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Chandouri B, Naves T, Yassine M, Ikhlef L, Tricard J, Chaunavel A, Homayed Z, Pannequin J, Girard N, Durand S, Carré V, Lalloué F. Comparison of methods for cancer stem cell detection in prognosis of early stages NSCLC. Br J Cancer 2024; 131:1425-1436. [PMID: 39304747 PMCID: PMC11519646 DOI: 10.1038/s41416-024-02839-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Revised: 08/21/2024] [Accepted: 08/27/2024] [Indexed: 09/22/2024] Open
Abstract
BACKGROUND Despite advances in diagnosis and treatment in lung cancer, therapies still fail to improve patient management due to resistance mechanisms and relapses. As Cancer stem cells (CSCs) directly contribute to tumor growth and therapeutic resistance, their clinical detection represents a major challenge. However specific and additional CSC markers lack. Thus, our aim was to achieve selective detection of CSCs with specific glycan patterns and assess the CSCs burden to predict the risk of relapse in NSCLC tumors. METHODS The lung CSCs detection and sorting with a lectin MIX were assessed and compared to CD133 in vitro. Then, its putative role as CSC biomarker was evaluated in vivo and its clinical significance on 221 NSCLC patients. RESULTS We showed a significant CSCs enrichment in the MIX+ sorted fraction compared to CD133+ cells and confirmed its high tumorigenic capacity. The MIX prognostic value on the overall survival from early stages patients was validated suggesting its potential for detecting CSCs directly linked to tumor aggressiveness. CONCLUSION The MIX could be more relevant for detecting and sorting CSCs than CD133. Moreover, its prognosis value could enable clinicians to better classify early-stage patients at high risk of relapse in order to tailor therapeutic decisions.
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Affiliation(s)
- Boutaîna Chandouri
- UMR INSERM 1308 CAPTuR, Faculty of Medicine, University of Limoges, Limoges, France.
- Carcidiag Biotechnologies company, Guéret, France.
| | - Thomas Naves
- UMR INSERM 1308 CAPTuR, Faculty of Medicine, University of Limoges, Limoges, France
| | - May Yassine
- UMR INSERM 1308 CAPTuR, Faculty of Medicine, University of Limoges, Limoges, France
| | - Léa Ikhlef
- UMR INSERM 1308 CAPTuR, Faculty of Medicine, University of Limoges, Limoges, France
| | - Jérémy Tricard
- UMR INSERM 1308 CAPTuR, Faculty of Medicine, University of Limoges, Limoges, France
- Thoracic and Cardiovascular Surgery Department, Limoges University Hospital Center, Limoges, France
| | - Alain Chaunavel
- Department of Pathology, Dupuytren University Hospital, Limoges, France
| | - Zeinab Homayed
- IGF, Univ. Montpellier, CNRS, INSERM, Montpellier, France
| | | | - Nicolas Girard
- Thorax Institute Curie Montsouris, Institut Curie, Paris, France
- UVSQ, Paris Saclay University, Versailles, France
| | - Stéphanie Durand
- UMR INSERM 1308 CAPTuR, Faculty of Medicine, University of Limoges, Limoges, France.
| | | | - Fabrice Lalloué
- UMR INSERM 1308 CAPTuR, Faculty of Medicine, University of Limoges, Limoges, France.
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Lin YY, Lin YS, Liang CW. Heterogeneity of cancer stem cell-related marker expression is associated with three-dimensional structures in malignant pleural effusion produced by lung adenocarcinoma. Cytopathology 2024; 35:105-112. [PMID: 37897199 DOI: 10.1111/cyt.13321] [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: 04/25/2023] [Revised: 07/28/2023] [Accepted: 10/11/2023] [Indexed: 10/29/2023]
Abstract
INTRODUCTION Cancer stem cells have been described in lung adenocarcinoma-associated malignant pleural effusion. They show clinically important features, including the ability to initiate new tumours and resistance to treatments. However, their correlation with the three-dimensional tumour structures in the effusion is not well understood. METHODS Cell blocks produced from lung adenocarcinoma patients' pleural effusion were examined for cancer stem cell-related markers Nanog and CD133 using immunocytochemistry. The three-dimensional cancer cell structures and CD133 expression patterns were visualized with tissue-clearing technology. The expression patterns were correlated with tumour cell structures, genetic variants and clinical outcomes. RESULTS Thirty-nine patients were analysed. Moderate-to-strong Nanog expression was detected in 27 cases (69%), while CD133 was expressed by more than 1% of cancer cells in 11 cases (28%). Nanog expression was more homogenous within individual specimens, while CD133 expression was detected in single tumour cells or cells within small clusters instead of larger structures in 8 of the 11 positive cases (73%). Although no statistically significant correlation between the markers and tumour genetic variants or patient survival was observed, we recorded seven cases with follow-up specimens after cancer treatment, and four (57%) showed a change in stem cell-related marker expression corresponding to treatment response. CONCLUSIONS Lung adenocarcinoma cells in the pleural effusion show variable expression of cancer stem cell-related markers, some showing a correlation with the size of cell clusters. Their expression level is potentially correlated with cancer treatment effects.
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Affiliation(s)
- Yen-Yu Lin
- Department of Pathology, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Yueh-Shen Lin
- Department of Pathology, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City, Taiwan
| | - Cher-Wei Liang
- Department of Pathology, Fu Jen Catholic University Hospital, Fu Jen Catholic University, New Taipei City, Taiwan
- School of Medicine, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
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Xie H, Chen J, Ma C, Zhao J, Cui M. UBP43 promotes epithelial ovarian carcinogenesis via activation of β-catenin signaling pathway. Cell Biol Int 2023. [PMID: 37186433 DOI: 10.1002/cbin.12028] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 03/17/2023] [Accepted: 04/09/2023] [Indexed: 05/17/2023]
Abstract
Dysregulation of the deubiquitinating protease, UBP43, has been implicated in many human diseases, including cancer. Here, we evaluated the functional significance and mechanism of action of UBP43 in epithelial ovarian cancer. We found that UBP43 was significantly upregulated in the tumor tissues of patients with epithelial ovarian cancer. Similar results were observed in OVCAR-3, Caov-3, TOV-112D, A2780, and SK-OV-3 cells. Furthermore, in vitro functional assays of A2780 and TOV-112D cells demonstrated that UBP43 overexpression promoted cell proliferation, migration, and invasion. Upregulation of UBP43 might result in epithelial-mesenchymal transition by inducing the nuclear transport of β-catenin, which was accompanied by enhanced N-cadherin but decreased E-cadherin expression. These malignant phenotypes were reversed by UBP43 silencing. Further investigation revealed that the knockdown of UBP43 inhibited cell proliferation by inducing a cell cycle arrest at the G2/M phase. The oncogenic characteristics of UBP43 were validated in a subcutaneous xenograft mouse model. In vivo, tumor growth was delayed in the UBP43-silenced group but accelerated after UBP43 overexpression. Finally, we demonstrated that β-catenin is a key protein in the UBP43-mediated malignant development of epithelial ovarian cancer. Specifically, overexpression of UBP43 decreased the ubiquitination degradation of β-catenin and enhanced its protein stability. Also, we observed that the downstream genes of beta-catenin such as cyclin D1, MMP2, and MMP9 were upregulated due to UBP43 overexpression. Thus, we concluded that UBP43 promoted epithelial ovarian cancer tumorigenesis and metastasis through activation of the β-catenin pathway, suggesting that UBP43 may be a potential therapeutic target for this intractable disease.
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Affiliation(s)
- Hongyang Xie
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Junyu Chen
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Changyan Ma
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Jingjing Zhao
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin Province, China
| | - Manhua Cui
- Department of Obstetrics and Gynecology, The Second Hospital of Jilin University, Changchun, Jilin Province, China
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Nicoś M, Krawczyk P. Genetic Clonality as the Hallmark Driving Evolution of Non-Small Cell Lung Cancer. Cancers (Basel) 2022; 14:1813. [PMID: 35406585 PMCID: PMC8998004 DOI: 10.3390/cancers14071813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/28/2022] [Accepted: 03/29/2022] [Indexed: 12/12/2022] Open
Abstract
Data indicate that many driver alterations from the primary tumor of non-small cell lung cancer (NSCLC) are predominantly shared across all metastases; however, disseminating cells may also acquire a new genetic landscape across their journey. By comparing the constituent subclonal mutations between pairs of primary and metastatic samples, it is possible to derive the ancestral relationships between tumor clones, rather than between tumor samples. Current treatment strategies mostly rely on the theory that metastases are genetically similar to the primary lesions from which they arise. However, intratumor heterogeneity (ITH) affects accurate diagnosis and treatment decisions and it is considered the main hallmark of anticancer therapy failure. Understanding the genetic changes that drive the metastatic process is critical for improving the treatment strategies of this deadly condition. Application of next generation sequencing (NGS) techniques has already created knowledge about tumorigenesis and cancer evolution; however, further NGS implementation may also allow to reconstruct phylogenetic clonal lineages and clonal expansion. In this review, we discuss how the clonality of genetic alterations influence the seeding of primary and metastatic lesions of NSCLC. We highlight that wide genetic analyses may reveal the phylogenetic trajectories of NSCLC evolution, and may pave the way to better management of follow-up and treatment.
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Affiliation(s)
- Marcin Nicoś
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-954 Lublin, Poland;
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Selection of Cancer Stem Cell-Targeting Agents Using Bacteriophage Display. METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.) 2022; 2394:787-810. [PMID: 35094358 DOI: 10.1007/978-1-0716-1811-0_41] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
There is a growing need to develop tumor targeting agents for aggressive cancers. Aggressive cancers frequently relapse and are resistant to various therapies. Cancer stem cells (CSCs) are believed to be the cause of relapse and the aggressive nature of many cancers. Targeting CSCs could lead to novel diagnostic and treatment options. Bacteriophage (phage) display is a powerful tool developed by George Smith in 1985 to aid in the discovery of CSC targeting agents. Phage display selections are typically performed in vitro against an immobilized target. There are inherent disadvantages with this technique that can be circumvented by performing phage display selections in vivo. However, in vivo phage display selections present new challenges. A combination of both in vitro and in vivo selections, however, can take advantage of both selection methods. In this chapter, we discuss in detail how to isolate a CSC like population of cells from an aggressive cancer cell line, perform in vivo and in vitro phage display selections against the CSCs, and then characterize the resulting phage/peptides for further use as a diagnostic and therapeutic tool.
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Mehlman C, Takam Kamga P, Costantini A, Julié C, Dumenil C, Dumoulin J, Ouaknine J, Giraud V, Chinet T, Emile JF, Giroux Leprieur E. Baseline Hedgehog Pathway Activation and Increase of Plasma Wnt1 Protein Are Associated with Resistance to Immune Checkpoint Inhibitors in Advanced Non-Small-Cell Lung Cancer. Cancers (Basel) 2021; 13:cancers13051107. [PMID: 33807552 PMCID: PMC7962040 DOI: 10.3390/cancers13051107] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 02/28/2021] [Accepted: 03/01/2021] [Indexed: 12/26/2022] Open
Abstract
Hedgehog (Hh) and Wingless-type (Wnt) pathways are associated with resistance to immune checkpoint inhibitors (ICIs) in preclinical studies. This study aimed to assess the association between expression and activation levels of Wnt and Sonic Hedgehog (Shh) pathways and resistance to ICIs in advanced NSCLC patients treated with ICI. Hh and Wnt pathways activation was assessed by immunohistochemistry (Gli1 and beta-catenin) on corresponding tumor tissues, and by plasma concentrations of Shh and Wnt (Wnt1, Wnt2 and Wnt3) at ICI introduction and at the first clinical evaluation. Sixty-three patients were included, with 36 patients (57.1%) with available tissue. Response rate was lower in Gli1+ NSCLC (20.0%) compared to Gli1 negative (Gli-) NSCLC (55.6%) (p = 0.015). Rate of primary resistance was 69.8%, vs. 31.2%, respectively (p = 0.04), and median progression-free survival (PFS) was 1.9 months (interquartile range (IQR) 1.2-5.7) vs. 6.1 months (1.6-26.0), respectively (p = 0.08). Median PFS and overall survival were shorter in case of increase of Wnt1 concentration during ICI treatment compared to other patients: 3.9 months vs. 11.2 months (p = 0.008), and 15.3 months vs. not reached (p = 0.003). In conclusion, baseline activation of Hh pathway and increase of Wnt1 concentrations during ICI treatment were associated with poor outcome in NSCLC patients treated with ICIs.
