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1
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Wang G, Chen Z, Tian Y, Zhu Y, Wang S, Song W, Wang X, Li Y. Multi-Omics Profiling Identifies a High-Risk Subgroup of Breast Cancer Stem Cells for Prognostic Stratification and Personalized Treatment. J Cancer 2025; 16:1860-1872. [PMID: 40092692 PMCID: PMC11905410 DOI: 10.7150/jca.109589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2024] [Accepted: 02/16/2025] [Indexed: 03/19/2025] Open
Abstract
Background: Breast cancer is the most prevalent malignancy among females worldwide. Extensive research has highlighted cancer stem cells (CSCs) as critical drivers of tumor initiation, progression, recurrence, and therapy resistance. However, the heterogeneity of breast cancer stem cells (BCSCs) and their dynamic roles within the tumor microenvironment remain inadequately understood. Methods: This study utilized the single-cell RNA sequencing dataset to categorize BCSCs into two subgroups within the breast cancer microenvironment and investigate their pseudo-time developmental dynamics. Bulk transcriptomic data from TCGA-BRCA were integrated to assess the prognostic significance and infiltration abundance of the BCSCs-2 subgroup. Functional enrichment, co-expression network analysis, and somatic mutation profiling were performed to elucidate key biological pathways and genetic features. Additionally, drug sensitivity analyses were conducted using the Connectivity Map database to identify potential therapeutic strategies. Results: A total of 459 BCSCs were identified and further classified into two distinct subpopulations: BCSCs-1 and BCSCs-2. High infiltration of BCSCs-2 was associated with poor prognosis and an immunosuppressive tumor microenvironment. Co-expression network analysis identified 16 key genes linked to BCSCs-2, while somatic mutation analysis revealed distinct mutation patterns associated with its infiltration. Drug sensitivity analysis suggested that patients with high BCSCs-2 infiltration could benefit from classical chemotherapy agents, such as Cisplatin, and other novel therapeutic compounds. Conclusions: This study offers novel insights into the heterogeneity and functional roles of BCSCs in breast cancer. The findings highlight the prognostic and therapeutic importance of the BCSCs-2 subgroup, providing potential biomarkers and therapeutic targets for precision medicine in breast cancer management.
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Affiliation(s)
- Guixin Wang
- The First Department of Breast Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China
| | - Ziyi Chen
- Department of Thoracic Oncology, Tianjin Lung Cancer Center, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China
| | - Yao Tian
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin General Surgery Institute, Tianjin, 300052, China
| | - Yuxin Zhu
- Tianjin Medical University, Tianjin, 300070, China
| | - Shuo Wang
- The First Department of Breast Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China
| | - Wenbin Song
- Department of General Surgery, Tianjin Medical University General Hospital, Tianjin Key Laboratory of Precise Vascular Reconstruction and Organ Function Repair, Tianjin General Surgery Institute, Tianjin, 300052, China
| | - Xin Wang
- The First Department of Breast Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, National Clinical Research Center for Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin Medical University, Tianjin, 300060, China
| | - Yingxi Li
- Immunology Department, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Tianjin Medical University, Tianjin, 300070, China
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2
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Verdugo-Sivianes EM, Espinosa-Sánchez A, Cases I, Rojas AM, Otero-Albiol D, Romero L, Blanco JR, Carnero A. MEG8 as an antagonistic pleiotropic mechanism in breast cancer. Cell Death Discov 2024; 10:509. [PMID: 39706842 DOI: 10.1038/s41420-024-02272-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 12/05/2024] [Accepted: 12/10/2024] [Indexed: 12/23/2024] Open
Abstract
Cellular senescence connects aging and cancer. Cellular senescence is a common program activated by cells in response to various types of stress. During this process, cells lose their proliferative capacity and undergo distinct morphological and metabolic changes. Senescence itself constitutes a tumor suppression mechanism and plays a significant role in organismal aging by promoting chronic inflammation. Additionally, age is one of the major risk factors for developing breast cancer. Therefore, while senescence can suppress tumor development early in life, it can also lead to an aging process that drives the development of age-related pathologies, suggesting an antagonistic pleiotropic effect. In this work, we identified Rian/MEG8 as a potential biomarker connecting aging and breast cancer for the first time. We found that Rian/MEG8 expression decreases with age; however, it is high in mice that age prematurely. We also observed decreased MEG8 expression in breast tumors compared to normal tissue. Furthermore, MEG8 overexpression reduced the proliferative and stemness properties of breast cancer cells both in vitro and in vivo by activating apoptosis. MEG8 could exemplify the antagonistic pleiotropic theory, where senescence is beneficial early in life as a tumor suppression mechanism due to increased MEG8, resulting in fewer breast tumors at an early age. Conversely, this effect could be detrimental later in life due to aging and cancer, when MEG8 is reduced and loses its tumor-suppressive role.
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Affiliation(s)
- Eva M Verdugo-Sivianes
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville, 41013, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, 28029, Spain
- Departamento de Ciencias de la Salud y Biomédicas, Facultad de Ciencias de la Salud, Universidad Loyola Andalucía, Avda. de las Universidades s/n, 41704, Dos Hermanas, Sevilla, Spain
| | - Asunción Espinosa-Sánchez
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville, 41013, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - Ildefonso Cases
- Centro Andaluz de Biología del Desarrollo (CABD), CSIC-Universidad Pablo de Olavide, Sevilla, Spain
| | - Ana M Rojas
- Centro Andaluz de Biología del Desarrollo (CABD), CSIC-Universidad Pablo de Olavide, Sevilla, Spain
| | - Daniel Otero-Albiol
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville, 41013, Spain
- CIBERONC, Instituto de Salud Carlos III, Madrid, 28029, Spain
| | - Lourdes Romero
- Hospital Universitario San Pedro, 26006, Logroño, Spain
- Centro de Investigación Biomédica de La Rioja (CIBIR), 26006, Logroño, Spain
| | - José Ramón Blanco
- Hospital Universitario San Pedro, 26006, Logroño, Spain
- Centro de Investigación Biomédica de La Rioja (CIBIR), 26006, Logroño, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío (HUVR), Consejo Superior de Investigaciones Científicas, Universidad de Sevilla, Seville, 41013, Spain.
- CIBERONC, Instituto de Salud Carlos III, Madrid, 28029, Spain.
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3
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Guo Q, Qiu P, Pan K, Liang H, Liu Z, Lin J. Integrated machine learning algorithms identify KIF15 as a potential prognostic biomarker and correlated with stemness in triple-negative breast cancer. Sci Rep 2024; 14:21449. [PMID: 39271768 PMCID: PMC11399402 DOI: 10.1038/s41598-024-72406-y] [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: 04/17/2024] [Accepted: 09/06/2024] [Indexed: 09/15/2024] Open
Abstract
Cancer stem cells (CSCs) have the potential to self-renew and induce cancer, which may contribute to a poor prognosis by enabling metastasis, recurrence, and therapy resistance. Hence, this study was performed to identify the association between CSC-related genes and triple-negative breast cancer (TNBC) development. Stemness gene sets were downloaded from StemChecker. Based on the online databases, a consensus clustering algorithm was conducted for unsupervised classification of TNBC samples. The variations between subtypes were assessed with regard to prognosis, tumor immune microenvironment (TIME), and chemotherapeutic sensitivity. The stemness-related gene signature was established and random survival forest analysis was employed to identify the core gene for validation experiments and tumor sphere formation assays. 499 patients with TNBC were classified into three subgroups and the Cluster 1 had a better OS than others. After that, WGCNA study was performed to identify genes important for Cluster 1 subtype. Out of all 8 modules, the subtype of Cluster 1 and the yellow module with 103 genes demonstrated the largest positive association. After that, a four-gene stemness-related signature was established. Based on the yellow module, the 39 potential pivotal genes were subjected to the random forest survival analysis to find out the gene that was relatively important for OS. KIF15 was confirmed as the targeted gene by LASSO and random survival forest analyses. In vitro experiments, the downregulation of KIF15 promoted the stemness of TNBC cells. The expression levels of stem cell markers Nanog, SOX2, and OCT4 were found to be elevated in TNBC cell lines after KIF15 inhibition. A stemness-associated risk model was constructed to forecast the clinical outcomes of TNBC patients. The downregulation of KIF15 expression in a subpopulation of TNBC stem cells may promote stemness and possibly TNBC progression.
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Affiliation(s)
- Qiaonan Guo
- Department of Breast and Thyroid Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Pengjun Qiu
- Department of Breast and Thyroid Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Kelun Pan
- Department of Breast and Thyroid Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Huikai Liang
- Department of Breast and Thyroid Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - Zundong Liu
- Stem Cell Laboratory, Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
| | - Jianqing Lin
- Department of Breast and Thyroid Surgery, Second Affiliated Hospital of Fujian Medical University, Quanzhou, China.
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4
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Parambil ST, Antony GR, Littleflower AB, Subhadradevi L. The molecular crosstalk of the hippo cascade in breast cancer: A potential central susceptibility. Biochimie 2024; 222:132-150. [PMID: 38494109 DOI: 10.1016/j.biochi.2024.03.008] [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: 01/22/2024] [Revised: 03/06/2024] [Accepted: 03/14/2024] [Indexed: 03/19/2024]
Abstract
The incidence of breast cancer is perpetually growing globally, and it remains a major public health problem and the leading cause of mortality in women. Though the aberrant activities of the Hippo pathway have been reported to be associated with cancer, constructive knowledge of the pathway connecting the various elements of breast cancer remains to be elucidated. The Hippo transducers, yes-associated protein (YAP) and transcriptional co-activator with PDZ binding motif (TAZ), are reported to be either tumor suppressors, oncogenes, or independent prognostic markers in breast cancer. Thus, there is further need for an explicative evaluation of the dilemma with this molecular contribution of Hippo transducers in modulating breast malignancy. In this review, we summarize the intricate crosstalk of the Hippo pathway in different aspects of breast malignancy, including stem-likeness, cellular signaling, metabolic adaptations, tumor microenvironment, and immune responses. The collective data shows that Hippo transducers play an indispensable role in mammary tumor formation, progression, and dissemination. However, the cellular functions of YAP/TAZ in tumorigenesis might be largely dependent on the mechanical and biophysical cues they interact with, as well as on the cell phenotype. This review provides a glimpse into the plausible biological contributions of the cascade to the inward progression of breast carcinoma and suggests potential therapeutic prospects.
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Affiliation(s)
- Sulfath Thottungal Parambil
- Laboratory of Molecular Medicine, Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, 695011, Kerala, India
| | - Gisha Rose Antony
- Laboratory of Molecular Medicine, Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, 695011, Kerala, India
| | - Ajeesh Babu Littleflower
- Laboratory of Molecular Medicine, Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, 695011, Kerala, India
| | - Lakshmi Subhadradevi
- Laboratory of Molecular Medicine, Division of Cancer Research, Regional Cancer Centre (Research Centre, University of Kerala), Thiruvananthapuram, 695011, Kerala, India.
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5
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Ariffin NS. Increased RUNX1 mutations in breast cancer disease progression. Pathol Res Pract 2024; 254:155076. [PMID: 38219493 DOI: 10.1016/j.prp.2023.155076] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2023] [Revised: 12/29/2023] [Accepted: 12/30/2023] [Indexed: 01/16/2024]
Abstract
Despite advances in screening, therapy and surveillance, breast cancer remains threatening to women. Worst, patients suffer from side effects of treatments and cancer cells become resistant. The emergence of RUNX1 in breast cancer has put it in a spotlight due to its roles in the disease progression. It also plays important roles in normal mammary glands such as for cell growth, proliferation, migration and stemness. However, mutations in the RUNX1 gene have changed the regulation of these phenotypes and the full spectrum of its implications in breast cancer patients is unknown. In this study therefore, the pattern of RUNX1 mutations in breast cancer patients was examined to understand its fundamental impacts on the disease. The perturbation of RUNX1 and its mutations in breast cancer was elucidated through different studies reported in cBioPortal in the past ten years. From our analyses, the majority of RUNX1 mutations were found in the primary breast cancer, with women constituted most of the mutations, especially on the left side of the breast. Similarly, increased number of mutations was observed in ER-positive breast cancer patients and this was also the case at the early stage of the disease development. The level of RUNX1 mutations also increased gradually as patients got older and the peak was highest in the patients of 60-70 years old. Altogether, these data indicated that the mutated RUNX1 gene contributed to the progression of breast cancer and understanding of its regulatory mechanisms is crucial to therapeutically target this gene in the future.
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Affiliation(s)
- Nur Syamimi Ariffin
- Department of Pharmacology and Pharmaceutical Chemistry, Faculty of Pharmacy, Universiti Teknologi MARA, 42300 Bandar Puncak Alam, Selangor, Malaysia.
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6
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Yaghjyan L, Heng YJ, Baker GM, Murthy D, Mahoney MB, Rosner B, Tamimi RM. Associations of stem cell markers in benign breast tissue with subsequent breast cancer risk. Am J Cancer Res 2023; 13:6280-6289. [PMID: 38187066 PMCID: PMC10767353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 11/06/2023] [Indexed: 01/09/2024] Open
Abstract
We examined associations of stem cell markers CD44, CD24, and ALDH1A1 in benign breast biopsy samples with subsequent breast cancer (BCa) risk and explored if these associations were mediated by mammographic breast density (MBD). We included 101 BCa cases/375 controls, all with previous biopsy-confirmed benign breast disease (BBD) within the Nurses' Health Study (NHS) and NHSII. The data on BCa risk factors were obtained from biennial questionnaires. MBD was assessed with computer-assisted techniques. Immunohistochemistry (IHC) was done on BBD tissue microarrays. For each core, the IHC expression was assessed using a semi-automated method, and expressed as % of cells that stained positive for a specific marker out of the total cell count. Logistic regression was used to examine the associations of each marker's expression of each (in epithelium and stroma) with BCa risk, adjusted for risk factors. Stromal CD44 expression was inversely associated with BCa risk (OR for ≥10% vs. <10%=0.58, 95% CI 0.34, 1.00). Combined stromal + epithelial CD24 expression was inversely associated with BCa risk (>50% vs. 0-10% OR=0.17, 95% CI 0.04-0.81, p-trend =0.03). Stromal CD24 and ALDH1A1 as well as epithelial expression of any of the three markers were not associated with BCa risk. In a smaller subset of women with available MBD, these observed associations did not appear to be mediated by MBD. Our findings suggest inverse associations of CD44 in stroma and combined stromal + epithelial CD24 with BCa risk. Future studies are warranted to confirm our findings and to examine these associations by BBD subtype.
