signet ring cell adenocarcinoma (SRCA) invasion. High expression of HPSE mRNA and protein was found in the tumor and in ascites of SRCA as well as in KATO-III cell line. Beside of collagen-I, growth factors (TGF-β1 and VEGF-A, except FGF-2) and epithelial mesenchymal transition (EMT) markers (Snail, Slug, Vimentin, α-SMA and Fibronectin, except E-cadherin) were found higher in main nodules of SRCA as compared to peritumoral sites. Among MDR proteins, MDR-1 and LRP (lung resistance protein) were highly expressed in tumor cells. The formation of 3D cell spheroids was found to be correlated with their origin (adherent or non-adherent KATO-III). After treatment of KATO-III cells with a HPSE inhibitor (suramin), cell proliferation and EMT-related markers, besides collagen-1 expression, were down regulated. In conclusion, in SRCA, HPSE via an autocrine secretion is involved in acquisition of mesenchymal phenotype and tumor cell malignancy. Therefore, HPSE could be an interesting pharmacological target for the treatment of SRCA.
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Affiliation(s)
- Shahid Shah
- Lariboisière Hospital, INSERM U965, Sorbonne University Paris Cité -Paris 7, 75010 Paris, France.,Present address: Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Government College University, Faisalabad, Pakistan
| | - Caroline Fourgeaud
- Lariboisière Hospital, INSERM U965, Sorbonne University Paris Cité -Paris 7, 75010 Paris, France
| | - Simon Derieux
- Lariboisière Hospital, INSERM U965, Sorbonne University Paris Cité -Paris 7, 75010 Paris, France
| | - Shahsoltan Mirshahi
- Lariboisière Hospital, INSERM U965, Sorbonne University Paris Cité -Paris 7, 75010 Paris, France
| | | | - Cynthia Pimpie
- Lariboisière Hospital, INSERM U965, Sorbonne University Paris Cité -Paris 7, 75010 Paris, France
| | - Rea Lo Dico
- Lariboisière Hospital, INSERM U965, Sorbonne University Paris Cité -Paris 7, 75010 Paris, France
| | - Jeannette Soria
- Lariboisière Hospital, INSERM U965, Sorbonne University Paris Cité -Paris 7, 75010 Paris, France
| | - Marc Pocard
- Lariboisière Hospital, INSERM U965, Sorbonne University Paris Cité -Paris 7, 75010 Paris, France
| | - Massoud Mirshahi
- Lariboisière Hospital, INSERM U965, Sorbonne University Paris Cité -Paris 7, 75010 Paris, France
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Gao JP, Xu W, Liu WT, Yan M, Zhu ZG. Tumor heterogeneity of gastric cancer: From the perspective of tumor-initiating cell. World J Gastroenterol 2018; 24:2567-2581. [PMID: 29962814 PMCID: PMC6021770 DOI: 10.3748/wjg.v24.i24.2567] [Citation(s) in RCA: 98] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 04/30/2018] [Accepted: 05/26/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains one of the most common and malignant types of cancer due to its rapid progression, distant metastasis, and resistance to conventional chemotherapy, although efforts have been made to understand the underlying mechanism of this resistance and to improve clinical outcome. It is well recognized that tumor heterogeneity, a fundamental feature of malignancy, plays an essential role in the cancer development and chemoresistance. The model of tumor-initiating cell (TIC) has been proposed to explain the genetic, histological, and phenotypical heterogeneity of GC. TIC accounts for a minor subpopulation of tumor cells with key characteristics including high tumorigenicity, maintenance of self-renewal potential, giving rise to both tumorigenic and non-tumorigenic cancer cells, and resistance to chemotherapy. Regarding tumor-initiating cell of GC (GATIC), substantial studies have been performed to (1) identify the putative specific cell markers for purification and functional validation of GATICs; (2) trace the origin of GATICs; and (3) decode the regulatory mechanism of GATICs. Furthermore, recent studies demonstrate the plasticity of GATIC and the interaction between GATIC and its surrounding factors (TIC niche or tumor microenvironment). All these investigations pave the way for the development of GATIC-targeted therapy, which is in the phase of preclinical studies and clinical trials. Here, we interpret the heterogeneity of GC from the perspectives of TIC by reviewing the above-mentioned fundamental and clinical studies of GATICs. Problems encountered during the GATIC investigations and the potential solutions are also discussed.