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Affiliation(s)
- Camille Mehlman
- EA 4340 BECCOH, UVSQ, Université Paris-Saclay, 92100 Boulogne-Billancourt, France; (C.M.); (P.T.K.); (A.C.); (C.J.); (T.C.); (J.-F.E.)
| | - Paul Takam Kamga
- EA 4340 BECCOH, UVSQ, Université Paris-Saclay, 92100 Boulogne-Billancourt, France; (C.M.); (P.T.K.); (A.C.); (C.J.); (T.C.); (J.-F.E.)
| | - Adrien Costantini
- EA 4340 BECCOH, UVSQ, Université Paris-Saclay, 92100 Boulogne-Billancourt, France; (C.M.); (P.T.K.); (A.C.); (C.J.); (T.C.); (J.-F.E.)
- Department of Respiratory Diseases and Thoracic Oncology, APHP—Hopital Ambroise Pare, 92100 Boulogne-Billancourt, France; (C.D.); (J.D.); (J.O.); (V.G.)
| | - Catherine Julié
- EA 4340 BECCOH, UVSQ, Université Paris-Saclay, 92100 Boulogne-Billancourt, France; (C.M.); (P.T.K.); (A.C.); (C.J.); (T.C.); (J.-F.E.)
- Department of Pathology, APHP—Hopital Ambroise Pare, 92100 Boulogne-Billancourt, France
| | - Coraline Dumenil
- Department of Respiratory Diseases and Thoracic Oncology, APHP—Hopital Ambroise Pare, 92100 Boulogne-Billancourt, France; (C.D.); (J.D.); (J.O.); (V.G.)
| | - Jennifer Dumoulin
- Department of Respiratory Diseases and Thoracic Oncology, APHP—Hopital Ambroise Pare, 92100 Boulogne-Billancourt, France; (C.D.); (J.D.); (J.O.); (V.G.)
| | - Julia Ouaknine
- Department of Respiratory Diseases and Thoracic Oncology, APHP—Hopital Ambroise Pare, 92100 Boulogne-Billancourt, France; (C.D.); (J.D.); (J.O.); (V.G.)
| | - Violaine Giraud
- Department of Respiratory Diseases and Thoracic Oncology, APHP—Hopital Ambroise Pare, 92100 Boulogne-Billancourt, France; (C.D.); (J.D.); (J.O.); (V.G.)
| | - Thierry Chinet
- EA 4340 BECCOH, UVSQ, Université Paris-Saclay, 92100 Boulogne-Billancourt, France; (C.M.); (P.T.K.); (A.C.); (C.J.); (T.C.); (J.-F.E.)
- Department of Respiratory Diseases and Thoracic Oncology, APHP—Hopital Ambroise Pare, 92100 Boulogne-Billancourt, France; (C.D.); (J.D.); (J.O.); (V.G.)
| | - Jean-François Emile
- EA 4340 BECCOH, UVSQ, Université Paris-Saclay, 92100 Boulogne-Billancourt, France; (C.M.); (P.T.K.); (A.C.); (C.J.); (T.C.); (J.-F.E.)
- Department of Pathology, APHP—Hopital Ambroise Pare, 92100 Boulogne-Billancourt, France
| | - Etienne Giroux Leprieur
- EA 4340 BECCOH, UVSQ, Université Paris-Saclay, 92100 Boulogne-Billancourt, France; (C.M.); (P.T.K.); (A.C.); (C.J.); (T.C.); (J.-F.E.)
- Department of Respiratory Diseases and Thoracic Oncology, APHP—Hopital Ambroise Pare, 92100 Boulogne-Billancourt, France; (C.D.); (J.D.); (J.O.); (V.G.)
- Correspondence: ; Tel.: +33-149-095-802; Fax: +33-149-095-806
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Marcu LG. Imaging Biomarkers of Tumour Proliferation and Invasion for Personalised Lung Cancer Therapy. J Pers Med 2020; 10:jpm10040222. [PMID: 33198090 PMCID: PMC7711676 DOI: 10.3390/jpm10040222] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 11/03/2020] [Accepted: 11/10/2020] [Indexed: 12/28/2022] Open
Abstract
Personalised treatment in oncology has seen great developments over the last decade, due to both technological advances and more in-depth knowledge of radiobiological processes occurring in tumours. Lung cancer therapy is no exception, as new molecular targets have been identified to further increase treatment specificity and sensitivity. Yet, tumour resistance to treatment is still one of the main reasons for treatment failure. This is due to a number of factors, among which tumour proliferation, the presence of cancer stem cells and the metastatic potential of the primary tumour are key features that require better controlling to further improve cancer management in general, and lung cancer treatment in particular. Imaging biomarkers play a key role in the identification of biological particularities within tumours and therefore are an important component of treatment personalisation in radiotherapy. Imaging techniques such as PET, SPECT, MRI that employ tumour-specific biomarkers already play a critical role in patient stratification towards individualized treatment. The aim of the current paper is to describe the radiobiological challenges of lung cancer treatment in relation to the latest imaging biomarkers that can aid in the identification of hostile cellular features for further treatment adaptation and tailoring to the individual patient’s needs.
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Affiliation(s)
- Loredana G. Marcu
- Faculty of Informatics and Science, University of Oradea, 410087 Oradea, Romania;
- Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
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Jariyal H, Gupta C, Bhat VS, Wagh JR, Srivastava A. Advancements in Cancer Stem Cell Isolation and Characterization. Stem Cell Rev Rep 2020; 15:755-773. [PMID: 31863337 DOI: 10.1007/s12015-019-09912-4] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Occurrence of stem cells (CSCs) in cancer is well established in last two decades. These rare cells share several properties including presence of common surface markers, stem cell markers, chemo- and radio- resistance and are highly metastatic in nature; thus, considered as valuable prognostic and therapeutic targets in cancer. However, the studies related to CSCs pave number of issues due to rare cell population and difficulties in their isolation ascribed to common stem cell marker. Various techniques including flow cytometry, laser micro-dissection, fluorescent nanodiamonds and microfluidics are used for the isolation of these rare cells. In this review, we have included the advance strategies adopted for the isolation of CSCs using above mentioned techniques. Furthermore, CSCs are primarily found in the core of the solid tumors and their microenvironment plays an important role in maintenance, self-renewal, division and tumor development. Therefore, in vivo tracking and model development become obligatory for functional studies of CSCs. Fluorescence and bioluminescence tagging has been widely used for transplantation assay and lineage tracking experiments to improve our understanding towards CSCs behaviour in their niche. Techniques such as Magnetic resonance imaging (MRI) and Positron emission tomography (PET) have proved useful for tracking of endogenous CSCs which could be helpful in their identification in clinical settings.
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Affiliation(s)
- Heena Jariyal
- Department of Biotechnology, National institute of Pharmaceutical Education and Research -Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India
| | - Chanchal Gupta
- Department of Biotechnology, National institute of Pharmaceutical Education and Research -Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India
| | - Vedika Sandeep Bhat
- Department of Biotechnology, National institute of Pharmaceutical Education and Research -Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India
| | - Jayant Ramakant Wagh
- Department of Biotechnology, National institute of Pharmaceutical Education and Research -Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India
| | - Akshay Srivastava
- Department of Medical Device, National institute of Pharmaceutical Education and Research -Ahmedabad (NIPER-A), Gandhinagar, Gujarat, India.
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Cancer Stem Cells: Acquisition, Characteristics, Therapeutic Implications, Targeting Strategies and Future Prospects. Stem Cell Rev Rep 2020; 15:331-355. [PMID: 30993589 DOI: 10.1007/s12015-019-09887-2] [Citation(s) in RCA: 83] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Since last two decades, the major cancer research has focused on understanding the characteristic properties and mechanism of formation of Cancer stem cells (CSCs), due to their ability to initiate tumor growth, self-renewal property and multi-drug resistance. The discovery of the mechanism of acquisition of stem-like properties by carcinoma cells via epithelial-mesenchymal transition (EMT) has paved a way towards a deeper understanding of CSCs and presented a possible avenue for the development of therapeutic strategies. In spite of years of research, various challenges, such as identification of CSC subpopulation, lack of appropriate experimental models, targeting cancer cells and CSCs specifically without harming normal cells, are being faced while dealing with CSCs. Here, we discuss the biology and characteristics of CSCs, mode of acquisition of stemness (via EMT) and development of multi-drug resistance, the role of tumor niche, the process of dissemination and metastasis, therapeutic implications of CSCs and necessity of targeting them. We emphasise various strategies being developed to specifically target CSCs, including those targeting biomarkers, key pathways and microenvironment. Finally, we focus on the challenges that need to be subdued and propose the aspects that need to be addressed in future studies in order to broaden the understanding of CSCs and develop novel strategies to eradicate them in clinical applications. Graphical Abstract Cancer Stem Cells(CSCs) have gained much attention in the last few decades due to their ability to initiate tumor growth and, self-renewal property and multi-drug resistance. Here, we represent the CSC model of cancer, Characteristics of CSCs, acquisition of stemness and metastatic dissemination of cancer, Therapeutic implications of CSCs and Various strategies being employed to target and eradicate CSCs.
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Tao X, Yin Y, Lian D, Gu H, Chen W, Yang L, Yin G, Liu P, Li L, Wei Y, Xie Z, Liu F, Sui H, Yan D, Tao W. Puerarin 6″-O-xyloside suppresses growth, self-renewal and invasion of lung cancer stem-like cells derived from A549 cells via regulating Akt/c-Myc signalling. Clin Exp Pharmacol Physiol 2020; 47:1311-1319. [PMID: 32124474 DOI: 10.1111/1440-1681.13294] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2019] [Revised: 02/12/2020] [Accepted: 02/27/2020] [Indexed: 01/21/2023]
Abstract
Cancer stem cells have been identified as the major cause of cancer initiation and progression. To investigate the effects of puerarin 6″-O-xyloside (PXY), derived from Pueraria lobata (Willd.) Ohwi, on lung cancer stem cells, we enriched and identified a subpopulation of lung cancer stem-like cells (LCSLCs) derived from lung adenocarcinoma A549 cells with traits including high self-renewal and invasive capability in vitro, elevated tumourigenicity in vivo, and high expression of stem cell markers CD44, CD133 and aldehyde dehydrogenase 1 (ALDH1). We found that PXY could impair cell viability, suppress self-renewal and invasive capability, and decrease CD133, CD44 and ALDH1 mRNA expression in LCSLCs in a dose-dependent manner. Furthermore, we showed that PXY suppressed the self-renewal and invasive capability of LCSLCs at least in part through suppressing the activation of Akt/c-Myc signalling. In conclusion, PXY can block the traits of LCSLCs, indicating that PXY may be a candidate compound for lung adenocarcinoma therapy via eliminating LCSLCs.
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Affiliation(s)
- Xiaomei Tao
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing, China
- International Cooperation & Joint Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing, China
| | - Yefeng Yin
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Dongbo Lian
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Hongyan Gu
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Wen Chen
- Guang'anmen Hospital of China Academy of Chinese Medical Sciences, Beijing, China
| | - Lu Yang
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Gang Yin
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Pengfei Liu
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Lili Li
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Yuanyuan Wei
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Zhengzheng Xie
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
| | - Fei Liu
- Department of Clinical Nutrition, Chengdu Fifth People's Hospital, Chengdu, China
| | - Hangshuo Sui
- Department of Clinical Nutrition, Chengde Central Hospital, Chengde, China
| | - Dan Yan
- Beijing Shijitan Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing, China
- International Cooperation & Joint Laboratory of Bio-characteristic Profiling for Evaluation of Rational Drug Use, Beijing, China
| | - Weiwei Tao
- College of Nursing, Dalian Medical University, Dalian, China
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Gor R, Ramalingam S. Controversies in Isolation and Characterization of Cancer Stem Cells. CANCER STEM CELLS: NEW HORIZONS IN CANCER THERAPIES 2020:257-272. [DOI: 10.1007/978-981-15-5120-8_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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12
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Akbari M, Shomali N, Faraji A, Shanehbandi D, Asadi M, Mokhtarzadeh A, Shabani A, Baradaran B. CD133: An emerging prognostic factor and therapeutic target in colorectal cancer. Cell Biol Int 2019; 44:368-380. [PMID: 31579983 DOI: 10.1002/cbin.11243] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2019] [Accepted: 09/29/2019] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) is one of the leading causes of death worldwide. Recently, the role of cancer stem cells (CSCs) has been highlighted as a crucial emerging factor in chemoresistance, cancer relapse, and metastasis. CD133 is a surface marker of CSCs and has been argued to have prognostic and therapeutic values in CRC along with its related pathways such as Wnt, Notch, and hedgehog. Several studies have successfully applied targeted therapies against CD133 in CRC models namely bispecific antibodies (BiAbs) and anti-Wnt and notch pathways agents. These studies have yielded initial promising results in this regard. However, none of the therapeutics have been used in the clinical setting and their efficacy and adverse effects profile are yet to be elucidated. This review aims to gather the old and most recent data on the prognostic and therapeutic values of CD133 and CD133-targeted therapies in CRC.