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Affiliation(s)
- Lusine Yaghjyan
- Department of Epidemiology, College of Public Health and Health Professions and College of Medicine, University of FloridaGainesville, FL, USA
| | - Yujing J Heng
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolBoston, MA, USA
| | - Gabrielle M Baker
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical SchoolBoston, MA, USA
| | - Divya Murthy
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical SchoolBoston, MA, USA
| | - Matt B Mahoney
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical SchoolBoston, MA, USA
| | - Bernard Rosner
- Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical SchoolBoston, MA, USA
| | - Rulla M Tamimi
- Department of Population Health Sciences, Weill Cornell MedicineNew York, NY, USA
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7
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Andreani C, Bartolacci C, Persico G, Casciaro F, Amatori S, Fanelli M, Giorgio M, Galié M, Tomassoni D, Wang J, Zhang X, Bick G, Coppari R, Marchini C, Amici A. SIRT6 promotes metastasis and relapse in HER2-positive breast cancer. Sci Rep 2023; 13:22000. [PMID: 38081972 PMCID: PMC10713583 DOI: 10.1038/s41598-023-49199-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 12/05/2023] [Indexed: 12/18/2023] Open
Abstract
The histone deacetylase sirtuin 6 (SIRT6) has been endowed with anti-cancer capabilities in many tumor types. Here, we investigate the impact of SIRT6-overexpression (SIRT6-OE) in Delta16HER2 mice, which are a bona fide model of HER2-positive breast cancer. After an initial delay in the tumor onset, SIRT6-OE induces a more aggressive phenotype of Delta16HER2 tumors promoting the formation of higher number of tumor foci and metastases than controls. This phenotype of SIRT6-OE tumors is associated with cancer stem cell (CSC)-like features and tumor dormancy, and low senescence and oxidative DNA damage. Accordingly, a sub-set of HER2-positive breast cancer patients with concurrent SIRT6-OE has a significant poorer relapse-free survival (RFS) probability than patients with low expression of SIRT6. ChIP-seq, RNA-seq and RT-PCR experiments indicate that SIRT6-OE represses the expression of the T-box transcription factor 3 (Tbx3) by deacetylation of H3K9ac. Accordingly, loss-of-function mutations of TBX3 or low TBX3 expression levels are predictive of poor prognosis in HER2-positive breast cancer patients. Our work indicates that high levels of SIRT6 are indicative of poor prognosis and high risk of metastasis in HER2-positive breast cancer and suggests further investigation of TBX3 as a downstream target of SIRT6 and co-marker of poor-prognosis. Our results point to a breast cancer subtype-specific effect of SIRT6 and warrant future studies dissecting the mechanisms of SIRT6 regulation in different breast cancer subtypes.
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Affiliation(s)
- Cristina Andreani
- Department of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy.
- Department of Internal Medicine, University of Cincinnati, 45219, Cincinnati, OH, USA.
| | - Caterina Bartolacci
- Department of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
- Department of Internal Medicine, University of Cincinnati, 45219, Cincinnati, OH, USA
| | - Giuseppe Persico
- Department of Experimental Oncology, IRCCS-European Institute of Oncology, Via Adamello 16, 20139, Milano, Italy
| | - Francesca Casciaro
- Department of Biomedical Sciences, University of Padua, Via Ugo Bassi 58/B, 35131, Padua, Italy
| | - Stefano Amatori
- Molecular Pathology Laboratory "PaoLa", Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61032, Fano, Italy
| | - Mirco Fanelli
- Molecular Pathology Laboratory "PaoLa", Department of Biomolecular Sciences, University of Urbino Carlo Bo, 61032, Fano, Italy
| | - Marco Giorgio
- Department of Experimental Oncology, IRCCS-European Institute of Oncology, Via Adamello 16, 20139, Milano, Italy
- Department of Biomedical Sciences, University of Padua, Via Ugo Bassi 58/B, 35131, Padua, Italy
| | - Mirco Galié
- Department of Neuroscience, Biomedicine and Movement, Section of Anatomy and Histology, University of Verona, 37134, Verona, Italy
| | - Daniele Tomassoni
- Department of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
| | - Junbiao Wang
- Department of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
| | - Xiaoting Zhang
- Department of Cancer Biology, University of Cincinnati, 45219, Cincinnati, OH, USA
| | - Gregory Bick
- Department of Cancer Biology, University of Cincinnati, 45219, Cincinnati, OH, USA
| | - Roberto Coppari
- Department of Cell Physiology and Metabolism, University of Geneva, 1211, Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva, 1211, Geneva, Switzerland
| | - Cristina Marchini
- Department of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy.
| | - Augusto Amici
- Department of Biosciences and Veterinary Medicine, University of Camerino, 62032, Camerino, Italy
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8
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Zhao H, Han R, Wang Z, Xian J, Bai X. Colorectal Cancer Stem Cells and Targeted Agents. Pharmaceutics 2023; 15:2763. [PMID: 38140103 PMCID: PMC10748092 DOI: 10.3390/pharmaceutics15122763] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2023] [Revised: 11/30/2023] [Accepted: 12/07/2023] [Indexed: 12/24/2023] Open
Abstract
Since their discovery, cancer stem cells have become a hot topic in cancer therapy research. These cells possess stem cell-like self-renewal and differentiation capacities and are important factors that dominate cancer metastasis, therapy-resistance and recurrence. Worse, their inherent characteristics make them difficult to eliminate. Colorectal cancer is the third-most common cancer and the second leading cause of cancer death worldwide. Targeting colorectal cancer stem cells (CR-CSCs) can inhibit colorectal cancer metastasis, enhance therapeutic efficacy and reduce recurrence. Here, we introduced the origin, biomarker proteins, identification, cultivation and research techniques of CR-CSCs, and we summarized the signaling pathways that regulate the stemness of CR-CSCs, such as Wnt, JAK/STAT3, Notch and Hh signaling pathway. In addition to these, we also reviewed recent anti-CR-CSC drugs targeting signaling pathways, biomarkers and other regulators. These will help researchers gain insight into the current agents targeting to CR-CSCs, explore new cancer drugs and propose potential therapies.
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Affiliation(s)
- Haobin Zhao
- Department of General Practice, People’s Hospital of Longhua, 38 Jinglong Jianshe Road, Shenzhen 518109, China; (H.Z.); (J.X.)
- Endocrinology Department, People’s Hospital of Longhua, 38 Jinglong Jianshe Road, Shenzhen 518109, China
| | - Ruining Han
- Obstetric Department, The Eighth Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518033, China;
| | - Zhankun Wang
- Emergency Department, People’s Hospital of Longhua, 38 Jinglong Jianshe Road, Shenzhen 518109, China;
| | - Junfang Xian
- Department of General Practice, People’s Hospital of Longhua, 38 Jinglong Jianshe Road, Shenzhen 518109, China; (H.Z.); (J.X.)
| | - Xiaosu Bai
- Endocrinology Department, People’s Hospital of Longhua, 38 Jinglong Jianshe Road, Shenzhen 518109, China
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9
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Johnson B. Targeting Myeloid-Derived Suppressor Cell Trafficking as a Novel Immunotherapeutic Approach in Microsatellite Stable Colorectal Cancer. Cancers (Basel) 2023; 15:5484. [PMID: 38001744 PMCID: PMC10670242 DOI: 10.3390/cancers15225484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 11/07/2023] [Accepted: 11/16/2023] [Indexed: 11/26/2023] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) are a unique subset of immune cells that promote an immunosuppressive phenotype due to their impacts on CD8 and regulatory T cell function. The inhibition of MDSC trafficking to the tumor microenvironment (TME) may represent a novel target in microsatellite stable (MSS) colorectal cancer with the potential to reprogram the immune system. Here, we review the rationale of inhibiting myeloid suppressor cell trafficking in treatment-refractory MSS colorectal cancer and circulating tumor DNA (ctDNA) positive settings to determine whether this approach can serve as a backbone for promoting immunotherapy response in this difficult-to-treat disease.
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Affiliation(s)
- Benny Johnson
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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10
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Hamid R, Alaziz M, Mahal AS, Ashton AW, Halama N, Jaeger D, Jiao X, Pestell RG. The Role and Therapeutic Targeting of CCR5 in Breast Cancer. Cells 2023; 12:2237. [PMID: 37759462 PMCID: PMC10526962 DOI: 10.3390/cells12182237] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2023] [Revised: 08/17/2023] [Accepted: 08/24/2023] [Indexed: 09/29/2023] Open
Abstract
The G-protein-coupled receptor C-C chemokine receptor 5 (CCR5) functions as a co-receptor for the entry of HIV into immune cells. CCR5 binds promiscuously to a diverse array of ligands initiating cell signaling that includes guided migration. Although well known to be expressed on immune cells, recent studies have shown the induction of CCR5 on the surface of breast cancer epithelial cells. The function of CCR5 on breast cancer epithelial cells includes the induction of aberrant cell survival signaling and tropism towards chemo attractants. As CCR5 is not expressed on normal epithelium, the receptor provides a potential useful target for therapy. Inhibitors of CCR5 (CCR5i), either small molecules (maraviroc, vicriviroc) or humanized monoclonal antibodies (leronlimab) have shown anti-tumor and anti-metastatic properties in preclinical studies. In early clinical studies, reviewed herein, CCR5i have shown promising results and evidence for effects on both the tumor and the anti-tumor immune response. Current clinical studies have therefore included combination therapy approaches with checkpoint inhibitors.
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Affiliation(s)
- Rasha Hamid
- Xavier University School of Medicine, Oranjestad, Aruba (A.S.M.)
| | - Mustafa Alaziz
- Xavier University School of Medicine, Oranjestad, Aruba (A.S.M.)
| | | | - Anthony W. Ashton
- Xavier University School of Medicine, Oranjestad, Aruba (A.S.M.)
- Lightseed Inc., Wynnewood, PA 19096, USA
- Lankenau Institute for Medical Research Philadelphia, Wynnewood, PA 19096, USA
| | - Niels Halama
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, 69120 Heidelberg, Germany; (N.H.); (D.J.)
- Department of Translational Immunotherapy, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Dirk Jaeger
- Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg University Hospital, 69120 Heidelberg, Germany; (N.H.); (D.J.)
- Clinical Cooperation Unit Applied Tumor-Immunity, 69120 Heidelberg, Germany
| | - Xuanmao Jiao
- Xavier University School of Medicine, Oranjestad, Aruba (A.S.M.)
- Lightseed Inc., Wynnewood, PA 19096, USA
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA
| | - Richard G. Pestell
- Xavier University School of Medicine, Oranjestad, Aruba (A.S.M.)
- Lightseed Inc., Wynnewood, PA 19096, USA
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA 19096, USA
- The Wistar Cancer Center, Philadelphia, PA 19107, USA
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11
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Nairuz T, Mahmud Z, Manik RK, Kabir Y. Cancer stem cells: an insight into the development of metastatic tumors and therapy resistance. Stem Cell Rev Rep 2023:10.1007/s12015-023-10529-x. [PMID: 37129728 DOI: 10.1007/s12015-023-10529-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/09/2023] [Indexed: 05/03/2023]
Abstract
The term "cancer stem cells" (CSCs) refers to cancer cells that exhibit traits parallel to normal stem cells, namely the potential to give rise to every type of cell identified in a tumor microenvironment. It has been found that CSCs usually develops from other neoplastic cells or non-cancerous somatic cells by acquiring stemness and malignant characteristics through particular genetic modifications. A trivial number of CSCs, identified in solid and liquid cancer, can give rise to an entire tumor population with aggressive anticancer drug resistance, metastasis, and invasiveness. Besides, cancer stem cells manipulate their intrinsic and extrinsic features, regulate the metabolic pattern of the cell, adjust efflux-influx efficiency, modulate different signaling pathways, block apoptotic signals, and cause genetic and epigenetic alterations to retain their pluripotency and ability of self-renewal. Notably, to keep the cancer stem cells' ability to become malignant cells, mesenchymal stem cells, tumor-associated fibroblasts, immune cells, etc., interact with one another. Furthermore, CSCs are characterized by the expression of particular molecular markers that carry significant diagnostic and prognostic significance. Because of this, scientific research on CSCs is becoming increasingly imperative, intending to understand the traits and behavior of cancer stem cells and create more potent anticancer therapeutics to fight cancer at the CSC level. In this review, we aimed to elucidate the critical role of CSCs in the onset and spread of cancer and the characteristics of CSCs that promote severe resistance to targeted therapy.
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Affiliation(s)
- Tahsin Nairuz
- Department of Biochemistry and Molecular Biology, Noakhali Science and Technology University, Noakhali, Bangladesh
| | - Zimam Mahmud
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Rasel Khan Manik
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh
| | - Yearul Kabir
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, 1000, Bangladesh.
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12
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Antmen E, Ermis M, Kuren O, Beksac K, Irkkan C, Hasirci V. Nuclear Deformability of Breast Cells Analyzed from Patients with Malignant and Benign Breast Diseases. ACS Biomater Sci Eng 2023; 9:1629-1643. [PMID: 36706038 DOI: 10.1021/acsbiomaterials.2c01059] [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] [Indexed: 01/28/2023]
Abstract
Breast cancer is a heterogeneous and dynamic disease, in which cancer cells are highly responsive to alterations in the microenvironment. Today, conventional methods of detecting cancer give a rather static image of the condition of the disease, so dynamic properties such as invasiveness and metastasis are difficult to capture. In this study, conventional molecular-level evaluations of the patients with breast adenocarcinoma were combined with in vitro methods on micropatterned poly(methyl methacrylate) (PMMA) biomaterial surfaces that deform cells. A correlation between deformability of the nuclei and cancer stemness, invasiveness, and metastasis was sought. Clinical patient samples were from regions of the breast with different proximities to the tumor. Responses at the single-cell level toward the micropatterned surfaces were studied using CD44/24, epithelial cell adhesion marker (EpCAM), MUC1, and PCK. Results showed that molecular markers and shape descriptors can discriminate the cells from different proximities to the tumor center and from different patients. The cells with the most metastatic and invasive properties showed both the highest deformability and the highest level of metastatic markers. In conclusion, by using a combination of molecular markers together with nuclear deformation, it is possible to improve detection and separation of subpopulations in heterogenous breast cancer specimens at the single-cell level.