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Affiliation(s)
- Jian-Peng Gao
- Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Wei Xu
- Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Wen-Tao Liu
- Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Min Yan
- Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Zheng-Gang Zhu
- Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
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Sun J, Xu K, Qiu Y, Gao H, Xu J, Tang Q, Yin P. Bufalin reverses acquired drug resistance by inhibiting stemness in colorectal cancer cells. Oncol Rep 2017; 38:1420-1430. [PMID: 28731184 PMCID: PMC5549034 DOI: 10.3892/or.2017.5826] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2017] [Accepted: 06/12/2017] [Indexed: 12/12/2022] Open
Abstract
Drug resistance is an obstacle to chemotherapy in tumor patients. Recent studies have shown that the high stemness of cancer cells may be induced by chemotherapeutic drugs, which is correlated with drug resistance. In the present study, we investigated the effects of bufalin on the stemness of colorectal cancer. We found that cisplatin could induce high stemness through the tumorsphere formation assay in vitro and in vivo in the colorectal cancer cell lines HCT116 and LoVo. In addition, cisplatin-treated tumorsphere cells showed drug-resistant properties. These results suggested that acquired drug resistance induced by cisplatin in colorectal cancer cells occurred via high stemness. On assessing the effects of bufalin, a traditional Chinese medicine monomer, we found that it could reverse the high stemness and drug resistance induced by cisplatin in colorectal cancer. These findings suggest that bufalin plays an adjuvant role in colorectal cancer chemotherapy and may help reverse acquired drug resistance. These findings may aid in the development of new therapeutic strategies.
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Affiliation(s)
- Jian Sun
- Interventional Cancer Institute of Integrative Medicine and Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Ke Xu
- Interventional Cancer Institute of Integrative Medicine and Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Yanyan Qiu
- Interventional Cancer Institute of Integrative Medicine and Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Hong Gao
- Interventional Cancer Institute of Integrative Medicine and Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Jianhua Xu
- Interventional Cancer Institute of Integrative Medicine and Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Qingfeng Tang
- Interventional Cancer Institute of Integrative Medicine and Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Peihao Yin
- Interventional Cancer Institute of Integrative Medicine and Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
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11
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Xia P, Xu XY. Epithelial–mesenchymal transition and gastric cancer stem cell. Tumour Biol 2017; 39:1010428317698373. [DOI: 10.1177/1010428317698373] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Gastric cancer remains a big health problem in China. Gastric cancer cells contain a small subpopulation of cells that exhibit capabilities of differentiation and tumorigenicity. A putative explanation for ineffective therapy is the presence of cancer stem-like cells. Side population cells, which have cancer stem-like cells’ property, are characterized by the high efflux ability of Hoechst 33342 dye. Side population cells have been isolated from gastric cancer cell lines in previous studies. The epithelial–mesenchymal transition is very important in the invasion and metastasis of epithelial-derived cancers. More and more studies showed that gastric cancer stem-like cells possess high invasive ability and epithelial–mesenchymal transition property. A brief overview of the recent advancements in gastric cancer stem-like cells and epithelial–mesenchymal transition will be helpful for providing novel insight into gastric cancer treatment.
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Affiliation(s)
- Pu Xia
- Department of Cell Biology, College of Basic Medical Science, Liaoning Medical University, Jinzhou, P.R. China
| | - Xiao-Yan Xu
- Department of Pathophysiology, College of Basic Medical Sciences, China Medical University, Shenyang, P.R. China
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12
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Song Y, Wang Y, Tong C, Xi H, Zhao X, Wang Y, Chen L. A unified model of the hierarchical and stochastic theories of gastric cancer. Br J Cancer 2017; 116:973-989. [PMID: 28301871 PMCID: PMC5396111 DOI: 10.1038/bjc.2017.54] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2016] [Revised: 01/16/2017] [Accepted: 01/26/2017] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) is a life-threatening disease worldwide. Despite remarkable advances in treatments for GC, it is still fatal to many patients due to cancer progression, recurrence and metastasis. Regarding the development of novel therapeutic techniques, many studies have focused on the biological mechanisms that initiate tumours and cause treatment resistance. Tumours have traditionally been considered to result from somatic mutations, either via clonal evolution or through a stochastic model. However, emerging evidence has characterised tumours using a hierarchical organisational structure, with cancer stem cells (CSCs) at the apex. Both stochastic and hierarchical models are reasonable systems that have been hypothesised to describe tumour heterogeneity. Although each model alone inadequately explains tumour diversity, the two models can be integrated to provide a more comprehensive explanation. In this review, we discuss existing evidence supporting a unified model of gastric CSCs, including the regulatory mechanisms of this unified model in addition to the current status of stemness-related targeted therapy in GC patients.