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Affiliation(s)
- Morteza Akbari
- Department of Biotechnology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan, 3514799422, Iran.,Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran.,Semnan Biotechnology Research Center, Semnan University of Medical sciences, Semnan, 3514799422, Iran
| | - Navid Shomali
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran.,Student Research Committee, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran.,Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Afsaneh Faraji
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Dariush Shanehbandi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Milad Asadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Ahad Mokhtarzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
| | - Aliakbar Shabani
- Semnan Biotechnology Research Center, Semnan University of Medical sciences, Semnan, 3514799422, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, 5166614766, Iran
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13
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5-O-Acetyl-Renieramycin T from Blue Sponge Xestospongia sp. Induces Lung Cancer Stem Cell Apoptosis. Mar Drugs 2019; 17:md17020109. [PMID: 30754694 PMCID: PMC6409812 DOI: 10.3390/md17020109] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 02/06/2019] [Accepted: 02/07/2019] [Indexed: 02/08/2023] Open
Abstract
Lung cancer is one of the most significant cancers as it accounts for almost 1 in 5 cancer deaths worldwide, with an increasing incident rate. Management of the cancer has been shown to frequently fail due to the ability of the cancer cells to resist therapy as well as metastasis. Recent evidence has suggested that the poor response to the current treatment drugs and the ability to undergo metastasis are driven by cancer stem cells (CSCs) within the tumor. The discovery of novel compounds able to suppress CSCs and sensitize the chemotherapeutic response could be beneficial to the improvement of clinical outcomes. Herein, we report for the first time that 5-O-acetyl-renieramycin T isolated from the blue sponge Xestospongia sp. mediated lung cancer cell death via the induction of p53-dependent apoptosis. Importantly, 5-O-acetyl-renieramycin T induced the death of CSCs as represented by the CSC markers CD44 and CD133, while the stem cell transcription factor Nanog was also found to be dramatically decreased in 5-O-acetyl-renieramycin T-treated cells. We also found that such a CSC suppression was due to the ability of the compound to deplete the protein kinase B (AKT) signal. Furthermore, 5-O-acetyl-renieramycin T was able to significantly sensitize cisplatin-mediated apoptosis in the lung cancer cells. Together, the present research findings indicate that this promising compound from the marine sponge is a potential candidate for anti-cancer approaches.
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14
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Testa U, Castelli G, Pelosi E. Lung Cancers: Molecular Characterization, Clonal Heterogeneity and Evolution, and Cancer Stem Cells. Cancers (Basel) 2018; 10:E248. [PMID: 30060526 PMCID: PMC6116004 DOI: 10.3390/cancers10080248] [Citation(s) in RCA: 251] [Impact Index Per Article: 35.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2018] [Revised: 07/19/2018] [Accepted: 07/20/2018] [Indexed: 12/21/2022] Open
Abstract
Lung cancer causes the largest number of cancer-related deaths in the world. Most (85%) of lung cancers are classified as non-small-cell lung cancer (NSCLC) and small-cell lung cancer (15%) (SCLC). The 5-year survival rate for NSCLC patients remains very low (about 16% at 5 years). The two predominant NSCLC histological phenotypes are adenocarcinoma (ADC) and squamous cell carcinoma (LSQCC). ADCs display several recurrent genetic alterations, including: KRAS, BRAF and EGFR mutations; recurrent mutations and amplifications of several oncogenes, including ERBB2, MET, FGFR1 and FGFR2; fusion oncogenes involving ALK, ROS1, Neuregulin1 (NRG1) and RET. In LSQCC recurrent mutations of TP53, FGFR1, FGFR2, FGFR3, DDR2 and genes of the PI3K pathway have been detected, quantitative gene abnormalities of PTEN and CDKN2A. Developments in the characterization of lung cancer molecular abnormalities provided a strong rationale for new therapeutic options and for understanding the mechanisms of drug resistance. However, the complexity of lung cancer genomes is particularly high, as shown by deep-sequencing studies supporting the heterogeneity of lung tumors at cellular level, with sub-clones exhibiting different combinations of mutations. Molecular studies performed on lung tumors during treatment have shown the phenomenon of clonal evolution, thus supporting the occurrence of a temporal tumor heterogeneity.
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Affiliation(s)
- Ugo Testa
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
| | - Germana Castelli
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
| | - Elvira Pelosi
- Department of Hematology, Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, Italy.
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15
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NF-κB-driven improvement of EHD1 contributes to erlotinib resistance in EGFR-mutant lung cancers. Cell Death Dis 2018; 9:418. [PMID: 29549343 PMCID: PMC5856828 DOI: 10.1038/s41419-018-0447-7] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Revised: 01/23/2018] [Accepted: 02/07/2018] [Indexed: 12/23/2022]
Abstract
Acquired resistance to epidermal growth factor receptor-tyrosine-kinase inhibitors (EGFR-TKIs), such as gefitinib and erlotinib, is a critical obstacle in the treatment of EGFR mutant-positive non-small cell lung cancer (NSCLC). EHD1, a protein of the C-terminal Eps15 homology domain-containing (EHD) family, plays a role in regulating endocytic recycling, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we found that a lower EHD1 expression improved both EGFR-TKIs sensitivity, which is consistent with a lower CD133 expression, and progression-free survival in NSCLC patients. The overexpression of EHD1 markedly increased erlotinib resistance and lung cancer cell stemness in vitro and in vivo. Moreover, we demonstrated that miR-590 targeted the 3′-UTR of EHD1 and was regulated by NK-κB, resulting in downregulated EHD1 expression, increased erlotinib sensitivity and repressed NSCLC cancer stem-like properties in vitro and in vivo. We found that EHD1 was an important factor in EGFR-TKI resistance and the cancer stem-like cell phenotype of lung cancer, and these results suggest that targeting the NF-κB/miR-590/EHD1 pathway has potential therapeutic promise in EGFR-mutant NSCLC patients with acquired EGFR-TKI resistance.
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16
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Colla R, Izzotti A, De Ciucis C, Fenoglio D, Ravera S, Speciale A, Ricciarelli R, Furfaro AL, Pulliero A, Passalacqua M, Traverso N, Pronzato MA, Domenicotti C, Marengo B. Glutathione-mediated antioxidant response and aerobic metabolism: two crucial factors involved in determining the multi-drug resistance of high-risk neuroblastoma. Oncotarget 2018; 7:70715-70737. [PMID: 27683112 PMCID: PMC5342585 DOI: 10.18632/oncotarget.12209] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 09/13/2016] [Indexed: 12/24/2022] Open
Abstract
Neuroblastoma, a paediatric malignant tumor, is initially sensitive to etoposide, a drug to which many patients develop chemoresistance. In order to investigate the molecular mechanisms responsible for etoposide chemoresistance, HTLA-230, a human MYCN-amplified neuroblastoma cell line, was chronically treated with etoposide at a concentration that in vitro mimics the clinically-used dose. The selected cells (HTLA-Chr) acquire multi-drug resistance (MDR), becoming less sensitive than parental cells to high doses of etoposide or doxorubicin. MDR is due to several mechanisms that together contribute to maintaining non-toxic levels of H2O2. In fact, HTLA-Chr cells, while having an efficient aerobic metabolism, are also characterized by an up-regulation of catalase activity and higher levels of reduced glutathione (GSH), a thiol antioxidant compound. The combination of such mechanisms contributes to prevent membrane lipoperoxidation and cell death. Treatment of HTLA-Chr cells with L-Buthionine-sulfoximine, an inhibitor of GSH biosynthesis, markedly reduces their tumorigenic potential that is instead enhanced by the exposure to N-Acetylcysteine, able to promote GSH synthesis. Collectively, these results demonstrate that GSH and GSH-related responses play a crucial role in the acquisition of MDR and suggest that GSH level monitoring is an efficient strategy to early identify the onset of drug resistance and to control the patient's response to therapy.
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Affiliation(s)
- Renata Colla
- Department of Experimental Medicine, University of Genova, Genova, Italy
| | - Alberto Izzotti
- Department of Health Sciences, University of Genova, Genova, Italy.,IRCCS AOU San Martino IST Genova, Genova, Italy
| | - Chiara De Ciucis
- Department of Experimental Medicine, University of Genova, Genova, Italy
| | - Daniela Fenoglio
- Center of Excellence for Biomedical Research, Department of Internal Medicine, University of Genova, Genova, Italy
| | - Silvia Ravera
- Department of Pharmacy, University of Genova, Genova, Italy
| | - Andrea Speciale
- Department of Experimental Medicine, University of Genova, Genova, Italy
| | | | | | | | - Mario Passalacqua
- Department of Experimental Medicine, University of Genova, Genova, Italy
| | - Nicola Traverso
- Department of Experimental Medicine, University of Genova, Genova, Italy
| | | | - Cinzia Domenicotti
- Department of Experimental Medicine, University of Genova, Genova, Italy
| | - Barbara Marengo
- Department of Experimental Medicine, University of Genova, Genova, Italy
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17
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Chen E, Zeng Z, Bai B, Zhu J, Song Z. The prognostic value of CSCs biomarker CD133 in NSCLC: a meta-analysis. Oncotarget 2018; 7:56526-56539. [PMID: 27489355 PMCID: PMC5302932 DOI: 10.18632/oncotarget.10964] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2016] [Accepted: 07/19/2016] [Indexed: 12/11/2022] Open
Abstract
The prognostic value of cancer stem cells (CSCs) marker CD133 in non-small-cell lung cancer (NSCLC) remains controversial. We performed this meta-analysis of 32 eligible studies to clarify the prognostic value of CD133 and provide evidence for CSCs hypothesis. We calculated pooled hazard ratio (HR) for survival outcomes and pooled odds ratio (OR) for clinical parameters associated with CD133 in total 3595 NSCLC patients by STATA. Our results showed that NSCLC patients with higher CD133 expression had shorter overall survival time only in Asian patients (HR = 3.80, 95% CI: 3.12-4.04, p < 0.001; I2 = 32%) but not in Caucasian patients (HR = 1.15, 95% CI: 0.88-1.52, p = 0.307; I2 = 0%), suggesting that differential prognostic value of CD133 in distinct ethnic group. We speculated that the intrinsic EGFR gene status of CSCs might be responsible for this racial difference. Additionally, we found that higher expression of CD133 was associated with poor differentiation (OR = 2.03, 95% CI: 1.32-3.14, p = 0.001) and lymph node metastasis (OR = 2.39, 95% CI: 1.62-3.52, p < 0.001) but there was no significant difference of CD133 expression between adenocarcinoma and squamous carcinoma (OR = 1.13, 95% CI: 0.93-1.38, p = 0.3) in NSCLC patients. These results may provide a new therapeutic perspective on the treatment of NSCLC patients according to the expression of CD133 in distinct ethnic group.