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Affiliation(s)
- Ezgi Antmen
- BIOMATEN, Middle East Technical University (METU) Center of Excellence in Biomaterials and Tissue Engineering, Ankara06800, Turkey
| | - Menekse Ermis
- BIOMATEN, Middle East Technical University (METU) Center of Excellence in Biomaterials and Tissue Engineering, Ankara06800, Turkey
| | - Ozgur Kuren
- BIOMATEN, Middle East Technical University (METU) Center of Excellence in Biomaterials and Tissue Engineering, Ankara06800, Turkey
| | - Kemal Beksac
- Department of General Surgery, Ankara Oncology Hospital, Yenimahalle, Ankara06800, Turkey
| | - Cigdem Irkkan
- Department of Pathology, Ankara Oncology Hospital, Yenimahalle, Ankara06800, Turkey
| | - Vasif Hasirci
- BIOMATEN, Middle East Technical University (METU) Center of Excellence in Biomaterials and Tissue Engineering, Ankara06800, Turkey
- Department of Biomedical Engineering, Acibadem Mehmet Ali Aydinlar University (ACU), Istanbul34752, Turkey
- ACU Biomaterials Center, Acibadem Mehmet Ali Aydinlar University (ACU), Atasehir, Istanbul34752, Turkey
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13
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Mallet JF, Shahbazi R, Alsadi N, Saleem A, Sobiesiak A, Arnason JT, Matar C. Role of a Mixture of Polyphenol Compounds Released after Blueberry Fermentation in Chemoprevention of Mammary Carcinoma: In Vivo Involvement of miR-145. Int J Mol Sci 2023; 24:ijms24043677. [PMID: 36835085 PMCID: PMC9966222 DOI: 10.3390/ijms24043677] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 01/29/2023] [Accepted: 01/30/2023] [Indexed: 02/17/2023] Open
Abstract
Epigenetic mechanisms such as microRNA (miRNA) deregulation seem to exert a central role in breast cancer initiation and progression. Therefore, targeting epigenetics deregulation may be an effective strategy for preventing and halting carcinogenesis. Studies have revealed the significant role of naturally occurring polyphenolic compounds derived from fermented blueberry fruits in cancer chemoprevention by modulation of cancer stem cell development through the epigenetic mechanism and regulation of cellular signaling pathways. In this study, we first investigated the phytochemical changes during the blueberry fermentation process. Fermentation favored the release of oligomers and bioactive compounds such as protocatechuic acid (PCA), gallic acid, and catechol. Next, we investigated the chemopreventive potentials of a polyphenolic mixture containing PCA, gallic acid, and catechin found in fermented blueberry juice in a breast cancer model by measuring miRNA expression and the signaling pathways involved in breast cancer stemness and invasion. To this end, 4T1 and MDA-MB-231 cell lines were treated with different doses of the polyphenolic mixture for 24 h. Additionally, female Balb/c mice were fed with this mixture for five weeks; two weeks before and three weeks after receiving 4T1 cells. Mammosphere formation was assayed in both cell lines and the single-cell suspension obtained from the tumor. Lung metastases were counted by isolating 6-thioguanine-resistant cells present in the lungs. In addition, we conducted RT-qPCR and Western blot analysis to validate the expression of targeted miRNAs and proteins, respectively. We found a significant reduction in mammosphere formation in both cell lines treated with the mixture and in tumoral primary cells isolated from mice treated with the polyphenolic compound. The number of colony-forming units of 4T1 cells in the lungs was significantly lower in the treatment group compared to the control group. miR-145 expression significantly increased in the tumor samples of mice treated with the polyphenolic mixture compared to the control group. Furthermore, a significant increase in FOXO1 levels was noted in both cell lines treated with the mixture. Overall, our results show that phenolic compounds found in fermented blueberry delay the formation of tumor-initiating cells in vitro and in vivo and reduce the spread of metastatic cells. The protective mechanisms seem to be related, at least partly, to the epigenetic modulation of mir-145 and its signaling pathways.
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Affiliation(s)
- Jean-François Mallet
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Roghayeh Shahbazi
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Nawal Alsadi
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
| | - Ammar Saleem
- Laboratory for the Analysis of Natural and Synthetic Environmental Toxins, Department of Biology, University of Ottawa, 30 Marie Curie Private, Ottawa, ON K1N 6N5, Canada
| | - Agnes Sobiesiak
- Laboratory for the Analysis of Natural and Synthetic Environmental Toxins, Department of Biology, University of Ottawa, 30 Marie Curie Private, Ottawa, ON K1N 6N5, Canada
| | - John Thor Arnason
- Laboratory for the Analysis of Natural and Synthetic Environmental Toxins, Department of Biology, University of Ottawa, 30 Marie Curie Private, Ottawa, ON K1N 6N5, Canada
| | - Chantal Matar
- Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- School of Nutrition Sciences, Faculty of Health Sciences, University of Ottawa, 451 Smyth Road, Ottawa, ON K1H 8M5, Canada
- Correspondence: ; Tel.: +613-562-5800 (ext. 8322)
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14
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Polverini PJ, Nör F, Nör JE. Crosstalk between cancer stem cells and the tumor microenvironment drives progression of premalignant oral epithelium. FRONTIERS IN ORAL HEALTH 2023; 3:1095842. [PMID: 36704239 PMCID: PMC9872128 DOI: 10.3389/froh.2022.1095842] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/19/2022] [Indexed: 01/11/2023] Open
Abstract
Cancer stem cells (CSC) are a subpopulation of cancer cells that exhibit properties of self-renewal and differentiation and have been implicated in metastasis and treatment failures. There is mounting evidence that carcinogen-initiated mucosal epithelial stem cells acquire the CSC phenotype following exposure to environmental or infectious mutagens and are responsible for promoting the malignant transformation of premalignant (dysplastic) epithelium. CSC further contribute to the progression of dysplasia by activating signaling pathways through crosstalk with various cell populations in the tumor microenvironment. Two cell types, tumor-associated macrophages (TAM) and vascular endothelial cells (EC) nurture CSC development, support CSC stemness, and contribute to tumor progression. Despite mounting evidence implicating CSC in the initiation and progression of dysplastic oral epithelium to squamous cell carcinoma (SCC), the molecular mechanisms underlying these synergistic biological processes remain unclear. This review will examine the mechanisms that underlie the transformation of normal epithelial stem cells into CSC and the mechanistic link between CSC, TAM, and EC in the growth and the malignant conversation of dysplastic oral epithelium.
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Affiliation(s)
- Peter J. Polverini
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, United States,Correspondence: Peter J. Polverini
| | - Felipe Nör
- Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, United States
| | - Jacques E. Nör
- Department of Cariology, Restorative Sciences, and Endodontics, University of Michigan School of Dentistry, Ann Arbor, MI, United States
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15
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Martin J, Islam F. Detection and Isolation of Cancer Stem Cells. CANCER STEM CELLS: BASIC CONCEPT AND THERAPEUTIC IMPLICATIONS 2023:45-69. [DOI: 10.1007/978-981-99-3185-9_3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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16
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Ingavle G, Das M. Bench to Bedside: New Therapeutic Approaches with Extracellular Vesicles and Engineered Biomaterials for Targeting Therapeutic Resistance of Cancer Stem Cells. ACS Biomater Sci Eng 2022; 8:4673-4696. [PMID: 36194142 DOI: 10.1021/acsbiomaterials.2c00484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Cancer has recently been the second leading cause of death worldwide, trailing only cardiovascular disease. Cancer stem cells (CSCs), represented as tumor-initiating cells (TICs), are mainly liable for chemoresistance and disease relapse due to their self-renewal capability and differentiating capacity into different types of tumor cells. The intricate molecular mechanism is necessary to elucidate CSC's chemoresistance properties and cancer recurrence. Establishing efficient strategies for CSC maintenance and enrichment is essential to elucidate the mechanisms and properties of CSCs and CSC-related therapeutic measures. Current approaches are insufficient to mimic the in vivo chemical and physical conditions for the maintenance and growth of CSC and yield unreliable research results. Biomaterials are now widely used for simulating the bone marrow microenvironment. Biomaterial-based three-dimensional (3D) approaches for the enrichment of CSC provide an excellent promise for future drug discovery and elucidation of molecular mechanisms. In the future, the biomaterial-based model will contribute to a more operative and predictive CSC model for cancer therapy. Design strategies for materials, physicochemical cues, and morphology will offer a new direction for future modification and new methods for studying the CSC microenvironment and its chemoresistance property. This review highlights the critical roles of the microenvironmental cues that regulate CSC function and endow them with drug resistance properties. This review also explores the latest advancement and challenges in biomaterial-based scaffold structure for therapeutic approaches against CSC chemoresistance. Since the recent entry of extracellular vesicles (EVs), cell-derived nanostructures, have opened new avenues of investigation into this field, which, together with other more conventionally studied signaling pathways, play an important role in cell-to-cell communication. Thus, this review further explores the subject of EVs in-depth. This review also discusses possible future biomaterial and biomaterial-EV-based models that could be used to study the tumor microenvironment (TME) and will provide possible therapeutic approaches. Finally, this review concludes with potential perspectives and conclusions in this area.
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Affiliation(s)
- Ganesh Ingavle
- Symbiosis Centre for Stem Cell Research (SCSCR) and Symbiosis School of Biological Sciences (SSBS), SIU, Lavale, Pune 412115, India
| | - Madhurima Das
- Symbiosis Centre for Stem Cell Research (SCSCR) and Symbiosis School of Biological Sciences (SSBS), SIU, Lavale, Pune 412115, India
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17
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Al-Dhfyan A, Alaiya A, Al-Mohanna F, Attwa MW, Alasmari AF, Bakheet SA, Korashy HM. Crosstalk Between Aryl Hydrocarbon Receptor (AhR) and BCL-2 Pathways Suggests the Use of AhR Antagonist to Maintain Normal Differentiation State of Mammary Epithelial Cells During BCL-2 Inhibition Therapy. J Adv Res 2022:S2090-1232(22)00234-X. [PMID: 36307019 PMCID: PMC10403657 DOI: 10.1016/j.jare.2022.10.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2022] [Revised: 10/01/2022] [Accepted: 10/11/2022] [Indexed: 11/05/2022] Open
Abstract
INTRODUCTION Activating the aryl hydrocarbon receptor upon exposure to environmental pollutants promotes development of breast cancer stem cell (CSCs). BCL-2 family proteins protect cancer cells from the apoptotic effects of chemotherapeutic drugs. However, the crosstalk between AhR and the BCL-2 family in CSC development remains uninvestigated. OBJECTIVES This study explored the interaction mechanisms between AhR and BCL-2 in CSC development and chemoresistance. METHODS A quantitative proteomic analysis study was performed as a tool for comparative expression analysis of breast cancer cells treated by AhR agonist. The basal and inducible levels of BCL-2, AhR, and CYP1A1 in vitro breast cancer and epithelial cell lines and in vivo mice animal models were determined by RT-PCR, Western blot analysis, immunofluorescence, flow cytometry, silencing of the target, and immunohistochemistry. In addition, an in silico toxicity study was conducted using DEREK software. RESULTS Activation of the AhR/CYP1A1 pathway in mice increased EpCAMHigh/CD49fLow CD61+ luminal progenitor-like cells in early tumor formation but not in advanced tumors. In parallel, a chemoproteomic study on breast cancer MCF-7 cells revealed that the BCL-2 protein expression was the most upregulated upon AhR activation. The crosstalk between the AhR and BCL-2 pathways in vitro and in vivo modulated the CSCs features and chemoresistance. Interestingly, inhibition of BCL-2 in mice by venetoclax (VCX) increased EpCAMHigh/CD49fLow CD61+ luminal progenitor-like cells, causing inhibition of epithelial lineage markers, disruption of mammary gland branching and induced the epithelial-mesenchymal transition in mammary epithelial cells (MECs). The combined treatment of VCX and AhR antagonists in mice corrected the abnormal differentiation in MECs and protected mammary gland branching and cell identity. CONCLUSIONS This is the first study to report crosstalk between AhR and BCL-2 in breast CSCs and provides the rationale for using a combined treatment of BCL-2 inhibitor and AhR antagonist for more effective cancer prevention and treatment.
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18
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Association of birth weight with cancer risk: a dose-response meta-analysis and Mendelian randomization study. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04171-2. [PMID: 36030285 DOI: 10.1007/s00432-022-04171-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 06/22/2022] [Indexed: 10/15/2022]
Abstract
BACKGROUND Several articles have shown that birth weight is associated with the risk of many types of cancers. However, the results are inconsistent, and whether the relationship has a causal effect remains unknown. METHODS We searched the PubMed and Embase libraries up to March 2021 and selected observational studies reporting the relationship between birth weight and adult-onset cancer risk. Dose-response meta-analysis and two-sample Mendelian randomization (MR) analysis were used to estimate the effect. RESULT In our dose-response meta-analysis, six cancers from 46 studies were found to have significant associations with birth weight. (Ovarian cancer: RR: 1.21, 95% CI 1.01-1.44; breast cancer: RR: 1.12, 95% CI 1.08-1.16; colorectal cancer: RR: 1.20, 95% CI 1.01-1.43; endometrial cancer: RR: 0.85, 95% CI 0.78-0.93; prostate cancer: RR: 1.27, 95% CI 1.01-1.61; testicular cancer: RR: 1.21, 95% CI 1.03-1.43). As birth weight increased, the slope of the dose-response curve of breast cancer increased continuously, and the curve of testicular cancer was U-shaped. In the MR study, seven cancers were included. Only invasive mucinous ovarian cancer was found to have a causal effect on birth weight (OR: 0.62; 95% CI 0.39-0.97), while other cancers did not. CONCLUSIONS Our findings suggest that birth weight are unlikely to have a casual effect on risk of cancers via the MR analysis, although the dose-response meta-analysis shows that there is a nonlinear relationship between birth weight and breast cancer and testicular cancer. More relevant researches are needed to further investigate their effect.
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19
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Jiang S, Hu Y, Zhou Y, Tang G, Cui W, Wang X, Chen B, Hu Z, Xu B. miRNAs as Biomarkers and Possible Therapeutic Strategies in Synovial Sarcoma. Front Pharmacol 2022; 13:881007. [PMID: 36003502 PMCID: PMC9394702 DOI: 10.3389/fphar.2022.881007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
Synovial sarcoma (SS) is an epithelial-differentiated malignant stromal tumor that has the highest incidence in young people and can occur almost anywhere in the body. Many noncoding RNAs are involved in the occurrence, development, or pathogenesis of SS. In particular, the role of MicroRNAs (miRNAs) in SS is receiving increasing attention. MiRNA is a noncoding RNA abundant in cells and extracellular serums. Increasing evidence suggests that miRNA has played a significant role in the incidence and development of tumors in recent years, including sarcomas. Previous studies show that various sarcomas have their unique miRNA expression patterns and that various miRNA expression profiles can illustrate the classes of miRNAs that may elicit cancer-relevant activities in specific sarcoma subtypes. Furthermore, SS has been reported to have the most number of differentially expressed miRNAs, which indicated that miRNA is linked to SS. In fact, according to many publications, miRNAs have been shown to have a role in the development and appearance of SS in recent years, according to many publications. Since many studies showing that various miRNAs have a role in the development and appearance of SS in recent years have not been systematically summarized, we summarize the recent studies on the relationship between miRNA and SS in this review. For example, miR-494 promotes the development of SS via modulating cytokine gene expression. The role of miR-494-3p as a tumor suppressor is most likely linked to the CXCR4 (C-X-C chemokine receptor 4) regulator, although the exact mechanism is unknown. Our review aims to reveal in detail the potential biological value and clinical significance of miRNAs for SS and the potential clinical value brought by the association between SS and miRNAs.