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Affiliation(s)
- Yanjing Song
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Yao Wang
- Department of Immunology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing 100853, China
| | - Chuan Tong
- Department of Immunology, Institute of Basic Medicine, School of Life Sciences, Chinese PLA General Hospital, Beijing 100853, China
| | - Hongqing Xi
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Xudong Zhao
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Yi Wang
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
| | - Lin Chen
- Department of General Surgery, Chinese PLA General Hospital, Beijing 100853, China
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13
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El Khoury F, Corcos L, Durand S, Simon B, Le Jossic-Corcos C. Acquisition of anticancer drug resistance is partially associated with cancer stemness in human colon cancer cells. Int J Oncol 2016; 49:2558-2568. [PMID: 27748801 DOI: 10.3892/ijo.2016.3725] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2016] [Accepted: 07/15/2016] [Indexed: 01/11/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most aggressive cancers worldwide. Several anticancer agents are available to treat CRC, but eventually cancer relapse occurs. One major cause of chemotherapy failure is the emergence of drug-resistant tumor cells, suspected to originate from the stem cell compartment. The aim of this study was to ask whether drug resistance was associated with the acquisition of stem cell-like properties. We isolated drug-resistant derivatives of two human CRC cell lines, HT29 and HCT116, using two anticancer drugs with distinct modes of action, oxaliplatin and docetaxel. HT29 cells resistant to oxaliplatin and both HT29 and HCT116 cells resistant to docetaxel were characterized for their expression of genes potentially involved in drug resistance, cell growth and cell division, and by surveying stem cell-like phenotypic traits, including marker genes, the ability to repair cell-wound and to form colonospheres. Among the genes involved in platinum or taxane resistance (MDR1, ABCG2, MRP2 or ATP7B), MDR1 was uniquely overexpressed in all the resistant cells. An increase in the cyclin-dependent kinase inhibitor p21, in cyclin D1 and in CD26, CD166 cancer stem cell markers, was noted in the resistant cells, together with a higher ability to form larger and more abundant colonospheres. However, many phenotypic traits were selectively altered in either HT29- or in HCT116-resistant cells. Expression of EPHB2, ITGβ-1 or Myc was specifically increased in the HT29-resistant cells, whereas only HCT116-resistant cells efficiently repaired cell- wounds. Taken together, our results show that human CRC cells selected for their resistance to anticancer drugs displayed a few stem cell characteristics, a small fraction of which was shared between cell lines. The occurrence of marked phenotypic differences between HT29- and HCT116-drug resistant cells indicates that the acquired resistance depends mostly on the parental cell characteristics, rather than on the drug type used.