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Affiliation(s)
- Engeng Chen
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, P.R. China.,Key Laboratory of Biotherapy of Zhejiang Province, 310016, P.R. China
| | - Zhiru Zeng
- The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310009, P.R. China
| | - Bingjun Bai
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, P.R. China.,Key Laboratory of Biotherapy of Zhejiang Province, 310016, P.R. China
| | - Jing Zhu
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, P.R. China.,Key Laboratory of Biotherapy of Zhejiang Province, 310016, P.R. China
| | - Zhangfa Song
- Department of Colorectal Surgery, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, Hangzhou, 310016, P.R. China.,Key Laboratory of Biotherapy of Zhejiang Province, 310016, P.R. China
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18
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Prognostic significance of stem cell-related marker expression and its correlation with histologic subtypes in lung adenocarcinoma. Oncotarget 2018; 7:42502-42512. [PMID: 27285762 PMCID: PMC5173151 DOI: 10.18632/oncotarget.9894] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 05/16/2016] [Indexed: 12/13/2022] Open
Abstract
Cancer stem cells (CSCs) are a small subset of tumor cells that exhibit stem cell-like properties and contribute in treatment failure. To clarify the expression and prognostic significance of several CSC markers in non-small cell lung cancer, we retrospectively analyzed 368 patients with adenocarcinoma (n = 226) or squamous cell carcinoma (n = 142). We correlated the expression of six CSC markers – CD133, CD44, aldehyde dehydrogenase 1 (ALDH1), sex determining region Y-box 2 (SOX2), octamer binding transcription factor 4 (OCT4), and Nanog – with clinicopathologic and molecular variables and survival outcomes. In adenocarcinoma, CD133, ALDH1 and CD44 expression was associated with low pathologic stage and absence of lymphovascular invasion, while Nanog expression correlated with high histologic grade, lymphatic invasion and increased expression of Snail-1, a transcription factor associated with epithelial-mesenchymal transition. CSC marker expression was also associated with histologic subtypes in adenocarcinoma. Multivariate analysis showed that high Nanog expression was an independent factor associated with a poor prognosis in adenocarcinoma. CSC markers had no prognostic value in squamous cell carcinoma. These results suggest that Nanog is an independent negative prognostic factor that may be associated with epithelial-mesenchymal transition in lung adenocarcinoma.
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19
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Zou B, Zhou XL, Lai SQ, Liu JC. Notch signaling and non-small cell lung cancer. Oncol Lett 2018; 15:3415-3421. [PMID: 29467866 PMCID: PMC5796339 DOI: 10.3892/ol.2018.7738] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2016] [Accepted: 10/19/2017] [Indexed: 12/25/2022] Open
Abstract
Lung cancer is the leading cause of cancer-associated mortality worldwide. Elucidation of the pathogenesis and biology of lung cancer is critical for the design of an effective treatment for patients. Non-small cell lung cancer (NSCLC) accounts for 80–85% of lung cancer cases. The abnormal expression of Notch signaling pathway members is a relatively frequent event in NSCLC. The Notch signaling pathway serves important roles in cell fate determination, proliferation, differentiation and apoptosis. Increasing evidence supports the association of Notch signaling dysregulation with various types of malignant tumor, including NSCLC. Several studies have demonstrated that members of the Notch signaling pathway may be potential biomarkers for predicting the progression and prognosis of patients with NSCLC. Furthermore, Notch signaling serves critical roles in the tumorigenesis and treatment resistance of NSCLC cells by promoting the proliferation or inhibiting the apoptosis of NSCLC cells. The present review provides a detailed summary of the roles of Notch signaling in NSCLC.
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Affiliation(s)
- Bin Zou
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Xue-Liang Zhou
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Song-Qing Lai
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
| | - Ji-Chun Liu
- Department of Cardiothoracic Surgery, First Affiliated Hospital, Nanchang University, Nanchang, Jiangxi 330006, P.R. China
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20
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CD133+ cancer stem-like cells promote migration and invasion of salivary adenoid cystic carcinoma by inducing vasculogenic mimicry formation. Oncotarget 2018; 7:29051-62. [PMID: 27074560 PMCID: PMC5045377 DOI: 10.18632/oncotarget.8665] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 03/28/2016] [Indexed: 02/05/2023] Open
Abstract
Cancer stem cells (CSCs) have gained much attention due to their roles in the invasion and metastasis of numerous kinds of human cancers. Here, we showed that the positive expression of CD133, the stemness marker, was positively associated with vasculogenic mimicry (VM) formation, local regional recurrence, distant metastasis and poorer prognosis in salivary adenoid cystic carcinoma (ACC) specimens. Compared with CD133− ACC cells, CD133+ cancer stem-like cells had more migration and invasion capabilities, as well as more VM formation. The levels of endothelial cell marker VE-cadherin, MMP-2 and MMP-9 expression in CD133+ cancer stem-like cells and xenograft tumors of nude mice injected with CD133+ cells were significantly higher than those with CD133− cells. The data indicated that CD133+ cancer stem-like cells might contribute to the migration and invasion of ACC through inducing VM formation.
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21
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Al-Ansary GH, Eldehna WM, Ghabbour HA, Al-Rashood STA, Al-Rashood KA, Eladwy RA, Al-Dhfyan A, Kabil MM, Abdel-Aziz HA. Cancer stem cells CD133 inhibition and cytotoxicity of certain 3-phenylthiazolo[3,2-a]benzimidazoles: design, direct synthesis, crystal study and in vitro biological evaluation. J Enzyme Inhib Med Chem 2017; 32:986-991. [PMID: 28726519 PMCID: PMC6010115 DOI: 10.1080/14756366.2017.1347166] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2017] [Revised: 06/09/2017] [Accepted: 06/21/2017] [Indexed: 12/20/2022] Open
Abstract
Cancer stem cells (CSCs) have been objects of intensive study since their identification in 1994. Adopting a structural rigidification approach, a novel series of 3-phenylthiazolo[3,2-a]benzimidazoles 4a-d was designed and synthesised, in an attempt to develop potent anticancer agent that can target the bulk of tumour cells and CSCs. The anti-proliferative activity of the synthesised compounds was evaluated against two cell lines, namely; colon cancer HT-29 and triple negative breast cancer MDA-MB-468 cell lines. Also, their inhibitory activity against the cell surface expression of CD133 was examined. In particular, compound 4b emerged as a promising hit molecule as it manifested good antineoplastic potency against both tested cell lines (IC50 = 9 and 12 μM, respectively), beside its ability to inhibit the cell surface expression of CD133 by 50% suggesting a promising potential of effectively controlling the tumour by eradicating the tumour bulk and inhibiting the proliferation of the CSCs. Moreover, compounds 4a and 4c showed moderate activity against HT-29 (IC50 = 21 and 29 μM, respectively) and MDA-MB-468 (IC50 = 23 and 24 μM, respectively) cell lines, while they inhibited the CD133 expression by 14% and 48%, respectively. Finally, a single crystal X-ray diffraction was recorded for compound 4d.
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Affiliation(s)
- Ghada H. Al-Ansary
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ain Shams University, Abbassia, Cairo, Egypt
| | - Wagdy M. Eldehna
- Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafr El-Sheikh, Egypt
| | - Hazem A. Ghabbour
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
- Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, Egypt
| | - Sara T. A. Al-Rashood
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Khalid A. Al-Rashood
- Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
| | - Radwa A. Eladwy
- Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, Egypt
| | - Abdullah Al-Dhfyan
- Stem Cell & Tissue Re-Engineering Program, Research Center, King Faisal Specialized Hospital & Research Center, MBC-03, Riyadh, Saudi Arabia
| | - Maha M. Kabil
- Department of Infection Control, King Saud University Medical City, Riyadh, Saudi Arabia
| | - Hatem A. Abdel-Aziz
- Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, Egypt
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22
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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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23
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Zakaria N, Satar NA, Abu Halim NH, Ngalim SH, Yusoff NM, Lin J, Yahaya BH. Targeting Lung Cancer Stem Cells: Research and Clinical Impacts. Front Oncol 2017; 7:80. [PMID: 28529925 PMCID: PMC5418222 DOI: 10.3389/fonc.2017.00080] [Citation(s) in RCA: 82] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Accepted: 04/11/2017] [Indexed: 12/26/2022] Open
Abstract
Lung cancer is the most common cancer worldwide, accounting for 1.8 million new cases and 1.6 million deaths in 2012. Non-small cell lung cancer (NSCLC), which is one of two types of lung cancer, accounts for 85–90% of all lung cancers. Despite advances in therapy, lung cancer still remains a leading cause of death. Cancer relapse and dissemination after treatment indicates the existence of a niche of cancer cells that are not fully eradicated by current therapies. These chemoresistant populations of cancer cells are called cancer stem cells (CSCs) because they possess the self-renewal and differentiation capabilities similar to those of normal stem cells. Targeting the niche of CSCs in combination with chemotherapy might provide a promising strategy to eradicate these cells. Thus, understanding the characteristics of CSCs has become a focus of studies of NSCLC therapies.
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Affiliation(s)
- Norashikin Zakaria
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | - Nazilah Abdul Satar
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | - Noor Hanis Abu Halim
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | - Siti Hawa Ngalim
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | - Narazah Mohd Yusoff
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
| | - Juntang Lin
- College of Life Science and Technology, Xinxiang Medical University (XXMU), Xinxiang, China.,College of Biomedical Engineering, Xinxiang Medical University (XXMU), Xinxiang, China
| | - Badrul Hisham Yahaya
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Kepala Batas, Penang, Malaysia
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24
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Sakabe T, Azumi J, Haruki T, Umekita Y, Nakamura H, Shiota G. CD117 expression is a predictive marker for poor prognosis in patients with non-small cell lung cancer. Oncol Lett 2017; 13:3703-3708. [PMID: 28521472 DOI: 10.3892/ol.2017.5925] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2016] [Accepted: 01/12/2017] [Indexed: 12/17/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) accounts for >85% of incidences of lung cancer, for which the predicted 5-year survival rates are low and recurrence rates remain high. Although it has been reported that the patients with SCLC cells that possess the cluster of differentiation (CD) 117 marker exhibited poor prognosis and poor response to chemotherapy, no studies concerning the association of CD117 expression with prognosis of the patients with NSCLC have been reported. An in vitro study reportedly revealed that CD117-positive cell populations in NSCLC cell lines exhibited cancer stem cell (CSC) phenotypes including self-renewal and chemoresistance. Therefore, the present study hypothesized that if CD117-positive cells are CSC-like cells, CD117 positivity may be associated with the prognosis of patients with NSCLC. To confirm this hypothesis, the association between CD117 expression in patients with NSCLC and clinicopathological characteristics was investigated. CD177 expression was examined by immunohistochemistry in 99 patients with NSCLC who underwent curative surgical resection. Tumor samples in the present study included 73 samples of adenocarcinoma and 26 of squamous carcinoma. The associations of CD177 expression with clinicopathological features and prognosis were examined. The lymph node metastasis and rates of recurrence were significantly associated with overall survival rates through multivariate analysis (P<0.001 and P<0.001), respectively. A Kaplan-Meier analysis for relapse-free survival and the log-rank test revealed that the patients with CD117-positive cell populations exhibited shorter relapse-free survival rates compared with patients whose cells were CD117-negative (P=0.014). The multivariate analysis demonstrated that venous invasion, pathological stage, and CD117 expression were independent prognostic parameters for relapse-free survival in patients with NSCLC (P=0.001, P=0.001 and P=0.002), respectively. In conclusion, these data suggest that CD117 expression in NSCLC may serve as a useful marker for predicting the prognosis of patients with NSCLC.