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Affiliation(s)
- Shaowei Jiang
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ying Hu
- Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Hefei, China
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Yi Zhou
- The First Clinical Medical College of Anhui Medical University, Hefei, China
| | - Guozheng Tang
- The First Clinical Medical College of Anhui Medical University, Hefei, China
- Department of Orthopedics, Lu’an People’s Hospital, Lu’an, China
| | - Wenxu Cui
- The First Clinical Medical College of Anhui Medical University, Hefei, China
| | - Xinyi Wang
- The First Clinical Medical College of Anhui Medical University, Hefei, China
| | - Bangjie Chen
- The First Clinical Medical College of Anhui Medical University, Hefei, China
| | - Zuhong Hu
- The First Clinical Medical College of Anhui Medical University, Hefei, China
| | - Bing Xu
- Department of Orthopedics, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- *Correspondence: Bing Xu,
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20
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The Functions of PCNA in Tumor Stemness and Invasion. Int J Mol Sci 2022; 23:ijms23105679. [PMID: 35628489 PMCID: PMC9143764 DOI: 10.3390/ijms23105679] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 05/13/2022] [Accepted: 05/17/2022] [Indexed: 12/14/2022] Open
Abstract
Invasion is the most prominent lethal feature of malignant cancer. However, how cell proliferation, another important feature of tumor development, is integrated with tumor invasion and the subsequent cell dissemination from primary tumors is not well understood. Proliferating cell nuclear antigen (PCNA) is essential for DNA replication in cancer cells. Loss of phosphorylation at tyrosine 211 (Y211) in PCNA (pY211-PCNA) mitigates PCNA function in proliferation, triggers replication fork arrest/collapse, which in turn sets off an anti-tumor inflammatory response, and suppresses distant metastasis. Here, we show that pY211-PCNA is important in stromal activation in tumor tissues. Loss of the phosphorylation resulted in reduced expression of mesenchymal proteins as well as tumor progenitor markers, and of the ability of invasion. Spontaneous mammary tumors that developed in mice lacking Y211 phosphorylation contained fewer tumor-initiating cells compared to tumors in wild-type mice. Our study demonstrates a novel function of PCNA as an essential factor for maintaining cancer stemness through Y211 phosphorylation.
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21
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Gu J, Chen D, Li Z, Yang Y, Ma Z, Huang G. Prognosis assessment of CD44 +/CD24 - in breast cancer patients: a systematic review and meta-analysis. Arch Gynecol Obstet 2022; 306:1147-1160. [PMID: 35435483 DOI: 10.1007/s00404-022-06402-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2021] [Accepted: 01/04/2022] [Indexed: 12/24/2022]
Abstract
PURPOSE This meta-analysis investigated the relationships between the CD44+/CD24- phenotype and tumor size, lymph node metastasis, distant metastasis, disease-free survival (DFS), and overall survival (OS) in 8036 postoperative breast cancer patients enrolled in 23 studies. METHODS A literature search of PubMed, Medline, Cochrane, Embase, and PMC was conducted to identify eligible studies. The combined odds ratios (ORs) and 95% confidence intervals (95% CIs) were analyzed to evaluate the relationships between the CD44+/CD24- phenotype and the pathological and biological characteristics of breast cancer patients, and the combined hazard ratios (HRs) and 95% CIs were calculated to evaluate the relationships between CD44+/CD24- and DFS and OS of breast cancer patients using Stata12.0 software. RESULTS The CD44+/CD24- phenotype were not related to the tumor size (tumor size > 2.0 vs ≤ 2.0 cm, combined OR = 0.98, 95% CI 0.68-1.34, p = 0.792) and did not promote lymph node metastasis (lymph node metastasis vs. no lymph node metastasis, OR = 0.92, 95% CI 0.67-1.27, p = 0.626) and distant metastasis (distant metastasis vs no distant metastasis, combined OR = 3.88, 95% CI 0.93-16.24, p = 0.064). The CD44+/CD24- phenotype was negatively correlated with postoperative DFS (HR = 1.67, 95% CI 1.35-2.07, p < 0.00001) and OS (combined HR = 1.52, 95% CI 1.21-1.91, p = 0.0004). CONCLUSION These results suggested expression of the CD44+/CD24- phenotype cannot be used as a reliable indicator of the tumor size, lymph node metastasis, and distant metastasis, however, it can be used be a potential therapeutic targets of DFS, OS in breast cancer patients.
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Affiliation(s)
- Jingjing Gu
- Lianyungang Second People's Hospital Affiliated to Bengbu Medical College, Lianyungang, China
| | - Dandan Chen
- Lianyungang Second People's Hospital Affiliated to Bengbu Medical College, Lianyungang, China
| | - Zhiqiang Li
- Lianyungang Second People's Hospital Affiliated to Bengbu Medical College, Lianyungang, China
| | - Yongliang Yang
- Lianyungang Second People's Hospital Affiliated to Bengbu Medical College, Lianyungang, China
| | - Zhaoming Ma
- Lianyungang Second People's Hospital Affiliated to Bengbu Medical College, Lianyungang, China.
| | - Guanhong Huang
- Lianyungang Second People's Hospital Affiliated to Bengbu Medical College, Lianyungang, China.
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22
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Abstract
Triple-negative breast cancer (TNBC) encompasses a heterogeneous group of fundamentally different diseases with different histologic, genomic, and immunologic profiles, which are aggregated under this term because of their lack of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. Massively parallel sequencing and other omics technologies have demonstrated the level of heterogeneity in TNBCs and shed light into the pathogenesis of this therapeutically challenging entity in breast cancer. In this review, we discuss the histologic and molecular classifications of TNBC, the genomic alterations these different tumor types harbor, and the potential impact of these alterations on the pathogenesis of these tumors. We also explore the role of the tumor microenvironment in the biology of TNBCs and its potential impact on therapeutic response. Dissecting the biology and understanding the therapeutic dependencies of each TNBC subtype will be essential to delivering on the promise of precision medicine for patients with triple-negative disease.
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Affiliation(s)
- Fatemeh Derakhshan
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA;
| | - Jorge S Reis-Filho
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA;
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23
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Jiao X, Upadhyaya C, Zhang Z, Zhao J, Li Z, Patel VI, Pestell RG. Assays for the Spectrum of Circulating Tumor Cells. Methods Mol Biol 2022; 2429:533-545. [PMID: 35507187 DOI: 10.1007/978-1-0716-1979-7_37] [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] [Indexed: 06/14/2023]
Abstract
Cancer cells sharing stem cell properties are called "cancer stem cells" (CSCs). CSCs have distinct metabolic properties, are intrinsically drug resistant evading chemotherapies, are regulated by miRNA networks and participate in tumor relapse and metastases. During metastatic dissemination, circulating tumor cells (CTCs) invade distant organs and settle in supportive niches. In this process, the stem cell-like properties within CTCs contribute to CTC survival and eventually seed the growth of a secondary tumor. We herein describe methodologies for the analysis of CTCs as they reside in distinct functional pools with distinct characteristics.
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Affiliation(s)
- Xuanmao Jiao
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, USA.
- Xavier University School of Medicine, Woodbury, NY, USA.
| | | | - Zhao Zhang
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, USA
| | - Jun Zhao
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, USA
| | - Zhiping Li
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, USA
- Xavier University School of Medicine, Woodbury, NY, USA
| | - Vivek I Patel
- Xavier University School of Medicine, Woodbury, NY, USA
| | - Richard G Pestell
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, USA
- Xavier University School of Medicine, Woodbury, NY, USA
- The Wistar Cancer Center, Wistar Institute, Philadelphia, PA, USA
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24
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Thongchot S, Jamjuntra P, Prasopsiri J, Thuwajit P, Sawasdee N, Poungvarin N, Warnnissorn M, Sa-Nguanraksa D, O-Charoenrat P, Yenchitsomanus PT, Thuwajit C. Establishment and characterization of novel highly aggressive HER2‑positive and triple‑negative breast cancer cell lines. Oncol Rep 2021; 46:254. [PMID: 34651665 PMCID: PMC8548790 DOI: 10.3892/or.2021.8205] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 09/16/2021] [Indexed: 11/05/2022] Open
Abstract
Breast cancer cell lines are widely used as an in vitro system with which to study the mechanisms underlying biological and chemotherapeutic resistance. In the present study, two novel breast cancer cell lines designated as PC‑B‑142CA and PC‑B‑148CA were successfully established from HER2‑positive and triple‑negative (TN) breast cancer tissues. The cell lines were characterized by cytokeratin (CK), α‑smooth muscle actin (α‑SMA), fibroblast‑activation protein (FAP) and programmed death‑ligand 1 (PD‑L1). Cell proliferation was assessed using a colony formation assay, an MTS assay, 3‑dimensional (3‑D) spheroid and 3‑D organoid models. Wound healing and Transwell migration assays were used to explore the cell migration capability. The responses to doxorubicin (DOX) and paclitaxel (PTX) were evaluated by 3‑D spheroids. The results showed that the PC‑B‑142CA and PC‑B‑148CA cell lines were α‑SMA‑negative, FAP‑negative, CK‑positive and PD‑L1‑positive. Both cell lines were adherent with the ability of 3‑D‑multicellular spheroid and organoid formations; invadopodia were found in the spheroids/organoids of only PC‑B‑148CA. PC‑B‑142CA had a faster proliferative but lower metastatic rate compared to PC‑B‑148CA. Compared to MDA‑MB‑231, a commercial TN breast cancer cell line, PC‑B‑148CA had a similar CD44+/CD24‑ stemness property (96.90%), whereas only 8.75% were found in PC‑B‑142CA. The mutations of BRCA1/2, KIT, PIK3CA, SMAD4, and TP53 were found in PC‑B‑142CA cells related to the resistance of several drugs, whereas PC‑B‑148CA had mutated BRCA2, NRAS and TP53. In conclusion, PC‑B‑142CA can serve as a novel HER2‑positive breast cancer cell line for drug resistance studies; while PC‑B‑148CA is a novel TN breast cancer cell line suitable for metastatic and stemness‑related properties.
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Affiliation(s)
- Suyanee Thongchot
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Pranisa Jamjuntra
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Jaturawitt Prasopsiri
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Nunghathai Sawasdee
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Naravat Poungvarin
- Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Malee Warnnissorn
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Doonyapat Sa-Nguanraksa
- Department of Surgery, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | | | - Pa-Thai Yenchitsomanus
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Research Department, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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25
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Motwani J, Eccles MR. Genetic and Genomic Pathways of Melanoma Development, Invasion and Metastasis. Genes (Basel) 2021; 12:1543. [PMID: 34680938 PMCID: PMC8535311 DOI: 10.3390/genes12101543] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Revised: 09/27/2021] [Accepted: 09/27/2021] [Indexed: 12/21/2022] Open
Abstract
Melanoma is a serious form of skin cancer that accounts for 80% of skin cancer deaths. Recent studies have suggested that melanoma invasiveness is attributed to phenotype switching, which is a reversible type of cell behaviour with similarities to epithelial to mesenchymal transition. Phenotype switching in melanoma is reported to be independent of genetic alterations, whereas changes in gene transcription, and epigenetic alterations have been associated with invasiveness in melanoma cell lines. Here, we review mutational, transcriptional, and epigenomic alterations that contribute to tumour heterogeneity in melanoma, and their potential to drive melanoma invasion and metastasis. We also discuss three models that are hypothesized to contribute towards aspects of tumour heterogeneity and tumour progression in melanoma, namely the clonal evolution model, the cancer stem cell model, and the phenotype switching model. We discuss the merits and disadvantages of each model in explaining tumour heterogeneity in melanoma, as a precursor to invasion and metastasis.
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Affiliation(s)
- Jyoti Motwani
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand;
| | - Michael R. Eccles
- Department of Pathology, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand;
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland 1010, New Zealand
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26
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Simeon J, Thrush J, Bailey TA. Angiopoietin-like protein 4 is a chromatin-bound protein that enhances mammosphere formation in vitro and experimental triple-negative breast cancer brain and liver metastases in vivo. J Carcinog 2021; 20:8. [PMID: 34447288 PMCID: PMC8356708 DOI: 10.4103/jcar.jcar_20_20] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 09/30/2020] [Accepted: 01/06/2021] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION: Metastatic progression in triple-negative breast cancer (TNBC) patients occurs primarily because of nuclear reprogramming that includes chromatin remodeling and epigenetic modifications. The existing and most successful chemotherapies available for metastatic TNBC target nuclear proteins or damage DNA. The objectives here are to investigate an undescribed role for the molecular biology of nuclear angiopoietin-like protein 4 (ANGPTL4) and to characterize the effect of ectopic overexpression of ANGPTL4 in the metastatic biology of TNBC. MATERIALS AND METHODS: Lentiviral-mediated transduction was used to overexpress ANGPTL4 in the TNBC cell line MD Anderson–metastatic breast cancer 231. The overexpression of ANGPTL4 was confirmed by western blot and ELISA. Subcellular fractionation, western blot, and immunofluorescence microscopy were used to characterize the intracellular localization of ANGPTL4. Mammosphere culture and the anchorage-independent growth assay analyzed the metastatic potential of the cell line. Xenograft assays assessed the effect of ANGPTL4 overexpression on TNBC metastases in vivo. RESULTS: The ANGPTL4 overexpressing cell line formed larger mammospheres and anchorage-independent colonies in vitro and developed larger primary tumors, more liver metastases, and brain metastatic outgrowth in vivo in comparison to a cell line that expressed endogenous levels of ANGPTL4. ANGPTL4, aurora kinase A (AURKA), a mitotic kinase, and Tat-interacting protein p60 kDa (Tip60), a lysine acetyltransferase, associated with chromatin in the ANGPTL4 overexpressing cells but not in cells that expressed endogenous levels of ANGPTL4. CONCLUSIONS: The ANGPTL4 overexpressing cell line showed in vitro and in vivo activities that suggest that nuclear ANGPTL4, AURKA, and Tip60 may cooperatively modulate TNBC metastases within chromatin-remodeling complexes or DNA-associated machinery.