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Affiliation(s)
- Flaria El Khoury
- INSERM-UBO UMR1078-ECLA, IBSAM, Faculty of Medicine, University of Brest, 29200 Brest, France
| | - Laurent Corcos
- INSERM-UBO UMR1078-ECLA, IBSAM, Faculty of Medicine, University of Brest, 29200 Brest, France
| | - Stéphanie Durand
- INSERM-UBO UMR1078-ECLA, IBSAM, Faculty of Medicine, University of Brest, 29200 Brest, France
| | - Brigitte Simon
- INSERM-UBO UMR1078-ECLA, IBSAM, Faculty of Medicine, University of Brest, 29200 Brest, France
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14
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Wang X, Wang C, Zhang X, Hua R, Gan L, Huang M, Zhao L, Ni S, Guo W. Bmi-1 regulates stem cell-like properties of gastric cancer cells via modulating miRNAs. J Hematol Oncol 2016; 9:90. [PMID: 27644439 PMCID: PMC5029045 DOI: 10.1186/s13045-016-0323-9] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2016] [Accepted: 09/09/2016] [Indexed: 12/18/2022] Open
Abstract
Background B cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1) plays an important role in regulating stemness in some kinds of cancer. However, the mechanisms remain unclear. This study was to investigate whether and how Bmi-1 regulates stemness of gastric cancer. Methods We firstly explored the role of Bmi-1 in regulating stem cell-like features in gastric cancer. Secondly, we screened out its downstream miRNAs and clarified whether these miRNAs are involved in the regulation of stemness. Finally, we investigated the mechanisms how Bmi-1 regulates miRNAs. Results Bmi-1 positively regulates stem cell-like properties of gastric cancer and upregulates miR-21 and miR-34a. There was a positive correlation between Bmi-1 and miR-21 expression in gastric cancer tissues. MiR-21 mediated the function of Bmi-1 in regulating stem cell-like properties, while miR-34a negatively regulates stem cell-like characteristics via downregulating Bmi-1. Bmi-1 binds to PTEN promoter and directly inhibits PTEN and thereafter activates AKT. Bmi-1 also regulates p53 and PTEN via miR-21. Bmi-1 activated NF-kB via AKT and enhanced the binding of NF-kB to the promoter of miR-21 and miR-34a and increased their expression. Conclusions Bmi-1 positively regulates stem cell-like properties via upregulating miR-21, and miR-34a negatively regulates stem cell-like characteristics by negative feedback regulation of Bmi-1 in gastric cancer. Bmi-1 upregulates miR-21 and miR-34a by activating AKT-NF-kB pathway. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0323-9) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Xiaofeng Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Chang Wang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Xiaowei Zhang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ruixi Hua
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lu Gan
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Mingzhu Huang
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Liqin Zhao
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Sujie Ni
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Weijian Guo
- Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai, China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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15
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Qian X, Tan C, Wang F, Yang B, Ge Y, Guan Z, Cai J. Esophageal cancer stem cells and implications for future therapeutics. Onco Targets Ther 2016; 9:2247-54. [PMID: 27143920 PMCID: PMC4846051 DOI: 10.2147/ott.s103179] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Esophageal carcinoma (EC) is a lethal disease with high morbidity and mortality worldwide, and the incidence has been increasing in recent years. Although the diagnosis and treatment of EC have improved considerably, EC has rapidly progressed in the clinical setting and has a poor prognosis for its metastasis and recurrence. The general idea of cancer stem cells (CSCs) is primarily based on clinical and experimental observations, indicating the existence of a subpopulation of cells that can self-renew and differentiate. The EC stem cells, which can be isolated from normal pluripotent stem cells by applying similar biomarkers, may participate in promoting esophageal tumorigenesis through renewal and repair. In this review, major emphasis is given to CSC markers, altered CSC-specific pathways, and molecular targeting agents currently available to target CSCs of esophageal cancer. The roles of numerous markers (CD44, aldehyde dehydrogenase, CD133, and ATP-binding cassette subfamily G member 2) and developmental signaling pathways (Wnt/β-catenin, Notch, hedgehog, and Hippo) in isolating esophageal CSCs are discussed in detail. Targeting CSCs can be a logical strategy to treat EC, as these cells are responsible for carcinoma recurrence and chemoradiation resistance.
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Affiliation(s)
- Xia Qian
- Department of Radiation Oncology, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Nantong, People's Republic of China
| | - Cheng Tan
- Department of Radiation Oncology, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Nantong, People's Republic of China
| | - Feng Wang
- Department of Radiation Oncology, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Nantong, People's Republic of China
| | - Baixia Yang
- Department of Radiation Oncology, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Nantong, People's Republic of China
| | - Yangyang Ge
- Department of Radiation Oncology, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Nantong, People's Republic of China
| | - Zhifeng Guan
- Department of Radiation Oncology, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Nantong, People's Republic of China
| | - Jing Cai
- Department of Radiation Oncology, Nantong Tumor Hospital, Affiliated Tumor Hospital of Nantong University, Nantong, People's Republic of China
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16
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Gastric cancer stem cells: evidence, potential markers, and clinical implications. J Gastroenterol 2016; 51:313-26. [PMID: 26428661 DOI: 10.1007/s00535-015-1125-5] [Citation(s) in RCA: 94] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2015] [Accepted: 09/13/2015] [Indexed: 02/04/2023]
Abstract
Gastric cancer is a significant global health problem. It is the fifth most common cancer and third leading cause of cancer-related death worldwide (Torre et al. in CA Cancer J Clin 65(2):87-108, 2015). Despite advances in treatment, overall prognosis remains poor, due to tumour relapse and metastasis. There is an urgent need for novel therapeutic approaches to improve clinical outcomes in gastric cancer. The cancer stem cell (CSC) model has been proposed to explain the high rate of relapse and subsequent resistance of cancer to current systemic treatments (Vermeulen et al. in Lancet Oncol 13(2):e83-e89, 2012). CSCs have been identified in many solid malignancies, including gastric cancer, and have significant clinical implications, as targeting the CSC population may be essential in preventing the recurrence and spread of a tumour (Dewi et al. in J Gastroenterol 46(10):1145-1157, 2011). This review seeks to summarise the current evidence for CSC in gastric cancer, with an emphasis on candidate CSC markers, clinical implications, and potential therapeutic approaches.