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Affiliation(s)
- Tomohiko Sakabe
- Division of Molecular and Genetic Medicine, Department of Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan.,Division of Organ Pathology, Department of Pathology, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Junya Azumi
- Division of Molecular and Genetic Medicine, Department of Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Tomohiro Haruki
- Division of General Thoracic Surgery, Tottori University Hospital, Yonago, Tottori 683-8504, Japan
| | - Yoshihisa Umekita
- Division of Organ Pathology, Department of Pathology, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
| | - Hiroshige Nakamura
- Division of General Thoracic Surgery, Tottori University Hospital, Yonago, Tottori 683-8504, Japan
| | - Goshi Shiota
- Division of Molecular and Genetic Medicine, Department of Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan
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25
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CD133 expression may be useful as a prognostic indicator in colorectal cancer, a tool for optimizing therapy and supportive evidence for the cancer stem cell hypothesis: a meta-analysis. Oncotarget 2017; 7:10023-36. [PMID: 26840260 PMCID: PMC4891101 DOI: 10.18632/oncotarget.7054] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2015] [Accepted: 12/08/2015] [Indexed: 12/14/2022] Open
Abstract
We performed a meta-analysis of CD133-related clinical data to investigate the role of cancer stem cells (CSCs) in the clinical outcomes of colorectal cancer (CRC) patients, analyzing the effectiveness of various therapeutic strategies and examining the validity of the CSC hypothesis. For 28 studies (4546 patients), the relative risk (RR) to survival outcomes associated with CD133+ CRCs were calculated using STATA 12.0 software. Pooled results showed that CD133High patients had poor 5-year overall survival (RR 0.713, 95% CI 0·616-0·826) and 5-year disease free survival (RR 0·707, 95% CI 0·602-0·831). Both associations were consistently observed across different races, research techniques and therapeutic strategies. In a subgroup receiving adjuvant therapy, CD133Low patients achieved significantly better survival than CD133High patients. The findings suggest that CD133 could serve as a predictive marker of poor prognosis and treatment failure in CRC. CD133Low patients could benefit from adjuvant treatments, while CD133High patients should be given novel treatments besides adjuvant therapy. Our results also provide evidence in support of the CSC hypothesis.
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Lu BC, Li J, Yu WF, Zhang GZ, Wang HM, Ma HM. Elevated expression of Nrf2 mediates multidrug resistance in CD133 + head and neck squamous cell carcinoma stem cells. Oncol Lett 2016; 12:4333-4338. [PMID: 28101198 PMCID: PMC5228276 DOI: 10.3892/ol.2016.5269] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 04/12/2016] [Indexed: 02/07/2023] Open
Abstract
Enhanced expression of the ATP-binding cassette (ABC) transporter protein ABC sub-family G member 2 (ABCG2) in cancer stem cells (CSCs) plays a major role in chemotherapeutic drug efflux, which results in therapy failure and tumor relapse. In addition to downregulating apoptosis in CSCs, it has been reported that the transcriptional upregulation of the redox sensing factor Nrf2 is involved in the upregulation of ABCG2 expression and consequent chemoresistance. The current study investigated the presence of cancer stem-like side population (SP) cells from head and neck squamous cell carcinoma (HNSCC) samples, and evaluated the Nrf2 expression profile and multidrug resistance properties of HNSCC stem cells. Fluorescence-activated cell sorting was used for SP cells detection, while reverse transcription-polymerase chain reaction was used for the analysis of Nrf2 expression. The present study identified ~2.1% SP cells present in HNSCC specimens, which were positive for cluster of differentiation (CD)133 expression and displayed significantly elevated messenger RNA expression of Nrf2, compared with non-SP cells. These data suggest that the ABC transporter ABCG2 is highly upregulated in SP cells, and this results in multidrug resistance. In addition, these CD133+ cells underwent rapid proliferation and exhibited high self-renewal and tumorigenic properties. Taken together, the present findings suggest that elevated expression of Nrf2 mediated drug resistance in HNSCC CSCs, which may be one of the causative factors for cancer treatment failure. Therefore, novel anti-cancer drugs that downregulate the Nrf2 signaling pathway could effectively improve the treatment and survival rate of patients with HNSCC.
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Affiliation(s)
- Bao-Cai Lu
- Department of Ear-Nose-Throat, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Jing Li
- Department of Ear-Nose-Throat, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Wen-Fa Yu
- Department of Ear-Nose-Throat, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Guo-Zheng Zhang
- Department of Ear-Nose-Throat, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Hui-Min Wang
- Department of Ear-Nose-Throat, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
| | - Hui-Min Ma
- Department of Ear-Nose-Throat, The First Affiliated Hospital of Xinxiang Medical University, Weihui, Henan 453100, P.R. China
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Abstract
Lung cancer remains a major cause of cancer-related deaths worldwide with unfavourable prognosis mainly due to the late stage of disease at presentation. High incidence and disease recurrence rates are a fact despite advances in treatment. Ongoing experimental and clinical observations suggest that the malignant phenotype in lung cancer is sustained by lung cancer stem cells (CSCs) which are putative stem cells situated throughout the airways that have the potential of initiating lung cancer formation. These cells share the common characteristic of increased proliferation and differentiation, long life span and resistance to chemotherapy and radiation therapy. This review summarises the current knowledge on their characteristics and phenotype.
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Affiliation(s)
- Georgia Hardavella
- 1 Department of Respiratory Medicine and Allergy, King's College, London, UK ; 2 Department of Respiratory Medicine, King's College Hospital, London, UK
| | - Rachel George
- 1 Department of Respiratory Medicine and Allergy, King's College, London, UK ; 2 Department of Respiratory Medicine, King's College Hospital, London, UK
| | - Tariq Sethi
- 1 Department of Respiratory Medicine and Allergy, King's College, London, UK ; 2 Department of Respiratory Medicine, King's College Hospital, London, UK
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28
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Hong M, Tan HY, Li S, Cheung F, Wang N, Nagamatsu T, Feng Y. Cancer Stem Cells: The Potential Targets of Chinese Medicines and Their Active Compounds. Int J Mol Sci 2016; 17:893. [PMID: 27338343 PMCID: PMC4926427 DOI: 10.3390/ijms17060893] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2016] [Revised: 05/28/2016] [Accepted: 05/30/2016] [Indexed: 12/27/2022] Open
Abstract
The pivotal role of cancer stem cells (CSCs) in the initiation and progression of malignancies has been rigorously validated, and the specific methods for identifying and isolating the CSCs from the parental cancer population have also been rapidly developed in recent years. This review aims to provide an overview of recent research progress of Chinese medicines (CMs) and their active compounds in inhibiting tumor progression by targeting CSCs. A great deal of CMs and their active compounds, such as Antrodia camphorate, berberine, resveratrol, and curcumin have been shown to regress CSCs, in terms of reversing drug resistance, inducing cell death and inhibiting cell proliferation as well as metastasis. Furthermore, one of the active compounds in coptis, berbamine may inhibit tumor progression by modulating microRNAs to regulate CSCs. The underlying molecular mechanisms and related signaling pathways involved in these processes were also discussed and concluded in this paper. Overall, the use of CMs and their active compounds may be a promising therapeutic strategy to eradicate cancer by targeting CSCs. However, further studies are needed to clarify the potential of clinical application of CMs and their active compounds as complementary and alternative therapy in this field.
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Affiliation(s)
- Ming Hong
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
| | - Hor Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
| | - Sha Li
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
| | - Fan Cheung
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
| | - Tadashi Nagamatsu
- Department of Pharmacobiology and Therapeutics, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tenpakuku, Nagoya 468-8503, Japan.
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong, China.
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29
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NF-κB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance. Proc Natl Acad Sci U S A 2016; 113:E2526-35. [PMID: 27091996 DOI: 10.1073/pnas.1522612113] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3'UTR of FOXO3a and was transcriptionally regulated by NF-κB, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF-κB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.
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30
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Sun J, Zhu M, Shen W, Wang C, Dai J, Xu L, Jin G, Hu Z, Ma H, Shen H. A potentially functional polymorphism in ABCG2 predicts clinical outcome of non-small cell lung cancer in a Chinese population. THE PHARMACOGENOMICS JOURNAL 2016; 17:280-285. [PMID: 26951883 DOI: 10.1038/tpj.2016.2] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Revised: 10/06/2015] [Accepted: 11/26/2015] [Indexed: 12/29/2022]
Abstract
ABCG2, CD133 and CD117 are pivotal markers of cancer stem cell, which are involved in carcinogenesis and cancer progression. The expression of these genes has been reported to be associated with the development and progression of many cancers, including non-small cell lung cancer (NSCLC). We selected and genotyped 9 potentially functional single-nucleotide polymorphisms in the 3 genes in a clinical cohort of 1001 NSCLC patients in a Chinese population. We found that variant genotypes of ABCG2 rs3114020 were associated with a significantly increased risk of death for NSCLC (additive model: adjusted hazard ratio=1.25, 95% confidence intervals=1.10-1.42, P<0.001). Further stepwise regression analysis suggested that rs3114020 was an independent risk factor for the prognosis of NSCLC. Besides, histology interacted with the genetic effect of rs3114020 in relation to NSCLC survival in the interaction analysis. Our findings show that ABCG2 rs3114020 might be one of the candidate biomarkers for NSCLC survival in this Chinese population, especially among patients with adenocarcinoma.
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Affiliation(s)
- J Sun
- Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - M Zhu
- Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - W Shen
- Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - C Wang
- Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - J Dai
- Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - L Xu
- Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, China
| | - G Jin
- Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - Z Hu
- Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - H Ma
- Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing, China
| | - H Shen
- Department of Epidemiology and Biostatistics, Collaborative Innovation Center of Cancer Medicine, School of Public Health, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center of Cancer Medicine, Nanjing Medical University, Nanjing, China
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31
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Abstract
Based on an analysis of a large number of sources of literature, the paper gives general information on the markers for cancer stem cells (CSCs), which allow the detection of this rare cell subpopulation, on the possibilities of estimating their immunohistochemical or immunofluorescent expression in tumors, and on the prognostic and predictive values of these molecules. For their detection, investigators generally use definite molecules, the so-called markers of CSCs, among which there are CD44, CD133, CD24, aldehyde dehydrogenase, and others. The expression of these molecules in the tumor tissue obtained from patients affects survival rates and permits the prediction of a response to therapy. A better insight into the immunophenotype of CSCs, the role of CSC markers in retaining the special properties of this call population, and the clinical significance of the expression of CSC markers will be able to elaborate new approaches to therapy for malignancies.
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Affiliation(s)
- M V Puchinskaya
- Belarusian State Medical University, Minsk, Republic of Belarus
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32
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Baharuddin P, Satar N, Fakiruddin KS, Zakaria N, Lim MN, Yusoff NM, Zakaria Z, Yahaya BH. Curcumin improves the efficacy of cisplatin by targeting cancer stem-like cells through p21 and cyclin D1-mediated tumour cell inhibition in non-small cell lung cancer cell lines. Oncol Rep 2015; 35:13-25. [PMID: 26531053 PMCID: PMC4699625 DOI: 10.3892/or.2015.4371] [Citation(s) in RCA: 92] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2015] [Accepted: 08/18/2015] [Indexed: 01/16/2023] Open
Abstract
Natural compounds such as curcumin have the ability to enhance the therapeutic effectiveness of common chemotherapy agents through cancer stem-like cell (CSC) sensitisation. In the present study, we showed that curcumin enhanced the sensitivity of the double-positive (CD166+/EpCAM+) CSC subpopulation in non-small cell lung cancer (NSCLC) cell lines (A549 and H2170) to cisplatin-induced apoptosis and inhibition of metastasis. Our results revealed that initial exposure of NSCLC cell lines to curcumin (10–40 µM) markedly reduced the percentage of viability to an average of ~51 and ~54% compared to treatment with low dose cisplatin (3 µM) with only 94 and 86% in both the A549 and H2170 cells. Moreover, sensitisation of NSCLC cell lines to curcumin through combined treatment enhanced the single effect induced by low dose cisplatin on the apoptosis of the double-positive CSC subpopulation by 18 and 20% in the A549 and H2170 cells, respectively. Furthermore, we found that curcumin enhanced the inhibitory effects of cisplatin on the highly migratory CD166+/EpCAM+ subpopulation, marked by a reduction in cell migration to 9 and 21% in the A549 and H2170 cells, respectively, indicating that curcumin may increase the sensitivity of CSCs to cisplatin-induced migratory inhibition. We also observed that the mRNA expression of cyclin D1 was downregulated, while a substantial increased in p21 expression was noted, followed by Apaf1 and caspase-9 activation in the double-positive (CD166+/EpCAM+) CSC subpopulation of A549 cells, suggested that the combined treatments induced cell cycle arrest, therefore triggering CSC growth inhibition via the intrinsic apoptotic pathway. In conclusion, we provided novel evidence of the previously unknown therapeutic effects of curcumin, either alone or in combination with cisplatin on the inhibition of the CD166+/EpCAM+ subpopulation of NSCLC cell lines. This finding demonstrated the potential therapeutic approach of using curcumin that may enhance the effects of cisplatin by targeting the CSC subpopulation in NSCLC.