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Affiliation(s)
- Jodi Simeon
- Department of Biological Sciences, University of Arkansas, Fayetteville, Arkansas, USA.,Department of Cell and Molecular Biology Program, University of Arkansas, Fayetteville, Arkansas, USA
| | - Jessica Thrush
- Department of Biological Sciences, University of Arkansas, Fayetteville, Arkansas, USA.,Department of Honors College, University of Arkansas, Fayetteville, Arkansas, USA
| | - Tameka A Bailey
- Department of Biological Sciences, University of Arkansas, Fayetteville, Arkansas, USA.,Department of Cell and Molecular Biology Program, University of Arkansas, Fayetteville, Arkansas, USA
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Liu X, Wang Q, Song S, Feng M, Wang X, Li L, Liu Y, Shi C. Epithelial Splicing Regulatory Protein 1 Is Overexpressed in Breast Cancer and Predicts Poor Prognosis for Breast Cancer Patients. Med Sci Monit 2021; 27:e931102. [PMID: 34262011 PMCID: PMC8290978 DOI: 10.12659/msm.931102] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Background Epithelial splicing regulatory proteins (ESRPs), including ESRP1 and ESRP2, are important proteins for alternative splicing of mRNAs and are reported to promote or inhibit the progression of some tumors. However, the effects of ESRPs in breast cancer are still unknown. Material/Methods In this study, we detected the transcriptional level and alterations of ESRP1 in patients with breast cancer based on the Oncomine, Gene Expression Profiling Interactive Analysis, Gene Expression-Based Outcome for Breast Cancer Online, and cBioPortal databases. Using immunohistochemistry and quantitative polymerase chain reaction, the expression pattern of ESRP1 in breast cancer was analyzed. Analysis of the clinicopathological characteristics and function of ESRP1 in breast cancer were actualized through the University of Alabama Cancer database and Database for Annotation, Visualization and Integrated Discovery. Using the Kaplan-Meier plotter, the prognostic values of ESRP1 in patients with breast cancer were analyzed. The Encyclopedia of RNA Interactomes database was used to predict miRNAs that regulated ESRP1. Results We found that ESRP1 was significantly overexpressed in patients with breast cancer, compared with patients without breast cancer, and had statistically significant clinicopathological characteristics. Kaplan-Meier plotter analysis indicated that the elevated expression of ESRP1 was associated with poor prognosis in patients with breast cancer. Furthermore, hsa-miR-181c-5p was identified to be potentially involved in the regulation of ESRP1. Conclusions These results suggest that ESRP1 is a valuable target for the precise treatment of breast cancer and a potential biomarker for the prognosis of patients with breast cancer.
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Affiliation(s)
- Xinyu Liu
- School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, China (mainland)
| | - Qiangshan Wang
- Jiaozhou Maternal and Child Health Hospital, Jiaozhou Maternal and Child Health Hospital, Qingdao, China (mainland)
| | - Siqi Song
- School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, China (mainland)
| | - Manman Feng
- School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, China (mainland)
| | - Xiaoya Wang
- School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, China (mainland)
| | - Ling Li
- School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, China (mainland)
| | - Ying Liu
- School of Basic Medicine, College of Medicine; Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, College of Medicine, Qingdao University, Qingdao, China (mainland)
| | - Chunying Shi
- School of Basic Medicine, College of Medicine, Qingdao University, Qingdao, China (mainland)
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28
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Ruth JR, Pant DK, Pan TC, Seidel HE, Baksh SC, Keister BA, Singh R, Sterner CJ, Bakewell SJ, Moody SE, Belka GK, Chodosh LA. Cellular dormancy in minimal residual disease following targeted therapy. Breast Cancer Res 2021; 23:63. [PMID: 34088357 PMCID: PMC8178846 DOI: 10.1186/s13058-021-01416-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 03/09/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Breast cancer mortality is principally due to tumor recurrence, which can occur following extended periods of clinical remission that may last decades. While clinical latency has been postulated to reflect the ability of residual tumor cells to persist in a dormant state, this hypothesis remains unproven since little is known about the biology of these cells. Consequently, defining the properties of residual tumor cells is an essential goal with important clinical implications for preventing recurrence and improving cancer outcomes. METHODS To identify conserved features of residual tumor cells, we modeled minimal residual disease using inducible transgenic mouse models for HER2/neu and Wnt1-driven tumorigenesis that recapitulate cardinal features of human breast cancer progression, as well as human breast cancer cell xenografts subjected to targeted therapy. Fluorescence-activated cell sorting was used to isolate tumor cells from primary tumors, residual lesions following oncogene blockade, and recurrent tumors to analyze gene expression signatures and evaluate tumor-initiating cell properties. RESULTS We demonstrate that residual tumor cells surviving oncogenic pathway inhibition at both local and distant sites exist in a state of cellular dormancy, despite adequate vascularization and the absence of adaptive immunity, and retain the ability to re-enter the cell cycle and give rise to recurrent tumors after extended latency periods. Compared to primary or recurrent tumor cells, dormant residual tumor cells possess unique features that are conserved across mouse models for human breast cancer driven by different oncogenes, and express a gene signature that is strongly associated with recurrence-free survival in breast cancer patients and similar to that of tumor cells in which dormancy is induced by the microenvironment. Although residual tumor cells in both the HER2/neu and Wnt1 models are enriched for phenotypic features associated with tumor-initiating cells, limiting dilution experiments revealed that residual tumor cells are not enriched for cells capable of giving rise to primary tumors, but are enriched for cells capable of giving rise to recurrent tumors, suggesting that tumor-initiating populations underlying primary tumorigenesis may be distinct from those that give rise to recurrence following therapy. CONCLUSIONS Residual cancer cells surviving targeted therapy reside in a well-vascularized, desmoplastic microenvironment at both local and distant sites. These cells exist in a state of cellular dormancy that bears little resemblance to primary or recurrent tumor cells, but shares similarities with cells in which dormancy is induced by microenvironmental cues. Our observations suggest that dormancy may be a conserved response to targeted therapy independent of the oncogenic pathway inhibited or properties of the primary tumor, that the mechanisms underlying dormancy at local and distant sites may be related, and that the dormant state represents a potential therapeutic target for preventing cancer recurrence.
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Affiliation(s)
- Jason R Ruth
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- 2-PREVENT Translational Center of Excellence at the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Dhruv K Pant
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- 2-PREVENT Translational Center of Excellence at the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- the Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Tien-Chi Pan
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- 2-PREVENT Translational Center of Excellence at the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- the Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Hans E Seidel
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- 2-PREVENT Translational Center of Excellence at the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sanjeethan C Baksh
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- 2-PREVENT Translational Center of Excellence at the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Blaine A Keister
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Rita Singh
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Christopher J Sterner
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- 2-PREVENT Translational Center of Excellence at the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- the Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Suzanne J Bakewell
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- 2-PREVENT Translational Center of Excellence at the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Susan E Moody
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- 2-PREVENT Translational Center of Excellence at the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - George K Belka
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- 2-PREVENT Translational Center of Excellence at the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
- the Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Lewis A Chodosh
- Department of Cancer Biology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
- 2-PREVENT Translational Center of Excellence at the Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
- the Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
- Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA.
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Borrero-García LD, Del Mar Maldonado M, Medina-Velázquez J, Troche-Torres AL, Velazquez L, Grafals-Ruiz N, Dharmawardhane S. Rac inhibition as a novel therapeutic strategy for EGFR/HER2 targeted therapy resistant breast cancer. BMC Cancer 2021; 21:652. [PMID: 34074257 PMCID: PMC8170972 DOI: 10.1186/s12885-021-08366-7] [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: 09/26/2020] [Accepted: 05/17/2021] [Indexed: 11/10/2022] Open
Abstract
Background Even though targeted therapies are available for cancers expressing oncogenic epidermal growth receptor (EGFR) and (or) human EGFR2 (HER2), acquired or intrinsic resistance often confounds therapy success. Common mechanisms of therapy resistance involve activating receptor point mutations and (or) upregulation of signaling downstream of EGFR/HER2 to Akt and (or) mitogen activated protein kinase (MAPK) pathways. However, additional pathways of resistance may exist thus, confounding successful therapy. Methods To determine novel mechanisms of EGFR/HER2 therapy resistance in breast cancer, gefitinib or lapatinib resistant variants were created from SKBR3 breast cancer cells. Syngenic therapy sensitive and resistant SKBR3 variants were characterized for mechanisms of resistance by mammosphere assays, viability assays, and western blotting for total and phospho proteins. Results Gefitinib and lapatinib treatments reduced mammosphere formation in the sensitive cells, but not in the therapy resistant variants, indicating enhanced mesenchymal and cancer stem cell-like characteristics in therapy resistant cells. The therapy resistant variants did not show significant changes in known therapy resistant pathways of AKT and MAPK activities downstream of EGFR/HER2. However, these cells exhibited elevated expression and activation of the small GTPase Rac, which is a pivotal intermediate of GFR signaling in EMT and metastasis. Therefore, the potential of the Rac inhibitors EHop-016 and MBQ-167 to overcome therapy resistance was tested, and found to inhibit viability and induce apoptosis of therapy resistant cells. Conclusions Rac inhibition may represent a viable strategy for treatment of EGFR/HER2 targeted therapy resistant breast cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08366-7.
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Affiliation(s)
- Luis D Borrero-García
- Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Maria Del Mar Maldonado
- Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Julia Medina-Velázquez
- Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Angel L Troche-Torres
- Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Luis Velazquez
- Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Nilmary Grafals-Ruiz
- Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico
| | - Suranganie Dharmawardhane
- Department of Biochemistry, School of Medicine, University of Puerto Rico Medical Sciences Campus, San Juan, Puerto Rico.
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30
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Batool I, Bajcinca N. Evolution of cancer stem cell lineage involving feedback regulation. PLoS One 2021; 16:e0251481. [PMID: 34014979 PMCID: PMC8136751 DOI: 10.1371/journal.pone.0251481] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 04/27/2021] [Indexed: 01/16/2023] Open
Abstract
Tumor emergence and progression is a complex phenomenon that assumes special molecular and cellular interactions. The hierarchical structuring and communication via feedback signaling of different cell types, which are categorized as the stem, progenitor, and differentiated cells in dependence of their maturity level, plays an important role. Under healthy conditions, these cells build a dynamical system that is responsible for facilitating the homeostatic regulation of the tissue. Generally, in this hierarchical setting, stem and progenitor cells are yet likely to undergo a mutation, when a cell divides into two daughter cells. This may lead to the development of abnormal characteristics, i.e. mutation in the cell, yielding an unrestrained number of cells. Therefore, the regulation of a stem cell’s proliferation and differentiation rate is crucial for maintaining the balance in the overall cell population. In this paper, a maturity based mathematical model with feedback regulation is formulated for healthy and mutated cell lineages. It is given in the form of coupled ordinary and partial differential equations. The focus is laid on the dynamical effects resulting from acquiring a mutation in the hierarchical structure of stem, progenitor and fully differentiated cells. Additionally, the effects of nonlinear feedback regulation from mature cells into both stem and progenitor cell populations have been inspected. The steady-state solutions of the model are derived analytically. Numerical simulations and results based on a finite volume scheme underpin various expected behavioral patterns of the homeostatic regulation and cancer evolution. For instance, it has been found that the mutated cells can experience significant growth even with a single somatic mutation, but under homeostatic regulation acquire a steady-state and thus, ensuing healthy cell population to either a steady-state or a lower cell concentration. Furthermore, the model behavior has been validated with different experimentally measured tumor values from the literature.
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Affiliation(s)
- Iqra Batool
- Faculty of Mechanical and Process Engineering, Technische Universität Kaiserslautern, Kaiserslautern, Rheinland Pfalz, Germany
| | - Naim Bajcinca
- Faculty of Mechanical and Process Engineering, Technische Universität Kaiserslautern, Kaiserslautern, Rheinland Pfalz, Germany
- * E-mail:
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31
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Kimani S, Chakraborty S, Irene I, de la Mare J, Edkins A, du Toit A, Loos B, Blanckenberg A, Van Niekerk A, Costa-Lotufo LV, ArulJothi KN, Mapolie S, Prince S. The palladacycle, BTC2, exhibits anti-breast cancer and breast cancer stem cell activity. Biochem Pharmacol 2021; 190:114598. [PMID: 33979647 DOI: 10.1016/j.bcp.2021.114598] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 05/01/2021] [Accepted: 05/06/2021] [Indexed: 11/15/2022]
Abstract
In women globally, breast cancer is responsible for most cancer-related deaths and thus, new effective therapeutic strategies are required to treat this malignancy. Platinum-based compounds like cisplatin are widely used to treat breast cancer, however, they come with limitations such as poor solubility, adverse effects, and drug resistance. To overcome these limitations, complexes containing other platinum group metals such as palladium have been studied and some have already entered clinical trials. Here we investigated the anti-cancer activity of a palladium complex, BTC2, in MCF-7 oestrogen receptor positive (ER+) and MDA-MB-231 triple negative (TN) human breast cancer cells as well as in a human breast cancer xenograft chick embryo model. BTC2 exhibited an average IC50 value of 0.54 μM, a desirable selectivity index of >2, inhibited the migration of ER+ and TN breast cancer cells, and displayed anti-cancer stem cell activity. We demonstrate that BTC2 induced DNA double strand breaks (increased levels of γ-H2AX) and activated the p-ATM/p-CHK2 and p-p38/MAPK pathways resulting in S- and G2/M-phase cell cycle arrests. Importantly, BTC2 sensitised breast cancer cells by triggering the intrinsic (cleaved caspase 9) and extrinsic (cleaved caspase 8) apoptotic as well as necroptotic (p-RIP3 and p-MLKL) cell death pathways and inhibiting autophagy and its pro-survival role. Furthermore, in the xenograft in vivo model, BTC2 displayed limited toxicity and arrested the tumour growth of breast cancer cells over a 9-day period in a manner comparable to that of the positive control drug, paclitaxel. BTC2 thus displayed promising anti-breast cancer activity.
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Affiliation(s)
- Serah Kimani
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, Western Cape, South Africa
| | - Suparna Chakraborty
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, Western Cape, South Africa
| | - Ikponmwosa Irene
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, Western Cape, South Africa
| | - Jo de la Mare
- Biomedical Biotechnology Research Unit, Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, Grahamstown, South Africa
| | - Adrienne Edkins
- Biomedical Biotechnology Research Unit, Department of Biochemistry, Microbiology and Biotechnology, Rhodes University, Grahamstown, South Africa
| | - André du Toit
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, Western Cape, South Africa
| | - Ben Loos
- Department of Physiological Sciences, Stellenbosch University, Stellenbosch, Western Cape, South Africa
| | - Angelique Blanckenberg
- Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Western Cape, South Africa
| | - Annick Van Niekerk
- Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Western Cape, South Africa
| | - Leticia V Costa-Lotufo
- Department of Pharmacology, Institute of Biomedical Science, University of São Paulo, São Paulo, Brazil
| | - K N ArulJothi
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, Western Cape, South Africa; Department of Genetic Engineering, SRM Institute of Science and Technology, Chennai, India
| | - Selwyn Mapolie
- Department of Chemistry and Polymer Science, Stellenbosch University, Stellenbosch, Western Cape, South Africa
| | - Sharon Prince
- Division of Cell Biology, Department of Human Biology, Faculty of Health Sciences, University of Cape Town, Cape Town, Western Cape, South Africa.