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17
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Cancer stem cells in human digestive tract malignancies. Tumour Biol 2015; 37:7-21. [PMID: 26446457 DOI: 10.1007/s13277-015-4155-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 09/23/2015] [Indexed: 12/18/2022] Open
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18
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Xu X, Qian LJ, Su XY, He KF, Jin KT, Gu LH, Feng JG, Li GL, Zhou Q, Xu ZZ, Wang HH, Zhang J, Cao J, Teng LS. Establishment and characterization of GCSR1, a multi-drug resistant signet ring cell gastric cancer cell line. Int J Oncol 2015; 46:2479-87. [PMID: 25892440 DOI: 10.3892/ijo.2015.2966] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 10/20/2014] [Indexed: 11/06/2022] Open
Abstract
Signet ring cell gastric cancer (SRCGC) has very poor prognosis worldwide, and studying its molecular characteristics is urgent for improving the outcome. However, few well-characterized SRCGC cell lines are available for research. Therefore, we established a novel cell line GCSR1, from a Chinese male SRCGC patient. Cell morphology of GCSR1 in culture, maintained in vitro for over 90 passages, is similar to the cells from the patient. GCSR1 cells proliferated in vitro with a doubling time of 67.65 h. Karyotyping showed they were aneuploid. Missense mutation occurred in codon 193 of P53 and deletion occurred in exons 1 and 3 of P16. Results of CCK8 assay revealed that GCSR1 was more resistant to 5-fluorouracil (5-FU) and mitomycin (MMC) than other gastric cancer cell lines. Stem cell marker assay by flow cytometry showed that GCSR1 had high proportion of CD44+ and/or CD133+ cells. It formed colonies easily in soft agar and generated xenograft tumors in nude mice. In conclusion, GCSR1 is a well-established, well-characterized multi-drug resistant cell line with abundant cancer stem cells.
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Affiliation(s)
- Xin Xu
- Department of Surgical Oncology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Li-Juan Qian
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang 310022, P.R. China
| | - Xing-Yun Su
- Department of Surgical Oncology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Kui-Feng He
- Department of Surgical Oncology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Ke-Tao Jin
- Department of Surgical Oncology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Lin-Hui Gu
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang 310022, P.R. China
| | - Jian-Guo Feng
- Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, Hangzhou, Zhejiang 310022, P.R. China
| | - Guang-Liang Li
- Department of Surgical Oncology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Quan Zhou
- Department of Surgical Oncology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Zhen-Zhen Xu
- Department of Surgical Oncology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Hao-Hao Wang
- Department of Surgical Oncology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Jing Zhang
- Department of Surgical Oncology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
| | - Jiang Cao
- Clinical Research Center, The 2nd Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, P.R. China
| | - Li-Song Teng
- Department of Surgical Oncology, The 1st Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310003, P.R. China
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19
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Preliminary analysis of stem cell-like cells in human neuroblastoma. World J Pediatr 2015; 11:54-60. [PMID: 25431041 DOI: 10.1007/s12519-014-0529-2] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 06/19/2014] [Indexed: 10/24/2022]
Abstract