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Affiliation(s)
- Puteri Baharuddin
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Jalan Pahang, Kuala Lumpur 50588, Malaysia
| | - Nazilah Satar
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), University Sains Malaysia, Kepala Batas, Penang 13200, Malaysia
| | - Kamal Shaik Fakiruddin
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Jalan Pahang, Kuala Lumpur 50588, Malaysia
| | - Norashikin Zakaria
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), University Sains Malaysia, Kepala Batas, Penang 13200, Malaysia
| | - Moon Nian Lim
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Jalan Pahang, Kuala Lumpur 50588, Malaysia
| | - Narazah Mohd Yusoff
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), University Sains Malaysia, Kepala Batas, Penang 13200, Malaysia
| | - Zubaidah Zakaria
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Jalan Pahang, Kuala Lumpur 50588, Malaysia
| | - Badrul Hisham Yahaya
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), University Sains Malaysia, Kepala Batas, Penang 13200, Malaysia
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Hadjimichael C, Chanoumidou K, Papadopoulou N, Arampatzi P, Papamatheakis J, Kretsovali A. Common stemness regulators of embryonic and cancer stem cells. World J Stem Cells 2015; 7:1150-1184. [PMID: 26516408 PMCID: PMC4620423 DOI: 10.4252/wjsc.v7.i9.1150] [Citation(s) in RCA: 136] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2015] [Revised: 05/30/2015] [Accepted: 10/08/2015] [Indexed: 02/06/2023] Open
Abstract
Pluripotency of embryonic stem cells (ESCs) and induced pluripotent stem cells is regulated by a well characterized gene transcription circuitry. The circuitry is assembled by ESC specific transcription factors, signal transducing molecules and epigenetic regulators. Growing understanding of stem-like cells, albeit of more complex phenotypes, present in tumors (cancer stem cells), provides a common conceptual and research framework for basic and applied stem cell biology. In this review, we highlight current results on biomarkers, gene signatures, signaling pathways and epigenetic regulators that are common in embryonic and cancer stem cells. We discuss their role in determining the cell phenotype and finally, their potential use to design next generation biological and pharmaceutical approaches for regenerative medicine and cancer therapies.
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Icotinib antagonizes ABCG2-mediated multidrug resistance, but not the pemetrexed resistance mediated by thymidylate synthase and ABCG2. Oncotarget 2015; 5:4529-42. [PMID: 24980828 PMCID: PMC4147343 DOI: 10.18632/oncotarget.2102] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
ABCG2 is a potential biomarker causing multidrug resistance (MDR) in Non-Small Cell Lung Cancer (NSCLC). We conducted this study to investigate whether Icotinib, a small-molecule inhibitor of EGFR tyrosine kinase, could interact with ABCG2 transporter in NSCLC. Our results showed that Icotinib reversed ABCG2-mediated MDR by antagonizing the drug efflux function of ABCG2. Icotinib stimulated the ATPase activity in a concentration-dependent manner and inhibited the photolabeling of ABCG2 with [125I]-Iodoarylazidoprazosin, demonstrating that it interacts at the drug-binding pocket. Homology modeling predicted the binding conformation of Icotinib at Asn629 centroid-based grid of ABCG2. However, Icotinib at reversal concentration did not affect the expression levels of AKT and ABCG2. Furthermore, a combination of Icotinib and topotecan exhibited significant synergistic anticancer activity against NCI-H460/MX20 tumor xenografts. However, the inhibition of transport activity of ABCG2 was insufficient to overcome pemetrexed resistance in NCI-H460/MX20 cells, which was due to the co-upregulated thymidylate synthase (TS) and ABCG2 expression. This is the first report to show that the up-regulation of TS in ABCG2-overexpressing cell line NCI-H460/MX20 may play a role of resistance to pemetrexate. Our findings suggested different possible strategies of overcoming the resistance of topotecan and pemetrexed in the NSCLC patients.
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35
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Zakaria N, Yusoff NM, Zakaria Z, Lim MN, Baharuddin PJN, Fakiruddin KS, Yahaya B. Human non-small cell lung cancer expresses putative cancer stem cell markers and exhibits the transcriptomic profile of multipotent cells. BMC Cancer 2015; 15:84. [PMID: 25881239 PMCID: PMC4349658 DOI: 10.1186/s12885-015-1086-3] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2014] [Accepted: 02/12/2015] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Despite significant advances in staging and therapies, lung cancer remains a major cause of cancer-related lethality due to its high incidence and recurrence. Clearly, a novel approach is required to develop new therapies to treat this devastating disease. Recent evidence indicates that tumours contain a small population of cells known as cancer stem cells (CSCs) that are responsible for tumour maintenance, spreading and resistant to chemotherapy. The genetic composition of CSCs so far is not fully understood, but manipulation of the specific genes that maintain their integrity would be beneficial for developing strategies to combat cancer. Therefore, the goal of this study isto identify the transcriptomic composition and biological functions of CSCs from non-small cell lung cancer (NSCLC). METHODS We isolated putative lung CSCs from lung adenocarcinoma cells (A549 and H2170) and normal stem cells from normal bronchial epithelial cells (PHBEC) on the basis of positive expression of stem cell surface markers (CD166, CD44, and EpCAM) using fluorescence-activated cell sorting. The isolated cells were then characterised for their self-renewal characteristics, differentiation capabilities, expression of stem cell transcription factor and in vivo tumouregenicity. The transcriptomic profiles of putative lung CSCs then were obtained using microarray analysis. Significantly regulated genes (p < 0.05, fold change (FC) > 2.0) in putative CSCs were identified and further analysed for their biological functions using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). RESULTS The putative lung CSCs phenotypes of CD166(+)/CD44(+) and CD166(+)/EpCAM(+) showed multipotent characteristics of stem cells, including the ability to differentiate into adipogenic and osteogenic cells, self-renewal, and expression of stem cell transcription factors such as Sox2 and Oct3/4. Moreover, the cells also shows the in vivo tumouregenicity characteristic when transplanted into nude mice. Microarray and bioinformatics data analyses revealed that the putative lung CSCs have molecular signatures of both normal and cancer stem cells and that the most prominent biological functions are associated with angiogenesis, migration, pro-apoptosis and anti-apoptosis, osteoblast differentiation, mesenchymal cell differentiation, and mesenchyme development. Additionally, self-renewal pathways such as the Wnt and hedgehog signalling pathways, cancer pathways, and extracellular matrix (ECM)-receptor interaction pathways are significantly associated with the putative lung CSCs. CONCLUSION This study revealed that isolated lung CSCs exhibit the characteristics of multipotent stem cells and that their genetic composition might be valuable for future gene and stem cells therapy for lung cancer.
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Affiliation(s)
- Norashikin Zakaria
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Bertam, 13200, Kepala Batas, Pulau Pinang, Malaysia.
| | - Narazah Mohd Yusoff
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Bertam, 13200, Kepala Batas, Pulau Pinang, Malaysia.
| | - Zubaidah Zakaria
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Kuala Lumpur, Malaysia.
| | - Moon Nian Lim
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Kuala Lumpur, Malaysia.
| | - Puteri J Noor Baharuddin
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Kuala Lumpur, Malaysia.
| | - Kamal Shaik Fakiruddin
- Stem Cell Laboratory, Haematology Unit, Cancer Research Centre, Institute for Medical Research (IMR), Kuala Lumpur, Malaysia.
| | - Badrul Yahaya
- Regenerative Medicine Cluster, Advanced Medical and Dental Institute (AMDI), Universiti Sains Malaysia, Bertam, 13200, Kepala Batas, Pulau Pinang, Malaysia.
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36
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High CD133 expression in the nucleus and cytoplasm predicts poor prognosis in non-small cell lung cancer. DISEASE MARKERS 2015; 2015:986095. [PMID: 25691807 PMCID: PMC4323063 DOI: 10.1155/2015/986095] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2014] [Revised: 12/08/2014] [Accepted: 12/22/2014] [Indexed: 01/31/2023]
Abstract
Objective. The aim of this study was to investigate the expression of Prominin-1 (CD133) in cancer cells and its potential value as a prognostic indicator of survival in patients with non-small cell lung cancer (NSCLC). Methods. Cancerous tissues and matched normal tissues adjacent to the carcinoma from 239 NSCLC patients were obtained immediately after surgery. Immunohistochemistry of tissue microarrays was used to characterize the expression of CD133 in NSCLC and adjacent tissues. The correlation of CD133 expression with clinical characteristics and prognosis was determined by statistical analysis. Results. CD133 protein expression levels in both the cytoplasm and nucleus were significantly higher in NSCLC tissues compared with corresponding peritumoral tissue (P < 0.05). CD133 expression in the nucleus of NSCLC cells was related to tumor diameter (P = 0.027), tumor differentiation (P < 0.001), and TNM stage (P = 0.007). Kaplan-Meier survival and Cox regression analyses revealed that high CD133 expression in the nucleus was an independent predictor of poor prognosis of NSCLC, as was high cytoplasmic CD133 expression (P < 0.001). Conclusion. Our findings provide the first evidence that high expression of CD133 in both the nucleus and cytoplasm is associated with poor prognosis in NSCLC.
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37
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Singh S, Chellappan S. Lung cancer stem cells: Molecular features and therapeutic targets. Mol Aspects Med 2014; 39:50-60. [PMID: 24016594 PMCID: PMC3949216 DOI: 10.1016/j.mam.2013.08.003] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2013] [Revised: 08/29/2013] [Accepted: 08/29/2013] [Indexed: 12/28/2022]
Abstract
Lung cancers are highly heterogeneous and resistant to available therapeutic agents, with a five year survival rate of less than 15%. Despite significant advances in our knowledge of the genetic alterations and aberrations in signaling pathways, it has been difficult to determine the basis of lung cancer heterogeneity and drug resistance. Cancer stem cell model has attracted a significant amount of attention in recent years as a viable explanation for the heterogeneity, drug resistance, dormancy and recurrence and metastasis of various tumors. At the same time, cancer stem cells have been relatively less characterized in lung cancers. This review summarizes the current understanding of lung cancer stem cells, including their molecular features and signaling pathways that drive their stemness. This review also discusses the potential startegies to inhibit the signaling pathways driving stemness, in an effort to eradicate these cells to combat lung cancer.
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Affiliation(s)
- Sandeep Singh
- National Institute of Biomedical Genomics (NIBMG), TB Hospital Building, 2nd floor, Kalyani, West Bengal, India
| | - Srikumar Chellappan
- Department of Tumor Biology, H. Lee Moffitt cancer Center and Research Institute, 12902 Magnolia Drive, Tampa, FL 33612, United States.
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38
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Wang S, Ma S, Li X, Xue Z, Zhang X, Fan W, Nie Y, Wu K, Chen X, Cao F. Attenuation of lung cancer stem cell tumorigenesis and metastasis by cisplatin. Exp Lung Res 2014; 40:404-414. [PMID: 25153512 DOI: 10.3109/01902148.2014.938201] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
PURPOSE To investigate the effect of cisplatin on the growth and metastasis abilities of lung cancer stem cells (CSCs) via molecular imaging. MATERIALS AND METHODS The expression changes of lung CSCs cell marker in A549-Luc-C8 human non-small-cell lung cancer (NSCLC) cell line with or without cisplatin treatment were detected by flow cytometry. The tumorigenesis and metastasis abilities of A549-Luc-C8 cells were monitored both in vitro and in vivo, and the mechanism was assessed by gene sequencing. RESULTS About 1%-2% of CSCs were detected in A549-Luc-C8 cells and decreased CSCs percentage was observed after cisplatin treatment. Attenuated tumorigenesis and metastasis abilities of A549-Luc-C8 cells were found in cisplatin treated group. CONCLUSIONS Decreased percentage of CSCs in A549-Luc-C8 cells can be induced by cisplatin treatment, which may partly be attributed to the attenuated expression of growth factors.