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13 R,20-Dihydroxydocosahexaenoic Acid, a Novel Dihydroxy- DHA Derivative, Inhibits Breast Cancer Stemness through Regulation of the Stat3/IL-6 Signaling Pathway by Inducing ROS Production. Antioxidants (Basel) 2021; 10:antiox10030457. [PMID: 33804152 PMCID: PMC7999786 DOI: 10.3390/antiox10030457] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 03/10/2021] [Accepted: 03/11/2021] [Indexed: 12/11/2022] Open
Abstract
Breast cancer is a major health problem worldwide. Cancer stem cells (CSCs) are known to mediate breast cancer metastasis and recurrence and are therefore a promising therapeutic target. In this study, we investigated the anti-inflammatory effect of 13R,20-dihydroxydocosahexaenoic acid (13R,20-diHDHA), a novel dihydroxy-DHA derivative, which was synthesized through an enzymatic reaction using cyanobacterial lipoxygenase. We found that 13R,20-diHDHA reduced the macrophage secretion of the inflammatory cytokines, IL-6 and TNF-α, and thus appeared to have anti-inflammatory effects. As the inflammatory tumor microenvironment is largely devoted to supporting the cancer stemness of breast cancer cells, we investigated the effect of 13R,20-diHDHA on breast cancer stemness. Indeed, 13R,20-diHDHA effectively inhibited breast cancer stemness, as evidenced by its ability to dose-dependently inhibit the mammospheres formation, colony formation, migration, and invasion of breast CSCs. 13R,20-diHDHA reduced the populations of CD44high/CD24low and aldehyde dehydrogenase (ALDH)-positive cells and the expression levels of the cancer stemness-related self-renewal genes, Nanog, Sox2, Oct4, c-Myc, and CD44. 13R,20-diHDHA increased reactive oxygen species (ROS) production, and the generated ROS reduced the phosphorylation of nuclear signal transducer and activator of transcription 3 (Stat3) and the secretion of IL-6 by mammospheres. These data collectively suggest that 13R,20-diHDHA inhibits breast cancer stemness through ROS production and downstream regulation of Stat3/IL-6 signaling, and thus might be developed as an anti-cancer agent acting against CSCs.
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Flores-Huerta N, Silva-Cázares MB, Arriaga-Pizano LA, Prieto-Chávez JL, López-Camarillo C. LncRNAs and microRNAs as Essential Regulators of Stemness in Breast Cancer Stem Cells. Biomolecules 2021; 11:380. [PMID: 33802575 PMCID: PMC7998729 DOI: 10.3390/biom11030380] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 02/13/2021] [Accepted: 02/22/2021] [Indexed: 12/24/2022] Open
Abstract
Breast cancer is an aggressive disease with a high incidence in women worldwide. Two decades ago, a controversial hypothesis was proposed that cancer arises from a subpopulation of "tumor initiating cells" or "cancer stem cells-like" (CSC). Today, CSC are defined as small subset of somatic cancer cells within a tumor with self-renewal properties driven by the aberrant expression of genes involved in the maintenance of a stemness-like phenotype. The understanding of the underlying cellular and molecular mechanisms involved in the maintenance of CSC subpopulation are fundamental in the development and persistence of breast cancer. Nowadays, the hypothesis suggests that genetic and epigenetic alterations give rise to breast cancer stem cells (bCSC), which are responsible for self-renewal, tumor growth, chemoresistance, poor prognosis and low survival in patients. However, the prominence of bCSC, as well as the molecular mechanisms that regulates and promotes the malignant phenotypes, are still poorly understood. The role of non-coding RNAs (ncRNAs), such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) acting as oncogenes or tumor suppressor genes has been recently highlighted by a plethora of studies in breast cancer. These ncRNAs positively or negatively impact on different signaling pathways that govern the cancer hallmarks associated with bCSC, making them attractive targets for therapy. In this review, we present a current summary of the studies on the pivotal roles of lncRNAs and microRNAs in the regulation of genes associated to stemness of bCSC.
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Affiliation(s)
- Nadia Flores-Huerta
- Laboratorio de Oncogenómica y Proteómica del Cáncer, Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, 03100 CDMX, Mexico;
| | - Macrina B. Silva-Cázares
- Doctorado Institucional en Ingeniería y Ciencias de los Materiales, Universidad Autónoma de San Luis Potosí, 78210 San Luis Potosí, Mexico;
| | - Lourdes A. Arriaga-Pizano
- Unidad de Investigación Médica en Inmunoquímica, Hospital de Especialidades del Centro Médico Siglo XXI, Instituto Mexicano del Seguro Social, 06720 CDMX, Mexico;
| | - Jessica L. Prieto-Chávez
- Laboratorio de Citometría de Flujo, Centro de Instrumentos, Coordinación de Investigación en Salud, Hospital de Especialidades del Centro Médico Siglo XXI, Instituto Mexicano del Seguro Social, 06720 CDMX, Mexico;
| | - César López-Camarillo
- Laboratorio de Oncogenómica y Proteómica del Cáncer, Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, 03100 CDMX, Mexico;
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Elian FA, Are U, Ghosh S, Nuin P, Footz T, McMullen TPW, Brindley DN, Walter MA. FOXQ1 is Differentially Expressed Across Breast Cancer Subtypes with Low Expression Associated with Poor Overall Survival. BREAST CANCER-TARGETS AND THERAPY 2021; 13:171-188. [PMID: 33688250 PMCID: PMC7935334 DOI: 10.2147/bctt.s282860] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 12/16/2020] [Indexed: 12/17/2022]
Abstract
Purpose Forkhead box Q1 (FOXQ1) has been shown to contribute to the development and progression of cancers, including ovarian and breast cancer (BC). However, research exploring FOXQ1 expression, copy number variation (CNV), and prognostic value across different BC subtypes is limited. Our purpose was to evaluate FOXQ1 mRNA expression, CNV, and prognostic value across BC subtypes. Materials and Methods We determined FOXQ1 expression and CNV in BC patient tumors using RT-qPCR and qPCR, respectively. We also analyzed FOXQ1 expression and CNV in BC cell lines in the CCLE database using K-means clustering. The prognostic value of FOXQ1 expression in the TCGA-BRCA database was assessed using univariate and multivariate Cox's regression analysis as well as using the online tools OncoLnc, GEPIA, and UALCAN. Results Our analyses reveal that FOXQ1 mRNA is differentially expressed between different subtypes of BC and is significantly decreased in luminal BC and HER2 patients when compared to normal breast tissue samples. Furthermore, analysis of BC cell lines showed that FOXQ1 mRNA expression was independent of CNV. Moreover, patients with low FOXQ1 mRNA expression had significantly poorer overall survival compared to those with high FOXQ1 mRNA expression. Finally, low FOXQ1 expression had a critical impact on the prognostic values of BC patients and was an independent predictor of overall survival when it was adjusted for BC subtypes and to two other FOX genes, FOXF2 and FOXM1. Conclusion Our study reveals for the first time that FOXQ1 is differentially expressed across BC subtypes and that low expression of FOXQ1 is indicative of poor prognosis in patients with BC.
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Affiliation(s)
- Fahed A Elian
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Ubah Are
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Sunita Ghosh
- Department of Medical Oncology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.,Department of Mathematical and Statistical Sciences, Faculty of Science, University of Alberta, Edmonton, AB, Canada
| | - Paulo Nuin
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Tim Footz
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - Todd P W McMullen
- Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
| | - David N Brindley
- Department of Biochemistry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.,Cancer Research Institute of Northern Alberta, University of Alberta, Edmonton, AB, Canada
| | - Michael A Walter
- Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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35
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Gao L, Gou N, Yao M, Amakye WK, Ren J. Food-derived natural compounds in the management of chronic diseases via Wnt signaling pathway. Crit Rev Food Sci Nutr 2021; 62:4769-4799. [PMID: 33554630 DOI: 10.1080/10408398.2021.1879001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Wnt signaling pathway is an evolutionarily conserved pathway that control embryonic development, adult tissue homeostasis, and pathological processes of organisms throughout life. However, dysregulation of the Wnt signaling is associated with the occurrence of chronic diseases. In comparison with the application of chemical drugs as traditional treatment for chronic diseases, dietary agents have unique advantages, such as less side effects, multiple targets, convenience in accessibility and higher acceptability in long-term intervention. In this review, we summarized current progress in manipulating the Wnt signaling using food components and its benefits in managing chronic diseases. The underlying mechanisms of bioactive food components in the management of the disease progression via the Wnt signaling was illustrated. Then, the review focused on the function of dietary pattern (which might act via combination of foods with multiple nutrients or food ingredients) on targeting Wnt signaling at multiple level. The potential caveats and challenges in developing new strategy via modulating Wnt-associated diseases with food-based agents and appropriate dietary pattern are also discussed in detail. This review shed light on the understanding of the regulatory effect of food bioactive components on chronic diseases management through the Wnt signaling, which can be expanded to other specific signaling pathway associated with disease.
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Affiliation(s)
- Li Gao
- School of Food Science and Engineering, South China University of Technology, Guangzhou, China
| | - Na Gou
- School of Food Science and Engineering, South China University of Technology, Guangzhou, China
| | - Maojin Yao
- Guangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - William Kwame Amakye
- School of Food Science and Engineering, South China University of Technology, Guangzhou, China
| | - Jiaoyan Ren
- School of Food Science and Engineering, South China University of Technology, Guangzhou, China
- Research Institute for Food Nutrition and Human Health, Guangzhou, China
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Murayama T, Takeuchi Y, Yamawaki K, Natsume T, Li M, Marcela RCN, Nishimura T, Kogure Y, Nakata A, Tominaga K, Sasahara A, Yano M, Ishikawa S, Ohta T, Ikeda K, Horie-Inoue K, Inoue S, Seki M, Suzuki Y, Sugano S, Enomoto T, Tanabe M, Tada KI, Kanemaki MT, Okamoto K, Tojo A, Gotoh N. MCM10 compensates for Myc-induced DNA replication stress in breast cancer stem-like cells. Cancer Sci 2021; 112:1209-1224. [PMID: 33340428 PMCID: PMC7935783 DOI: 10.1111/cas.14776] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Revised: 11/16/2020] [Accepted: 12/14/2020] [Indexed: 12/15/2022] Open
Abstract
Cancer stem-like cells (CSCs) induce drug resistance and recurrence of tumors when they experience DNA replication stress. However, the mechanisms underlying DNA replication stress in CSCs and its compensation remain unclear. Here, we demonstrate that upregulated c-Myc expression induces stronger DNA replication stress in patient-derived breast CSCs than in differentiated cancer cells. Our results suggest critical roles for mini-chromosome maintenance protein 10 (MCM10), a firing (activating) factor of DNA replication origins, to compensate for DNA replication stress in CSCs. MCM10 expression is upregulated in CSCs and is maintained by c-Myc. c-Myc-dependent collisions between RNA transcription and DNA replication machinery may occur in nuclei, thereby causing DNA replication stress. MCM10 may activate dormant replication origins close to these collisions to ensure the progression of replication. Moreover, patient-derived breast CSCs were found to be dependent on MCM10 for their maintenance, even after enrichment for CSCs that were resistant to paclitaxel, the standard chemotherapeutic agent. Further, MCM10 depletion decreased the growth of cancer cells, but not of normal cells. Therefore, MCM10 may robustly compensate for DNA replication stress and facilitate genome duplication in cancer cells in the S-phase, which is more pronounced in CSCs. Overall, we provide a preclinical rationale to target the c-Myc-MCM10 axis for preventing drug resistance and recurrence of tumors.
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Affiliation(s)
- Takahiko Murayama
- Division of Molecular Therapy, Institute of Medical Science, The University of Tokyo, Minato-ku, Japan.,Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan
| | - Yasuto Takeuchi
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan
| | - Kaoru Yamawaki
- Division of Cancer Differentiation, National Cancer Center Research Institute, Chuo-ku, Japan.,Department of Obstetrics and Gynecology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Toyoaki Natsume
- Department of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Mishima City, Japan.,Department of Genetics, SOKENDAI, Mishima City, Japan
| | - Mengjiao Li
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan
| | - Rojas-Chaverra N Marcela
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan
| | - Tatsunori Nishimura
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan
| | - Yuta Kogure
- Department of Computational Biology and Medical Sciences, Graduate School of Frontier Science, The University of Tokyo, Kashiwa City, Japan
| | - Asuka Nakata
- Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan.,Department of Pediatrics, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Kana Tominaga
- Division of Molecular Therapy, Institute of Medical Science, The University of Tokyo, Minato-ku, Japan.,Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan.,Division of Cancer Differentiation, National Cancer Center Research Institute, Chuo-ku, Japan
| | - Asako Sasahara
- Division of Molecular Therapy, Institute of Medical Science, The University of Tokyo, Minato-ku, Japan.,Department of Breast & Endocrine Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Masao Yano
- Department of Surgery, Minamimachida Hospital, Machida City, Japan
| | - Satoko Ishikawa
- Department of Gastroenterological Surgery, Kanazawa University, Kanazawa City, Japan
| | - Tetsuo Ohta
- Department of Gastroenterological Surgery, Kanazawa University, Kanazawa City, Japan
| | - Kazuhiro Ikeda
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka City, Japan
| | - Kuniko Horie-Inoue
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka City, Japan
| | - Satoshi Inoue
- Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Hidaka City, Japan
| | - Masahide Seki
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa City, Japan
| | - Yutaka Suzuki
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa City, Japan
| | - Sumio Sugano
- Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa City, Japan
| | - Takayuki Enomoto
- Department of Obstetrics and Gynecology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Japan
| | - Masahiko Tanabe
- Department of Breast & Endocrine Surgery, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Japan
| | - Kei-Ichiro Tada
- Department of Pediatrics, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Masato T Kanemaki
- Department of Chromosome Science, National Institute of Genetics, Research Organization of Information and Systems (ROIS), Mishima City, Japan.,Department of Genetics, SOKENDAI, Mishima City, Japan
| | - Koji Okamoto
- Division of Cancer Differentiation, National Cancer Center Research Institute, Chuo-ku, Japan
| | - Arinobu Tojo
- Division of Molecular Therapy, Institute of Medical Science, The University of Tokyo, Minato-ku, Japan
| | - Noriko Gotoh
- Division of Molecular Therapy, Institute of Medical Science, The University of Tokyo, Minato-ku, Japan.,Division of Cancer Cell Biology, Cancer Research Institute, Kanazawa University, Kanazawa City, Japan
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The Chick Chorioallantoic Membrane Model: A New In Vivo Tool to Evaluate Breast Cancer Stem Cell Activity. Int J Mol Sci 2020; 22:ijms22010334. [PMID: 33396951 PMCID: PMC7795925 DOI: 10.3390/ijms22010334] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 12/23/2020] [Accepted: 12/25/2020] [Indexed: 12/20/2022] Open
Abstract
The high plasticity of cancer stem-like cells (CSCs) allows them to differentiate and proliferate, specifically when xenotransplanted subcutaneously into immunocompromised mice. CSCs are highly tumorigenic, even when inoculated in small numbers. Thus, in vivo limiting dilution assays (LDA) in mice are the current gold standard method to evaluate CSC enrichment and activity. The chick embryo chorioallantoic membrane (CAM) is a low cost, naturally immune-incompetent and reproducible model widely used to evaluate the spontaneous growth of human tumor cells. Here, we established a CAM-LDA assay able to rapidly reproduce tumor specificities—in particular, the ability of the small population of CSCs to form tumors. We used a panel of organotropic metastatic breast cancer cells, which show an enrichment in a stem cell gene signature, enhanced CD44+/CD24−/low cell surface expression and increased mammosphere-forming efficiency (MFE). The size of CAM-xenografted tumors correlate with the number of inoculated cancer cells, following mice xenograft growth pattern. CAM and mice tumors are histologically comparable, displaying both breast CSC markers CD44 and CD49f. Therefore, we propose a new tool for studying CSC prevalence and function—the chick CAM-LDA—a model with easy handling, accessibility, rapid growth and the absence of ethical and regulatory constraints.