BACKGROUND Neuroblastoma is an embryonic neoplasm originating from the neural crest with cellular heterogeneity as one of its oncobiological characteristics. This study was undertaken to determine whether human neuroblastoma contains stem cell-like cells. METHODS Twenty patients with neuroblastoma who have been treated in our hospital since January 2005 were divided into pre-operative chemotherapy (10 patients) and non-chemotherapy (10) groups. Tumor specimens of the patients were taken and paraffin sections were made. The expressions of stem cell markers CD133, ABCG2, CD117 and nestin were immunohistochemically detected in the specimens. Neuroblastoma cells were stained with Hoechst 33342 and PI. The side population (SP) cells were analyzed by the fluorescence-activated cell sorter. The disparity drug resistance to cisplatin (DDP) of SP and non-SP cells was measured with MTT colorimetric assay. The oncogenicity of SP and non-SP cells was identified in nude mice. RESULTS There was no significant difference in the expression intensity of CD117 and nestin between the two groups of specimens (P>0.05). There was a significant difference between the two groups in terms of the expression intensity of CD133 and ABCG2 (P<0.05). The SP cells accounted for 0.2%-1.3% of the total human neuroblastoma cells and were decreased to 0.1%-0.5% after verapamil treatment. The SP and non-SP cells showed disparity in cell growth experiment and drug resistance to DDP. Oncogenicity experiment revealed that nude mice could erupt tumor by an injection of l×10(6) SHSY5Y and WIV SP cells. However, the nude mice could not form tumor by an injection of l×10(6) non-SP cells. CONCLUSION Neuroblastoma might contain cancer stem cell-like cells.
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20
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Zhang YC, Li YJ, Shi J, Qin ZF, Wei PK, Yan B. Notch signaling pathway and gastric cancer. Shijie Huaren Xiaohua Zazhi 2015; 23:381-387. [DOI: 10.11569/wcjd.v23.i3.381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer is still the second leading cause of cancer-related death. Currently, all the available therapeutic methods in practice appear to be blunt for the majority of advanced-stage patients and their long time-survival rate is also still rather frustrating. The Notch signaling pathway is increasingly demonstrated to play an important role in controlling the fate of gastric cancer cells and gastric cancer stem cells, and some previous studies have indicated that different Notch receptors and ligands, such as Notch-1, 2, 3, Dll-1, 4 and Jag-1, 2, were highly expressed in gastric cancer tissues and were associated with various clinical parameters. More notably, these receptors and ligands were also found to be expressed in gastric cancer stem cells, which were CD44 positive, and could have a key role in regulating the fate of these cells. Taking into consideration the pivotal role of Notch signaling pathway in gastric cancer and cancer stem cells, it would be promising to predict that it could become therapeutic targets in the future.
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21
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Wang JL, Yu JP, Sun ZQ, Sun SP. Radiobiological characteristics of cancer stem cells from esophageal cancer cell lines. World J Gastroenterol 2014; 20:18296-18305. [PMID: 25561796 PMCID: PMC4277966 DOI: 10.3748/wjg.v20.i48.18296] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2014] [Revised: 06/28/2014] [Accepted: 07/16/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the cancer stem cell population in esophageal cancer cell lines KYSE-150 and TE-1 and identify whether the resulting stem-like spheroid cells display cancer stem cells and radiation resistance characteristics.
METHODS: A serum-free medium (SFM) suspension was used to culture esophageal cancer stem cell lines and enrich the esophageal stem-like spheres. A reverse transcription polymerase chain reaction assay was used to detect stem cell gene expression in the spheroid cells. Radiosensitivity of stem-like spheres and parental cells were evaluated by clonogenic assays. Furthermore, different cells after different doses of irradiation were tested to evaluate the change in sphere formation, cell cycle and CD44+CD271+ expression of tumor stem-like spheroid cells using flow cytometry before and after irradiation.