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Affiliation(s)
- Shenxu Wang
- Cardiology Department, Chinese PLA General Hospital, Beijing, China.,Cardiology Department, No. 150 Hospital of PLA, LuoYang, Henan, China
| | - Sai Ma
- Cardiology Department, Xijing Hospital, Xi'an, Shaanxi, China
| | - Xiujuan Li
- Cardiology Department, Xijing Hospital, Xi'an, Shaanxi, China
| | - Zengfu Xue
- Digestive Disease Department, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiaotian Zhang
- Cardiology Department, Xijing Hospital, Xi'an, Shaanxi, China
| | - Weiwei Fan
- Cardiology Department, Xijing Hospital, Xi'an, Shaanxi, China
| | - Yongzhan Nie
- Digestive Disease Department, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Kaichun Wu
- Digestive Disease Department, Xijing Hospital, Fourth Military Medical University, Xi'an, Shaanxi, China
| | - Xiaoyuan Chen
- Center for Molecular Imaging and Translational Medicine, School of Public Health, Xiamen University, Xiamen, China
| | - Feng Cao
- Cardiology Department, Chinese PLA General Hospital, Beijing, China.,Cardiology Department, Xijing Hospital, Xi'an, Shaanxi, China
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Wang H, Zheng S, Tu Y, Zhang Y. [Screening and identification of novel drug-resistant genes in CD133+ and CD133- lung adenosarcoma cells using cDNA microarray]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2014; 17:437-43. [PMID: 24949682 PMCID: PMC6000102 DOI: 10.3779/j.issn.1009-3419.2014.06.01] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
背景与目的 肿瘤干细胞可能是肿瘤多药耐药的主要原因，CD133是目前较为公认的肿瘤干细胞标记物。本研究旨在应用功能分类基因芯片筛选CD133+和CD133-肺腺癌细胞中差异表达的肿瘤耐药基因，寻求新的肺癌耐药相关基因。 方法 免疫磁珠分选法分选A549细胞，采用功能分类基因芯片筛选CD133+和CD133-肺腺癌细胞中差异表达的肿瘤耐药基因，并使用RT-qPCR验证。顺铂半数有效抑制浓度（half inhibiting concentration, IC50）、阿霉素IC50作用A549细胞48 h后，RT-qPCR检测肿瘤耐药基因CYP2C19、CYP2D6、CYP2E1、GSK3α、PPARα和PPARβ/δ的表达变化。 结果 共筛查出31个差异表达的肿瘤耐药基因，与CD133-细胞相比，CD133+细胞有30个基因表达上调，1个基因表达下调。RT-qPCR结果与芯片一致。A549细胞经1.97 μg/mL顺铂或0.61 μg/mL阿霉素作用48 h后，CYP2C19、CYP2D6、CYP2E1、GSK3α、PPARα和PPARβ/δ等肿瘤耐药基因表达上调。 结论 利用功能分类基因芯片筛选出31个可能与CD133+肺腺癌细胞耐药相关的基因，其中CYP2C19、CYP2D6、CYP2E1、GSK3α、PPARα和PPARβ/δ为新发现的肺癌耐药相关基因。
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Affiliation(s)
- Hongyan Wang
- Department of Pathology, Guangzhou Medical University, Guangzhou 510182, China
| | - Shaoqiu Zheng
- Department of Pathology, Guangzhou Medical University, Guangzhou 510182, China
| | - Yongsheng Tu
- Department of Physiology, Guangzhou Medical University, Guangzhou 510182, China
| | - Yajie Zhang
- Department of Pathology, Guangzhou Medical University, Guangzhou 510182, China
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Wu H, Qi XW, Yan GN, Zhang QB, Xu C, Bian XW. Is CD133 expression a prognostic biomarker of non-small-cell lung cancer? A systematic review and meta-analysis. PLoS One 2014; 9:e100168. [PMID: 24940615 PMCID: PMC4062503 DOI: 10.1371/journal.pone.0100168] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Accepted: 05/22/2014] [Indexed: 11/18/2022] Open
Abstract
Background The clinical and prognostic significance of CD133 in non-small-cell lung cancer (NSCLC) remains controversial. To clarify a precise determinant of the clinical significance of CD133, we conducted a systematic review and meta-analysis to evaluate the association of CD133 with prognosis and clinicopathological features of NSCLC patients. Methods The electronic and manual searches were performed through the database of Pubmed, Medline, Web of Science, Scopus, and Chinese CNKI (from January 1, 1982 to January 1, 2014) for titles and abstracts by using the following keywords: “CD133”, “ac133” or “Prominin-1”, and “lung cancer” to identify the studies eligible for our analysis. Meta-analysis was performed by using Review Manager 5.0 and the outcomes included the overall survival and various clinicopathological features. Results A total of 23 studies were finally included, and our results showed that CD133 level was significantly correlated with the overall survival (OR = 2.25, 95% CI: 1.24–4.07, P = 0.008) of NSCLC patients but not with the disease free survival (OR = 1.33, 95% CI = 0.77–2.30, P = 0.31). With respect to clinicopathological features, CD133 level was positively correlated with lymph node metastasis (OR = 1.99, 95%CI = 1.06–3.74, P = 0.03), but not correlated with the histological classification (OR = 1.00, 95%CI = 0.81–1.23, P = 0.99(ac), OR = 0.87, 95%CI = 0.61–1.24, P = 0.45(sc)), or differentiation (OR = 0.94, 95%CI 0.53–1.68, Z = 0.20, P = 0.84 random-effect) of NSCLC patients. Conclusion High level of CD133 expression trends to correlate with a worse prognosis and a higher rate of lymph node metastasis in NSCLC patients, revealing CD133 as a potential pathological prognostic marker for NSCLC patients.
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Affiliation(s)
- Hong Wu
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
- Department of Oncology, Chengdu Military General Hospital, Chengdu, Sichuan, China
- Department of Public Health, Luzhou Medical College, Luzhou, Sichuan, China
| | - Xiao-wei Qi
- Breast Disease Center, Southwest Hospital, Third Military Medical University, Chongqing, China
| | - Guang-ning Yan
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
| | - Qing-bi Zhang
- Department of Public Health, Luzhou Medical College, Luzhou, Sichuan, China
- * E-mail: (QBZ); (CX)
| | - Chuan Xu
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
- Department of Oncology, Chengdu Military General Hospital, Chengdu, Sichuan, China
- * E-mail: (QBZ); (CX)
| | - Xiu-wu Bian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, and Key Laboratory of Tumor Immunopathology, Ministry of Education of China, Chongqing, China
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Zhang W, Lei P, Dong X, Xu C. The new concepts on overcoming drug resistance in lung cancer. DRUG DESIGN DEVELOPMENT AND THERAPY 2014; 8:735-44. [PMID: 24944510 PMCID: PMC4057322 DOI: 10.2147/dddt.s60672] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Lung cancer is one of the most deadly diseases worldwide. The current first-line therapies include chemotherapy using epidermal growth factor receptor tyrosine kinase inhibitors and radiotherapies. With the current progress in identifying new molecular targets, acquired drug resistance stands as an obstacle for good prognosis. About half the patients receiving epidermal growth factor receptor-tyrosine kinase inhibitor treatments develop resistance. Although extensive studies have been applied to elucidate the underlying mechanisms, evidence is far from enough to establish a well-defined picture to correct resistance. In the review, we will discuss four different currently developed strategies that have the potential to overcome drug resistance in lung cancer therapies and facilitate prolonged anticancer effects of the first-line therapies.
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Affiliation(s)
- Weisan Zhang
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Ping Lei
- Department of Geriatrics, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Xifeng Dong
- Department of Hematology-Oncology, Tianjin Medical University General Hospital, Tianjin, People's Republic of China
| | - Cuiping Xu
- Qianfoshan Hospital, Shandong University, Jinan, People's Republic of China
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Shao C, Sullivan JP, Girard L, Augustyn A, Yenerall P, Rodriguez-Canales J, Liu H, Behrens C, Shay JW, Wistuba II, Minna JD. Essential role of aldehyde dehydrogenase 1A3 for the maintenance of non-small cell lung cancer stem cells is associated with the STAT3 pathway. Clin Cancer Res 2014; 20:4154-66. [PMID: 24907115 DOI: 10.1158/1078-0432.ccr-13-3292] [Citation(s) in RCA: 120] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
PURPOSE Lung cancer stem cells (CSC) with elevated aldehyde dehydrogenase (ALDH) activity are self-renewing, clonogenic, and tumorigenic. The purpose of our study is to elucidate the mechanisms by which lung CSCs are regulated. EXPERIMENTAL DESIGN A genome-wide gene expression analysis was performed to identify genes differentially expressed in the ALDH(+) versus ALDH -: cells. RT-PCR, Western blot analysis, and Aldefluor assay were used to validate identified genes. To explore the function in CSCs, we manipulated their expression followed by colony and tumor formation assays. RESULTS We identified a subset of genes that were differentially expressed in common in ALDH(+) cells, among which ALDH1A3 was the most upregulated gene in ALDH(+) versus ALDH -: cells. shRNA-mediated knockdown of ALDH1A3 in non-small cell lung cancer (NSCLC) resulted in a dramatic reduction in ALDH activity, clonogenicity, and tumorigenicity, indicating that ALDH1A3 is required for tumorigenic properties. In contrast, overexpression of ALDH1A3 by itself it was not sufficient to increase tumorigenicity. The ALDH(+) cells also expressed more activated STAT3 than ALDH -: cells. Inhibition of STAT3 or its activator EZH2 genetically or pharmacologically diminished the level of ALDH(+) cells and clonogenicity. Unexpectedly, ALDH1A3 was highly expressed in female, never smokers, well-differentiated tumors, or adenocarcinoma. ALDH1A3 low expression was associated with poor overall survival. CONCLUSIONS Our data show that ALDH1A3 is the predominant ALDH isozyme responsible for ALDH activity and tumorigenicity in most NSCLCs, and that inhibiting either ALDH1A3 or the STAT3 pathway are potential therapeutic strategies to eliminate the ALDH(+) subpopulation in NSCLCs.
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Affiliation(s)
- Chunli Shao
- Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center
| | - James P Sullivan
- Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts
| | - Luc Girard
- Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Pharmacology, and
| | - Alexander Augustyn
- Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center
| | - Paul Yenerall
- Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center
| | - Jaime Rodriguez-Canales
- Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston; Departments of
| | - Hui Liu
- Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston; Departments of
| | - Carmen Behrens
- Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston; Departments of
| | | | - Ignacio I Wistuba
- Department of Translational Molecular Pathology, University of Texas M.D. Anderson Cancer Center, Houston; Departments of
| | - John D Minna
- Hamon Center for Therapeutic Oncology Research, Simmons Comprehensive Cancer Center, Pharmacology, and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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Templeton AK, Miyamoto S, Babu A, Munshi A, Ramesh R. Cancer stem cells: progress and challenges in lung cancer. Stem Cell Investig 2014; 1:9. [PMID: 27358855 DOI: 10.3978/j.issn.2306-9759.2014.03.06] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2014] [Accepted: 03/07/2014] [Indexed: 12/17/2022]
Abstract
The identification of a subpopulation of tumor cells with stem cell-like characteristics first in hematological malignancies and later in solid tumors has emerged into a novel field of cancer research. It has been proposed that this aberrant population of cells now called "cancer stem cells" (CSCs) drives tumor initiation, progression, metastasis, recurrence, and drug resistance. CSCs have been shown to have the capacity of self-renewal and multipotency. Adopting strategies from the field of stem cell research has aided in identification, localization, and targeting of CSCs in many tumors. Despite the huge progress in other solid tumors such as brain, breast, and colon cancers no substantial advancements have been made in lung cancer. This is most likely due to the current rudimentary understanding of lung stem cell hierarchy and heterogeneous nature of lung disease. In this review, we will discuss the most recent findings related to identification of normal lung stem cells and CSCs, pathways involved in regulating the development of CSCs, and the importance of the stem cell niche in development and maintenance of CSCs. Additionally, we will examine the development and feasibility of novel CSC-targeted therapeutic strategies aimed at eradicating lung CSCs.