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He L, Yu A, Deng L, Zhang H. Eradicating the Roots: Advanced Therapeutic Approaches Targeting Breast Cancer Stem Cells. Curr Pharm Des 2020; 26:2009-2021. [PMID: 32183663 DOI: 10.2174/1381612826666200317132949] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Accepted: 03/08/2020] [Indexed: 12/30/2022]
Abstract
Accumulating evidences have demonstrated that the existence of breast cancer-initiating cells, which drives the original tumorigenicity, local invasion and migration propensity of breast cancer. These cells, termed as breast cancer stem cells (BCSCs), possess properties including self-renewal, multidirectional differentiation and proliferative potential, and are believed to play important roles in the intrinsic drug resistance of breast cancer. One of the reasons why BCBCs cause difficulties in breast cancer treating is that BCBCs can control both genetic and non-genetic elements to keep their niches safe and sound, which allows BCSCs for constant self-renewal and differentiation. Therapeutic strategies designed to target BCSCs may ultimately result in effective interventions for the treatment of breast cancer. Novel strategies including nanomedicine, oncolytic virus therapy, immunotherapy and induced differentiation therapy are emerging and proved to be efficient in anti-BCSCs therapy. In this review, we summarized breast tumor biology and the current challenges of breast cancer therapies, focused on breast cancer stem cells, and introduced promising therapeutic strategies targeting BCSCs.
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Affiliation(s)
- Lili He
- College of Pharmacy, Southwest Minzu University, Chengdu, China
| | - Anran Yu
- The State University of New York, Buffalo, NY 12246, United States
| | - Li Deng
- West China School of Pharmacy, Sichuan University, Chengdu, China
| | - Hongwei Zhang
- School of Pharmacy, MCPHS University, Boston, MA 02115, United States
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Balcioglu O, Heinz RE, Freeman DW, Gates BL, Hagos BM, Booker E, Mirzaei Mehrabad E, Diesen HT, Bhakta K, Ranganathan S, Kachi M, Leblanc M, Gray PC, Spike BT. CRIPTO antagonist ALK4 L75A-Fc inhibits breast cancer cell plasticity and adaptation to stress. Breast Cancer Res 2020; 22:125. [PMID: 33187540 PMCID: PMC7664111 DOI: 10.1186/s13058-020-01361-z] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 10/20/2020] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND CRIPTO is a multi-functional signaling protein that promotes stemness and oncogenesis. We previously developed a CRIPTO antagonist, ALK4L75A-Fc, and showed that it causes loss of the stem cell phenotype in normal mammary epithelia suggesting it may similarly inhibit CRIPTO-dependent plasticity in breast cancer cells. METHODS We focused on two triple negative breast cancer cell lines (MDA-MB-231 and MDA-MB-468) to measure the effects of ALK4L75A-Fc on cancer cell behavior under nutrient deprivation and endoplasmic reticulum stress. We characterized the proliferation and migration of these cells in vitro using time-lapse microscopy and characterized stress-dependent changes in the levels and distribution of CRIPTO signaling mediators and cancer stem cell markers. We also assessed the effects of ALK4L75A-Fc on proliferation, EMT, and stem cell markers in vivo as well as on tumor growth and metastasis using inducible lentiviral delivery or systemic administration of purified ALK4L75A-Fc, which represents a candidate therapeutic approach. RESULTS ALK4L75A-Fc inhibited adaptive responses of breast cancer cells under conditions of nutrient and ER stress and reduced their proliferation, migration, clonogenicity, and expression of EMT and cancer stem cell markers. ALK4L75A-Fc also inhibited proliferation of human breast cancer cells in stressed tumor microenvironments in xenografts and reduced both primary tumor size and metastatic burden. CONCLUSIONS Cancer cell adaptation to stresses such as nutrient deprivation, hypoxia, and chemotherapy can critically contribute to dormancy, metastasis, therapy resistance, and recurrence. Identifying mechanisms that govern cellular adaptation, plasticity, and the emergence of stem-like cancer cells may be key to effective anticancer therapies. Results presented here indicate that targeting CRIPTO with ALK4L75A-Fc may have potential as such a therapy since it inhibits breast cancer cell adaptation to microenvironmental challenges and associated stem-like and EMT phenotypes.
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Affiliation(s)
- Ozlen Balcioglu
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA
| | - Richard E Heinz
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA
| | - David W Freeman
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA
| | - Brooke L Gates
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA
| | - Berhane M Hagos
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA
| | - Evan Booker
- Peptide Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | | | - Hyrum T Diesen
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA
| | - Kishan Bhakta
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA
| | - Supraja Ranganathan
- Department of Biochemistry, University of Utah, Salt Lake City, UT, 84112, USA
| | - Masami Kachi
- Peptide Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Mathias Leblanc
- Peptide Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
| | - Peter C Gray
- Peptide Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA, 92037, USA
- Present Address: Biotheranostics Inc., San Diego, CA, 92121, USA
| | - Benjamin T Spike
- Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
- Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA.
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Zagorac S, de Giorgio A, Dabrowska A, Kalisz M, Casas-Vila N, Cathcart P, Yiu A, Ottaviani S, Degani N, Lombardo Y, Tweedie A, Nissan T, Vance KW, Ulitsky I, Stebbing J, Castellano L. SCIRT lncRNA Restrains Tumorigenesis by Opposing Transcriptional Programs of Tumor-Initiating Cells. Cancer Res 2020; 81:580-593. [PMID: 33172932 DOI: 10.1158/0008-5472.can-20-2612] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 10/05/2020] [Accepted: 11/05/2020] [Indexed: 11/16/2022]
Abstract
In many tumors, cells transition reversibly between slow-proliferating tumor-initiating cells (TIC) and their differentiated, faster-growing progeny. Yet, how transcriptional regulation of cell-cycle and self-renewal genes is orchestrated during these conversions remains unclear. In this study, we show that as breast TIC form, a decrease in cell-cycle gene expression and increase in self-renewal gene expression are coregulated by SOX2 and EZH2, which colocalize at CpG islands. This pattern was negatively controlled by a novel long noncoding RNA (lncRNA) that we named Stem Cell Inhibitory RNA Transcript (SCIRT), which was markedly upregulated in tumorspheres but colocalized with and counteracted EZH2 and SOX2 during cell-cycle and self-renewal regulation to restrain tumorigenesis. SCIRT specifically interacted with EZH2 to increase EZH2 affinity to FOXM1 without binding the latter. In this manner, SCIRT induced transcription at cell-cycle gene promoters by recruiting FOXM1 through EZH2 to antagonize EZH2-mediated effects at target genes. Conversely, on stemness genes, FOXM1 was absent and SCIRT antagonized EZH2 and SOX2 activity, balancing toward repression. These data suggest that the interaction of an lncRNA with EZH2 can alter the affinity of EZH2 for its protein-binding partners to regulate cancer cell state transitions. SIGNIFICANCE: These findings show that a novel lncRNA SCIRT counteracts breast tumorigenesis by opposing transcriptional networks associated with cell cycle and self-renewal.See related commentary by Pardini and Dragomir, p. 535.
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Affiliation(s)
- Sladjana Zagorac
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom
| | - Alex de Giorgio
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom
| | - Aleksandra Dabrowska
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom
| | - Mark Kalisz
- Epithelial Carcinogenesis Group, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
| | | | - Paul Cathcart
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom
| | - Angela Yiu
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom
| | - Silvia Ottaviani
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom
| | - Neta Degani
- Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel
| | - Ylenia Lombardo
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom.,Nature Communications, The Macmillan Campus, London, United Kingdom
| | - Alistair Tweedie
- University of Sussex, School of life Sciences, John Maynard Smith Building, Falmer, Brighton, United Kingdom
| | - Tracy Nissan
- University of Sussex, School of life Sciences, John Maynard Smith Building, Falmer, Brighton, United Kingdom
| | - Keith W Vance
- Department of Biology and Biochemistry, University of Bath, Bath, United Kingdom
| | - Igor Ulitsky
- Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, Israel
| | - Justin Stebbing
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom
| | - Leandro Castellano
- Division of Cancer, Department of Surgery and Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, United Kingdom. .,University of Sussex, School of life Sciences, John Maynard Smith Building, Falmer, Brighton, United Kingdom
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García-Heredia JM, Otero-Albiol D, Pérez M, Pérez-Castejón E, Muñoz-Galván S, Carnero A. Breast tumor cells promotes the horizontal propagation of EMT, stemness, and metastasis by transferring the MAP17 protein between subsets of neoplastic cells. Oncogenesis 2020; 9:96. [PMID: 33106480 PMCID: PMC7589521 DOI: 10.1038/s41389-020-00280-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 09/29/2020] [Accepted: 10/05/2020] [Indexed: 12/13/2022] Open
Abstract
MAP17 (PDZK1IP1) is a small protein regulating inflammation and tumor progression, upregulated in a broad range of carcinomas. MAP17 levels increase during tumor progression in a large percentage of advanced tumors. In the present work, we explored the role of this protein shaping tumor evolution. Here we show that in breast cancer, cells increased MAP17 levels in tumors by demethylation induced multiple changes in gene expression through specific miRNAs downregulation. These miRNA changes are dependent on Notch pathway activation. As a consequence, epithelial mesenchymal transition (EMT) and stemness are induced promoting the metastatic potential of these cells both in vitro and in vivo. Furthermore, MAP17 increased the exosomes in tumor cells, where MAP17 was released as cargo, and this horizontal propagation also increased the EMT in the recipient cells. Importantly, an antibody against MAP17 in the media reduces the EMT and stemness alterations promoted by the conditioned media from MAP17-expressing cells. Therefore, MAP17 expression promotes the horizontal propagation of EMT and metastasis by transferring the MAP17 protein between subsets of neoplastic cells. Thus, MAP17 can be used to describe a new mechanism for cell malignity at distance, without the involvement of genetic or epigenetic modifications. MAP17 can also be taken in consideration as new target for metastatic high-grade breast tumors.
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Affiliation(s)
- José Manuel García-Heredia
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain.,Departamento de Bioquímica Vegetal y Biología Molecular, Universidad de Sevilla, Seville, Spain.,CIBER de Cancer, Seville, Spain
| | - Daniel Otero-Albiol
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain.,CIBER de Cancer, Seville, Spain
| | - Marco Pérez
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain.,CIBER de Cancer, Seville, Spain
| | - Elena Pérez-Castejón
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain
| | - Sandra Muñoz-Galván
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain.,CIBER de Cancer, Seville, Spain
| | - Amancio Carnero
- Instituto de Biomedicina de Sevilla (IBIS), Hospital Universitario Virgen del Rocío, Universidad de Sevilla, Consejo Superior de Investigaciones Científicas, Seville, Spain. .,CIBER de Cancer, Seville, Spain.
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BeLow M, Osipo C. Notch Signaling in Breast Cancer: A Role in Drug Resistance. Cells 2020; 9:cells9102204. [PMID: 33003540 PMCID: PMC7601482 DOI: 10.3390/cells9102204] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 09/25/2020] [Accepted: 09/28/2020] [Indexed: 12/18/2022] Open
Abstract
Breast cancer is a heterogeneous disease that can be subdivided into unique molecular subtypes based on protein expression of the Estrogen Receptor, Progesterone Receptor, and/or the Human Epidermal Growth Factor Receptor 2. Therapeutic approaches are designed to inhibit these overexpressed receptors either by endocrine therapy, targeted therapies, or combinations with cytotoxic chemotherapy. However, a significant percentage of breast cancers are inherently resistant or acquire resistance to therapies, and mechanisms that promote resistance remain poorly understood. Notch signaling is an evolutionarily conserved signaling pathway that regulates cell fate, including survival and self-renewal of stem cells, proliferation, or differentiation. Deregulation of Notch signaling promotes resistance to targeted or cytotoxic therapies by enriching of a small population of resistant cells, referred to as breast cancer stem cells, within the bulk tumor; enhancing stem-like features during the process of de-differentiation of tumor cells; or promoting epithelial to mesenchymal transition. Preclinical studies have shown that targeting the Notch pathway can prevent or reverse resistance through reduction or elimination of breast cancer stem cells. However, Notch inhibitors have yet to be clinically approved for the treatment of breast cancer, mainly due to dose-limiting gastrointestinal toxicity. In this review, we discuss potential mechanisms of Notch-mediated resistance in breast cancer cells and breast cancer stem cells, and various methods of targeting Notch through γ-secretase inhibitors, Notch signaling biologics, or transcriptional inhibitors. We also discuss future plans for identification of novel Notch-targeted therapies, in order to reduce toxicity and improve outcomes for women with resistant breast cancer.
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Affiliation(s)
- McKenna BeLow
- Integrated Cell Biology Program, Loyola University Chicago, Maywood, IL 60513, USA;
| | - Clodia Osipo
- Integrated Cell Biology Program, Loyola University Chicago, Maywood, IL 60513, USA;
- Department of Cancer Biology, Loyola University Chicago, Maywood, IL 60513, USA
- Department of Microbiology and Immunology, Loyola University Chicago, Maywood, IL 60513, USA
- Correspondence: ; Tel.: +1-708-327-2372
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Primary tumor removal improves the prognosis in patients with stage IV breast cancer: A population-based study (cohort study). Int J Surg 2020; 83:109-114. [PMID: 32931976 DOI: 10.1016/j.ijsu.2020.08.056] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/25/2020] [Accepted: 08/27/2020] [Indexed: 01/01/2023]
Abstract
Adjuvant therapy including chemotherapy, hormonal therapy, and radiotherapy were often used as a common stereotypy for female stage IV breast cancer rather than surgery. This study aimed to define the role of local surgery in metastatic breast cancer. Female metastatic breast cancer patients were identified in the Surveillance, Epidemiology, and End Results (SEER) program data (2010-2013). We compared survival time between patients who received primary tumor removal (PTR) versus those who did not. Multivariate Cox regression models and competitive risk models were built to adjust potential confounders. Of 7669 female stage IV breast cancer patients, 2704 (35.3%) had surgery on their breast tumor and 4965 (64.7%) did not. In the entire cohort, women who underwent PTR had a 45% reduced risk of breast cancer-related death (multi-adjusted hazard ratio [HR], 0.55; 95% CI, 0.50 to 0.60) compared with women who did not undergo PTR (P < 0.001). In a cause-specific hazard model (CS model), the multivariable HRs (95% CI) for the association of PTR with breast cancer related-death were 0.54 (0.50-0.60) in the multivariate-adjusted analysis. Similar results were also observed in the sub-distribution hazard function model (SD model) with corresponding multivariate HRs (95%CI) of 0.57 (0.52-0.63). Our study suggested that PTR was associated with improved survival in female stage IV breast cancer patients. The role of PTR in these patients needs to be re-evaluated.