RESULTS: The cells were observed to generate an increased number of spheres in SFM with increasing cell passage. Radiation increased the rate of generation of stem-like spheres in both types of cells. The average survival fraction (SF2) of the cultured KYSE-150 compared with TE-1 stem-like spheres after 2 Gy of radiation was 0.81 ± 0.03 vs 0.87 ± 0.01 (P < 0.05), while the average SF2 of KYSE-150 compared with TE-1 parental cells was 0.69 ± 0.04 vs 0.80 ± 0.03, P < 0.05. In the esophageal parental cells, irradiation dose-dependently induced G2 arrest. Stem-like esophageal spheres were resistant to irradiation-induced G2 arrest without significant changes in the percentage population of irradiated stem-like cells. Under irradiation at 0, 4, and 8 Gy, the CD44+CD271+ cell percentage for KYSE150 parental cells was 1.08% ± 0.03% vs 1.29% ± 0.07% vs 1.11% ± 0.09%, respectively; the CD44+CD271+ cell percentage for TE1 parental cells was 1.16% ± 0.11% vs 0.97% ± 0.08% vs 1.45% ± 0.35%, respectively. The differences were not statistically significant. Under irradiation at 0, 4, and 8 Gy, the CD44+CD271+ cell percentage for KYSE-150 stem-like spheres was 35.83% ± 1.23% vs 44.9% ± 1.67% vs 57.77% ± 1.88%, respectively; the CD44+CD271+ cell percentage for TE1 stem-like spheres was 16.07% ± 0.91% vs 22.67% ± 1.12%, 16.07% ± 0.91% vs 33.27% ± 1.07%, respectively. The 4 and 8 Gy irradiated KYSE-150 and TE-1 stem-like spheres were compared with the 0 Gy irradiated group, and the differences were statistically significant (P < 0.05).
CONCLUSION: The KYSE-150 and TE-1 stem-like spheres are more radioresistant than their parental cells which may suggest that cancer stem cells are related to radioresistance.
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22
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Allegra A, Alonci A, Penna G, Innao V, Gerace D, Rotondo F, Musolino C. The cancer stem cell hypothesis: a guide to potential molecular targets. Cancer Invest 2014; 32:470-95. [PMID: 25254602 DOI: 10.3109/07357907.2014.958231] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Common cancer theories hold that tumor is an uncontrolled somatic cell proliferation caused by the progressive addition of random mutations in critical genes that control cell growth. Nevertheless, various contradictions related to the mutation theory have been reported previously. These events may be elucidated by the persistence of residual tumor cells, called Cancer Stem Cells (CSCs) responsible for tumorigenesis, tumor maintenance, tumor spread, and tumor relapse. Herein, we summarize the current understanding of CSCs, with a focus on the possibility to identify specific markers of CSCs, and discuss the clinical application of targeting CSCs for cancer treatment.
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23
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Xiong B, Ma L, Hu X, Zhang C, Cheng Y. Characterization of side population cells isolated from the colon cancer cell line SW480. Int J Oncol 2014; 45:1175-83. [PMID: 24926880 DOI: 10.3892/ijo.2014.2498] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2013] [Accepted: 02/06/2014] [Indexed: 12/26/2022] Open
Abstract
Side population (SP) cells may play a crucial role in tumorigenesis and the recurrence of cancer. Many types of cell lines and tissues have demonstrated the presence of SP cells, including colon cancer cell lines. This study aimed to identify cancer stem cells (CSCs) in the SP of the colon cancer cell line SW480. SP cells were isolated by fluorescence-activated cell sorting (FACS), followed by serum-free medium (SFM) culture. The self-renewal, differentiated progeny, clone formation, proliferation, invasion ability, cell cycle, chemosensitivity and tumorigenic properties in SP and non-SP (NSP) cells were investigated through in vitro culture and in vivo serial transplantation. The expression profiles of ATP-binding cassette (ABC) protein transporters and stem cell-related genes were examined by RT-PCR and western blot analysis. The human colon cancer cell lines SW480, Lovo and HCT116 contain 1.1 ± 0.10, 0.93 ± 0.11 and 1.33 ± 0.05% SP cells, respectively. Flow cytometry analysis revealed that SP cells could differentiate into SP and NSP cells. SP cells had a higher proliferation potency and CFE than NSP cells. Compared to NSP cells, SP cells were also more resistant to CDDP and 5-FU, and were more invasive and displayed increased tumorigenic ability. Moreover, SP cells showed higher mRNA and protein expression of ABCG2, MDR1, OCT-4, NANOG, SOX-2, CD44 and CD133. SP cells isolated from human colon cancer cell lines harbor CSC properties that may be related to the invasive potential and therapeutic resistance of colon cancer.