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Affiliation(s)
- Amanda K Templeton
- 1 Department of Pathology, 2 Peggy and Charles Stephenson Cancer Center, 3 Department of Radiation Oncology, 4 Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Shinya Miyamoto
- 1 Department of Pathology, 2 Peggy and Charles Stephenson Cancer Center, 3 Department of Radiation Oncology, 4 Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Anish Babu
- 1 Department of Pathology, 2 Peggy and Charles Stephenson Cancer Center, 3 Department of Radiation Oncology, 4 Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Anupama Munshi
- 1 Department of Pathology, 2 Peggy and Charles Stephenson Cancer Center, 3 Department of Radiation Oncology, 4 Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Rajagopal Ramesh
- 1 Department of Pathology, 2 Peggy and Charles Stephenson Cancer Center, 3 Department of Radiation Oncology, 4 Graduate Program in Biomedical Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
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Tan Y, Chen B, Xu W, Zhao W, Wu J. Clinicopathological significance of CD133 in lung cancer: A meta-analysis. Mol Clin Oncol 2013; 2:111-115. [PMID: 24649317 DOI: 10.3892/mco.2013.195] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2013] [Accepted: 07/09/2013] [Indexed: 11/06/2022] Open
Abstract
CD133 is one of the most commonly used markers of lung cancer stem cells (CSCs), which are characterized by their ability for self-renewal and tumorigenicity. However, the clinical value and significance of CD133 in lung cancer remains controversial. Due to the limited size of the individual studies, the association between CD133 and the clinicopathological characteristics of lung cancer had not been fully elucidated. A meta-analysis based on published studies was performed with the aim of evaluating the effect of CD133 on the clinicopathological characteristics of lung cancer and to investigate the role of CSCs in the prognosis of lung cancer. A total of 15 eligible studies were included in this meta-analysis and our results indicated that a positive CD133 expression was significantly associated with poor differentiation and lymph node metastasis, although it was not associated with tumor stage or histological type. Therefore, CD133 may be considered as a prognostic maker of lung cancer. Further clinical studies, with larger patient samples, unified methods and cut-off levels to detect CD133 expression, classified by tumor stage, therapeutic schedule, follow-up time and survival events, are required to determine the role of CD133 in clinical application and the association between CD133 and the prognosis of lung cancer.
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Affiliation(s)
- Yaoxi Tan
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Bo Chen
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Wei Xu
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Weihong Zhao
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
| | - Jianqing Wu
- Department of Geriatrics, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China
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Alamgeer M, Ganju V, Szczepny A, Russell PA, Prodanovic Z, Kumar B, Wainer Z, Brown T, Schneider-Kolsky M, Conron M, Wright G, Watkins DN. The prognostic significance of aldehyde dehydrogenase 1A1 (ALDH1A1) and CD133 expression in early stage non-small cell lung cancer. Thorax 2013; 68:1095-104. [PMID: 23878161 PMCID: PMC3841805 DOI: 10.1136/thoraxjnl-2012-203021] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Expression of aldehyde dehydrogenase 1A1 (ALDH1A1) and CD133 has been functionally associated with a stem cell phenotype in normal and malignant cells. The prevalence of such cells in solid tumours should therefore correlate with recurrence and/or metastasis following definitive surgical resection. The aim of this study was to evaluate the prognostic significance of ALDH1A1 and CD133 in surgically resected, early stage non-small cell lung cancer (NSCLC). METHODS A retrospective analysis of ALDH1A1 and CD133 expression in 205 patients with pathologic stage I NSCLC was performed using immunohistochemistry. The association between the expression of both markers and survival was determined. RESULTS We identified 62 relapses and 58 cancer-related deaths in 144 stage 1A and 61 stage 1B patients, analysed at a median of 5-years follow-up. Overexpression of ALDH1A1 and CD133, detected in 68.7% and 50.7% of primary tumours, respectively, was an independent prognostic indicator for overall survival by multivariable Cox proportional hazard model (p=0.017 and 0.039, respectively). Overexpression of ALDH1A1, but not of CD133, predicted poor recurrence-free survival (p=0.025). When categorised into three groups according to expression of ALDH1A1/CD133, patients with overexpression of both ALDH1A1 and CD133 belonged to the group with the shortest recurrence-free and overall survival (p=0.015 and 0.017, respectively). CONCLUSIONS Expression of ALDH1A1 and CD133, and coexpression of ALDH1A1 and CD133, is strongly associated with poor survival in early-stage NSCLC following surgical resection. These data are consistent with the hypothesis that expression of stem cell markers correlates with recurrence as an indirect measure of self-renewal capacity.
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Affiliation(s)
- Muhammad Alamgeer
- Department of Medical Oncology, Monash Medical Centre, , East Bentleigh, Melbourne, Australia
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Alamgeer M, Peacock CD, Matsui W, Ganju V, Watkins DN. Cancer stem cells in lung cancer: Evidence and controversies. Respirology 2013; 18:757-64. [PMID: 23586700 PMCID: PMC3991120 DOI: 10.1111/resp.12094] [Citation(s) in RCA: 108] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2013] [Accepted: 04/02/2013] [Indexed: 12/16/2022]
Abstract
The cancer stem cell (CSC) model is based on a myriad of experimental and clinical observations suggesting that the malignant phenotype is sustained by a subset of cells characterized by the capacity for self-renewal, differentiation and innate resistance to chemotherapy and radiation. CSC may be responsible for disease recurrence after definitive therapy and may therefore be functionally synonymous with minimal residual disease. Similar to other solid tumours, several putative surface markers for lung CSC have been identified, including CD133 and CD44. In addition, expression and/or activity of the cytoplasmic enzyme aldehyde dehydrogenase ALDH and capacity of cells to exclude membrane permeable dyes (known as the 'side population') correlate with stem-like function in vitro and in vivo. Embryonic stem cell pathways such as Hedgehog, Notch and WNT may also be active in lung cancers stem cells and therefore may be therapeutically targetable for maintenance therapy in patients achieving a complete response to surgery, radiotherapy or chemotherapy. This paper will review the evidence regarding the existence and function of lung CSC in the context of the experimental and clinical evidence and discuss some ongoing controversies regarding this model.
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Affiliation(s)
- Muhammad Alamgeer
- Department of Medical Oncology, Monash Medical Centre, East Bentleigh, Australia
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Ren F, Sheng WQ, Du X. CD133: A cancer stem cells marker, is used in colorectal cancers. World J Gastroenterol 2013; 19:2603-2611. [PMID: 23674867 PMCID: PMC3645378 DOI: 10.3748/wjg.v19.i17.2603] [Citation(s) in RCA: 129] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/24/2012] [Revised: 02/03/2013] [Accepted: 02/07/2013] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is one of the most common malignant tumors worldwide. A model of cancer development involving cancer stem cells has been put forward because it provides a possible explanation of tumor hierarchy. Cancer stem cells are characterized by their proliferation, tumorigenesis, differentiation, and self-renewal capacities, and chemoradiotherapy resistance. Due to the role of cancer stem cells in tumor initiation and treatment failure, studies of cancer stem cell markers, such as CD133, have been of great interest. CD133, a five-transmembrane glycoprotein, is widely used as a marker to identify and isolate colorectal cancer stem cells. This marker has been investigated to better understand the characteristics and functions of cancer stem cells. Moreover, it can also be used to predict tumor progression, patient survival, chemoradiotherapy resistance and other clinical parameters. In this review, we discuss the use of CD133 in the identification of colorectal cancer stem cell, which is currently controversial. Although the function of CD133 is as yet unclear, we have discussed several possible functions and associated mechanisms that may partially explain the role of CD133 in colorectal cancers. In addition, we focus on the prognostic value of CD133 in colorectal cancers. Finally, we predict that CD133 may be used as a possible target for colorectal cancer treatment.
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Mia-Jan K, Jung SY, Kim IY, Oh SS, Choi E, Chang SJ, Kang TY, Cho MY. CD133 expression is not an independent prognostic factor in stage II and III colorectal cancer but may predict the better outcome in patients with adjuvant therapy. BMC Cancer 2013; 13:166. [PMID: 23537343 PMCID: PMC3621413 DOI: 10.1186/1471-2407-13-166] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2012] [Accepted: 03/21/2013] [Indexed: 02/07/2023] Open
Abstract
Background Cancer stem cells (CSCs) are notorious for their capacity of tumor progression, metastasis or resistance to chemo-radiotherapy. However, the undisputed role of cancer stem marker, CD133, in colorectal cancers (CRCs) is not clear yet. Methods We assessed 271 surgically-resected stage II and III primary CRCs with (171) and without (100) adjuvant therapy after surgery. CD133 expression was analyzed by immunohistochemical (IHC) staining and real-time RT-PCR. CD133 promoter methylation was quantified by pyrosequencing. Results The CD133 IHC expression was significantly correlated with mRNA expression (p=0.0257) and inversely correlated with the promoter methylation (p=0.0001). CD133 was expressed more frequently in rectal cancer (p=0.0035), and in moderately differentiated tumors (p=0.0378). In survival analysis, CD133 expression was not significantly correlated with overall survival (OS) (p=0.9689) as well as disease-free survival (DFS) (p=0.2103). However, CD133+ tumors were significantly associated with better OS in patients with adjuvant therapy compared to those without adjuvant therapy (p<0.0001, HR 0.125, 95% CI 0.052-0.299). But the patients with CD133- tumors did not show any significant difference of survival according to adjuvant therapy (p=0.055, HR 0.500, 95% CI 0.247-1.015). Conclusions In stage II and III CRCs, CD133 IHC expression may signify the benefit for adjuvant therapy although it is not an independent prognostic factor.
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Affiliation(s)
- Khalilullah Mia-Jan
- Department of Pathology, Yonsei University Wonju College of Medicine, Wonju, South Korea
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Okamoto H, Fujishima F, Nakamura Y, Zuguchi M, Ozawa Y, Takahashi Y, Miyata G, Kamei T, Nakano T, Taniyama Y, Teshima J, Watanabe M, Sato A, Ohuchi N, Sasano H. Significance of CD133 expression in esophageal squamous cell carcinoma. World J Surg Oncol 2013; 11:51. [PMID: 23448401 PMCID: PMC3599647 DOI: 10.1186/1477-7819-11-51] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 02/12/2013] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND CD133 was recently reported to be a cancer stem cell marker and a prognostic marker for several tumors. However, few studies have investigated CD133 expression in esophageal squamous cell carcinoma (ESCC). Therefore, we examined whether CD133 could serve as a prognostic marker of ESCC and investigated the correlation between CD133 expression and the clinicopathological findings of ESCC patients and several markers. METHODS We studied 86 ESCC patients who underwent curative surgery without neoadjuvant treatment at Tohoku University Hospital (Sendai, Japan) between January 2000 and December 2005. We analyzed tissue specimens by immunohistochemical staining for CD133, p53, p16, p27, murine double minute 2 (MDM2), Ki-67, and epidermal growth factor receptor (EGFR). RESULTS Pathological tumor depth and tumor stage were significantly more advanced among CD133-negative patients than among CD133-positive patients. A log-rank test showed that CD133 immunoreactivity was significantly correlated with the overall survival of the patients (P = 0.049). However, multivariate analysis showed that it was not significantly correlated (P = 0.078). Moreover, CD133 was significantly positively correlated with p27 immunoreactivity (P = 0.0013) and tended to be positively correlated with p16 immunoreactivity (P = 0.057). In addition, p16 immunoreactivity was correlated with smoking history (P = 0.018), pathological lymph node status (P = 0.033), and lymphatic invasion (P = 0.018). CONCLUSIONS This study indicated that CD133 immunoreactivity is a good predictor of prognosis in ESCC patients. In addition, CD133 may play a role in the regulation of tumor cell cycle through p27 and p16 in ESCC. At present, it thus remains controversial whether CD133 expression is a valid prognostic marker for ESCC. To elucidate this relationship, further investigations are required.
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Affiliation(s)
- Hiroshi Okamoto
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
- Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Fumiyoshi Fujishima
- Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Yasuhiro Nakamura
- Department of Pathology, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
| | - Masashi Zuguchi
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Yohei Ozawa
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Yayoi Takahashi
- Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Go Miyata
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Takashi Kamei
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Toru Nakano
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Yusuke Taniyama
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Jin Teshima
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Mika Watanabe
- Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Akira Sato
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Noriaki Ohuchi
- Division of Advanced Surgical Science and Technology, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
| | - Hironobu Sasano
- Department of Pathology, Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan
- Department of Pathology, Graduate School of Medicine, Tohoku University, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan
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Lung. Regen Med 2013. [DOI: 10.1007/978-94-007-5690-8_34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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