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Affiliation(s)
- Binghong Xiong
- Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuanjiagang, Yuzhong, Chongqing 400016, P.R. China
| | - Li Ma
- Department of Internal Medicine, Chongqing Huaxi Hospital, Banan, Chongqing 400054, P.R. China
| | - Xiang Hu
- Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuanjiagang, Yuzhong, Chongqing 400016, P.R. China
| | - Caiquan Zhang
- Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuanjiagang, Yuzhong, Chongqing 400016, P.R. China
| | - Yong Cheng
- Department of General Surgery, The First Affiliated Hospital of Chongqing Medical University, Yuanjiagang, Yuzhong, Chongqing 400016, P.R. China
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24
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Li K, Dan Z, Nie YQ. Gastric cancer stem cells in gastric carcinogenesis, progression, prevention and treatment. World J Gastroenterol 2014; 20:5420-5426. [PMID: 24833872 PMCID: PMC4017057 DOI: 10.3748/wjg.v20.i18.5420] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
In recent decades, the study of the mechanism of tumorigenesis has brought much progress to cancer treatment. However, cancer stem cell (CSC) theory has changed previous views of tumors, and has provided a new method for treatment of cancer. The discovery of CSCs and their characteristics have contributed to understanding the molecular mechanism of tumor genesis and development, resulting in a new effective strategy for cancer treatment. Gastric CSCs (GCSCs) are the basis for the onset of gastric cancer. They may be derived from gastric stem cells in gastric tissues, or bone marrow mesenchymal stem cells. As with other stem cells, GCSCs highly express drug-resistance genes such as aldehyde dehydrogenase and multidrug resistance, which are resistant to chemotherapy and thus form the basis of drug resistance. Many specific molecular markers such as CD44 and CD133 have been used for identification and isolation of GCSCs, diagnosis and grading of gastric cancer, and research on GCSC-targeted therapy for gastric cancer. Therefore, discussion of the recent development and advancements in GCSCs will be helpful for providing novel insight into gastric cancer treatment.
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25
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Yu L, Yang L, An W, Su X. Anticancer Bioactive Peptide-3 Inhibits Human Gastric Cancer Growth by Suppressing Gastric Cancer Stem Cells. J Cell Biochem 2014; 115:697-711. [DOI: 10.1002/jcb.24711] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2013] [Accepted: 11/05/2013] [Indexed: 11/07/2022]
Affiliation(s)
- Lan Yu
- Department of Cell Biology; Capital Medical University; No. 10 You An Men Wai Street Fengtai District Beijing 100069 China
| | - Ling Yang
- Clinical Medical Research Center of the Affiliated Hospital; Inner Mongolia Medical University; No. 1 Tongdao North Street Huimin District Hohhot 010050 China
| | - Wei An
- Department of Cell Biology; Capital Medical University; No. 10 You An Men Wai Street Fengtai District Beijing 100069 China
| | - Xiulan Su
- Department of Cell Biology; Capital Medical University; No. 10 You An Men Wai Street Fengtai District Beijing 100069 China
- Clinical Medical Research Center of the Affiliated Hospital; Inner Mongolia Medical University; No. 1 Tongdao North Street Huimin District Hohhot 010050 China
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26
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Singh SR. Gastric cancer stem cells: a novel therapeutic target. Cancer Lett 2013; 338:110-9. [PMID: 23583679 DOI: 10.1016/j.canlet.2013.03.035] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Revised: 03/25/2013] [Accepted: 03/30/2013] [Indexed: 12/14/2022]
Abstract
Gastric cancer remains one of the leading causes of global cancer mortality. Multipotent gastric stem cells have been identified in both mouse and human stomachs, and they play an essential role in the self-renewal and homeostasis of gastric mucosa. There are several environmental and genetic factors known to promote gastric cancer. In recent years, numerous in vitro and in vivo studies suggest that gastric cancer may originate from normal stem cells or bone marrow-derived mesenchymal cells, and that gastric tumors contain cancer stem cells. Cancer stem cells are believed to share a common microenvironment with normal niche, which play an important role in gastric cancer and tumor growth. This mini-review presents a brief overview of the recent developments in gastric cancer stem cell research. The knowledge gained by studying cancer stem cells in gastric mucosa will support the development of novel therapeutic strategies for gastric cancer.
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Affiliation(s)
- Shree Ram Singh
- Mouse Cancer Genetics Program, National Cancer Institute, Frederick, MD 21702, USA.
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