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Alraouji NN, Al-Mohanna FH, Ghebeh H, Arafah M, Almeer R, Al-Tweigeri T, Aboussekhra A. Tocilizumab potentiates cisplatin cytotoxicity and targets cancer stem cells in triple-negative breast cancer. Mol Carcinog 2020; 59:1041-1051. [PMID: 32537818 DOI: 10.1002/mc.23234] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2020] [Revised: 05/18/2020] [Accepted: 06/02/2020] [Indexed: 01/09/2023]
Abstract
Triple-negative breast cancer (TNBC) is a very aggressive subtype with high recurrence rate and no molecular targets for therapies. This subtype is characterized by high expression/secretion of the proinvasive/metastatic interleukin-6 (IL-6) cytokine. In the present study, we have shown that tocilizumab inhibits the IL-6/STAT3 signaling and suppresses the cancer/inflammatory epigenetic IL-6/STAT3/NF-κB positive feedback loop. Furthermore, tocilizumab inhibited the proliferative and the migratory/invasiveness capacities as well as the epithelial-to-mesenchymal transition (EMT) process in TNBC cells. Importantly, tocilizumab suppressed the stemness-related characteristics of TNBC cells, through the inhibition of the Wnt/β-catenin breast cancer stem cell-related pathway. Additionally, we have shown that tocilizumab suppresses the paracrine activation of normal breast stromal fibroblasts to myofibroblats. Moreover, tocilizumab sensitized TNBC cells to the cytotoxic effect of cisplatin in vitro. Furthermore, pharmacological inhibition of IL-6 by tocilizumab had great inhibitory effect on tumor growth and the EMT process in humanized orthotopic breast tumors in mice. In addition, tocilizumab potentiated the proapoptotic effect of cisplatin in humanized breast tumors. Together, these findings indicate that tocilizumab can suppress the prometastatic capacity of TNBC cells and enhances the cytotoxic effect of cisplatin against these cells. Therefore, tocilizumab could be of great therapeutic value for these hard-to-treat TNBC patients.
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Affiliation(s)
- Noura N Alraouji
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Falah H Al-Mohanna
- Department of Comparative Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Hazem Ghebeh
- Stem Cell and Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Maria Arafah
- Department of Pathology, College of Medicine, King Saud University, Riyadh, Saudi Arabia
| | - Rafa Almeer
- Department of Zoology, College of Sciences, King Saud University, Riyadh, Saudi Arabia
| | - Taher Al-Tweigeri
- King Abdullah Centre for Oncology & Liver Diseases, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Abdelilah Aboussekhra
- Department of Molecular Oncology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Sun X, Lv X, Yan Y, Zhao Y, Ma R, He M, Wei M. Hypoxia-mediated cancer stem cell resistance and targeted therapy. Biomed Pharmacother 2020; 130:110623. [PMID: 32791395 DOI: 10.1016/j.biopha.2020.110623] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 08/02/2020] [Accepted: 08/05/2020] [Indexed: 02/07/2023] Open
Abstract
Drug resistance is a major obstacle in the treatment of tumors, which easily lead to relapse or poor prognosis. Cancer stem cells (CSCs) are regarded as one of the important targets that mediate tumor resistance. Increasing evidence shows that the tumor hypoxia microenvironment is closely related to the resistance of CSCs to chemotherapy and radiotherapy. In this review, we intend to review the articles that have described how the hypoxic microenvironment affects CSC stemness and mediates tumor resistance and provide new directions and methods in the clinical treatment of tumors. Here, we also discuss the feasibility and development prospects of using hypoxia-inducible factors (HIFs) that regulate the hypoxic microenvironment of tumors as targeted agents to treat tumors, as well as to reduce or even reverse the resistance of tumors to chemotherapy and radiotherapy.
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Affiliation(s)
- Xiaoyu Sun
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China; Liaoning Engineering Technology Research Center for the Research, Development and Industrialization of Innovative Peptide Drugs, China Medical University, Shenyang, Liaoning Province, China.
| | - Xuemei Lv
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China; Liaoning Engineering Technology Research Center for the Research, Development and Industrialization of Innovative Peptide Drugs, China Medical University, Shenyang, Liaoning Province, China.
| | - Yuanyuan Yan
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China; Liaoning Engineering Technology Research Center for the Research, Development and Industrialization of Innovative Peptide Drugs, China Medical University, Shenyang, Liaoning Province, China.
| | - Yanyun Zhao
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China; Liaoning Engineering Technology Research Center for the Research, Development and Industrialization of Innovative Peptide Drugs, China Medical University, Shenyang, Liaoning Province, China.
| | - Rong Ma
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China; Liaoning Engineering Technology Research Center for the Research, Development and Industrialization of Innovative Peptide Drugs, China Medical University, Shenyang, Liaoning Province, China.
| | - Miao He
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China; Liaoning Engineering Technology Research Center for the Research, Development and Industrialization of Innovative Peptide Drugs, China Medical University, Shenyang, Liaoning Province, China.
| | - Minjie Wei
- Department of Pharmacology, School of Pharmacy, China Medical University, Shenyang, Liaoning Province, China; Liaoning Engineering Technology Research Center for the Research, Development and Industrialization of Innovative Peptide Drugs, China Medical University, Shenyang, Liaoning Province, China.
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46
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Teo WS, Holliday H, Karthikeyan N, Cazet AS, Roden DL, Harvey K, Konrad CV, Murali R, Varghese BA, Thankamony AP, Chan CL, McFarland A, Junankar S, Ye S, Yang J, Nikolic I, Shah JS, Baker LA, Millar EKA, Naylor MJ, Ormandy CJ, Lakhani SR, Kaplan W, Mellick AS, O'Toole SA, Swarbrick A, Nair R. Id Proteins Promote a Cancer Stem Cell Phenotype in Mouse Models of Triple Negative Breast Cancer via Negative Regulation of Robo1. Front Cell Dev Biol 2020; 8:552. [PMID: 32766238 PMCID: PMC7380117 DOI: 10.3389/fcell.2020.00552] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 06/10/2020] [Indexed: 01/02/2023] Open
Abstract
Breast cancers display phenotypic and functional heterogeneity and several lines of evidence support the existence of cancer stem cells (CSCs) in certain breast cancers, a minor population of cells capable of tumor initiation and metastatic dissemination. Identifying factors that regulate the CSC phenotype is therefore important for developing strategies to treat metastatic disease. The Inhibitor of Differentiation Protein 1 (Id1) and its closely related family member Inhibitor of Differentiation 3 (Id3) (collectively termed Id) are expressed by a diversity of stem cells and are required for metastatic dissemination in experimental models of breast cancer. In this study, we show that ID1 is expressed in rare neoplastic cells within ER-negative breast cancers. To address the function of Id1 expressing cells within tumors, we developed independent murine models of Triple Negative Breast Cancer (TNBC) in which a genetic reporter permitted the prospective isolation of Id1+ cells. Id1+ cells are enriched for self-renewal in tumorsphere assays in vitro and for tumor initiation in vivo. Conversely, depletion of Id1 and Id3 in the 4T1 murine model of TNBC demonstrates that Id1/3 are required for cell proliferation and self-renewal in vitro, as well as primary tumor growth and metastatic colonization of the lung in vivo. Using combined bioinformatic analysis, we have defined a novel mechanism of Id protein function via negative regulation of the Roundabout Axon Guidance Receptor Homolog 1 (Robo1) leading to activation of a Myc transcriptional programme.
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Affiliation(s)
- Wee S. Teo
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Holly Holliday
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Nitheesh Karthikeyan
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Aurélie S. Cazet
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Daniel L. Roden
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Kate Harvey
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | | | - Reshma Murali
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Binitha Anu Varghese
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
| | - Archana P. Thankamony
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
- Manipal Academy of Higher Education, Manipal, India
| | - Chia-Ling Chan
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Andrea McFarland
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Simon Junankar
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Sunny Ye
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Jessica Yang
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Iva Nikolic
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Jaynish S. Shah
- Gene & Stem Cell Therapy Program, Centenary Institute, The University of Sydney, Camperdown, NSW, Australia
| | - Laura A. Baker
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Ewan K. A. Millar
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Department of Anatomical Pathology, NSW Health Pathology, St George Hospital, Kogarah, NSW, Australia
- School of Medical Sciences, UNSW Sydney, Kensington, NSW, Australia
- School of Medicine, Western Sydney University, Penrith, NSW, Australia
| | - Matthew J. Naylor
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- School of Medical Sciences, Discipline of Physiology & Bosch Institute, University of Sydney, Sydney, NSW, Australia
| | - Christopher J. Ormandy
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Sunil R. Lakhani
- UQ Centre for Clinical Research, School of Medicine and Pathology Queensland, Royal Brisbane & Women's Hospital, The University of Queensland, Herston, QLD, Australia
| | - Warren Kaplan
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Peter Wills Bioinformatics Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
| | - Albert S. Mellick
- UNSW Medicine, University of NSW, Kensington, NSW, Australia
- Medical Oncology Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School UNSW & CONCERT Translational Cancer Research Centre, Liverpool, NSW, Australia
| | - Sandra A. O'Toole
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Alexander Swarbrick
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
| | - Radhika Nair
- Cancer Research Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
- Faculty of Medicine, St Vincent's Clinical School, UNSW Sydney, Sydney, NSW, Australia
- Cancer Research Program, Rajiv Gandhi Centre for Biotechnology, Thiruvananthapuram, India
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Kitaeva KV, Rutland CS, Rizvanov AA, Solovyeva VV. Cell Culture Based in vitro Test Systems for Anticancer Drug Screening. Front Bioeng Biotechnol 2020; 8:322. [PMID: 32328489 PMCID: PMC7160228 DOI: 10.3389/fbioe.2020.00322] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 03/24/2020] [Indexed: 12/18/2022] Open
Abstract
The development of new high-tech systems for screening anticancer drugs is one of the main problems of preclinical screening. Poor correlation between preclinical in vitro and in vivo data with clinical trials remains a major concern. The choice of the correct tumor model at the stage of in vitro testing provides reduction in both financial and time costs during later stages due to the timely screening of ineffective agents. In view of the growing incidence of oncology, increasing the pace of the creation, development and testing of new antitumor agents, the improvement and expansion of new high-tech systems for preclinical in vitro screening is becoming very important. The pharmaceutical industry presently relies on several widely used in vitro models, including two-dimensional models, three-dimensional models, microfluidic systems, Boyden's chamber and models created using 3D bioprinting. This review outlines and describes these tumor models including their use in research, in addition to their characteristics. This review therefore gives an insight into in vitro based testing which is of interest to researchers and clinicians from differing fields including pharmacy, preclinical studies and cell biology.
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Affiliation(s)
- Kristina V. Kitaeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
| | - Catrin S. Rutland
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom
| | - Albert A. Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
- School of Veterinary Medicine and Science, University of Nottingham, Nottingham, United Kingdom
| | - Valeriya V. Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan, Russia
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48
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Wu S, Zhang H, Fouladdel S, Li H, Keller E, Wicha MS, Omenn GS, Azizi E, Guan Y. Cellular, transcriptomic and isoform heterogeneity of breast cancer cell line revealed by full-length single-cell RNA sequencing. Comput Struct Biotechnol J 2020; 18:676-685. [PMID: 32257051 PMCID: PMC7114460 DOI: 10.1016/j.csbj.2020.03.005] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 01/28/2020] [Accepted: 03/11/2020] [Indexed: 12/13/2022] Open
Abstract
Tumor heterogeneity is generated through a combination of genetic and epigenetic mechanisms, the latter of which plays an important role in the generation of stem like cells responsible for tumor formation and metastasis. Although the development of single cell transcriptomic technologies holds promise to deconvolute this complexity, a number of these techniques have limitations including drop-out and uneven coverage, which challenge the further delineation of tumor heterogeneity. We adopted deep and full-length single-cell RNA sequencing on Fluidigm's Polaris platform to reveal the cellular, transcriptomic, and isoform heterogeneity of SUM149, a triple negative breast cancer (TNBC) cell line. We first validate the quality of the TNBC sequencing data with the sequencing data from erythroleukemia K562 cell line as control. We next scrutinized well-defined marker genes for cancer stem-like cell to identify different cell populations. We then profile the isoform expression data to investigate the heterogeneity of alternative splicing patterns. Though classified as triple-negative breast cancer, the SUM149 stem cells show heterogeneous expression of marker receptors (ER, PR, and HER2) across the cells. We identified three cell populations that express patterns of stemness: epithelial-mesenchymal transition (EMT) cancer stem cells (CSCs), mesenchymal-epithelial transition (MET) CSCs and Dual-EMT-MET CSCs. These cells also manifested a high level of heterogeneity in alternative splicing patterns. For example, CSCs have shown different expression patterns of the CD44v6 exon, as well as different levels of truncated EGFR transcripts, which may suggest different potentials for proliferation and invasion among cancer stem cells. Our study identified features of the landscape of previously underestimated cellular, transcriptomic, and isoform heterogeneity of cancer stem cells in triple-negative breast cancers.
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Affiliation(s)
- Shaocheng Wu
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor 48109, MI, United States
- Bioinformatics Graduate Program, University of British Columbia, 570 West 7th Avenue, V5Z 4S6 Vancouver, BC, Canada
- Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada
| | - Hongjiu Zhang
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor 48109, MI, United States
- Microsoft, Inc., Bellevue, WA, United States
| | - Shamileh Fouladdel
- Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109, MI, United States
| | - Hongyang Li
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor 48109, MI, United States
| | - Evan Keller
- Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109, MI, United States
- Department of Urology, Biointerfaces Institute and Single Cell Spatial Analysis Program, University of Michigan, Ann Arbor 48109, MI, United States
| | - Max S. Wicha
- Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109, MI, United States
| | - Gilbert S. Omenn
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor 48109, MI, United States
| | - Ebrahim Azizi
- Comprehensive Cancer Center, University of Michigan, Ann Arbor 48109, MI, United States
| | - Yuanfang Guan
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor 48109, MI, United States
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Dou X, Tong P, Huang H, Zellmer L, He Y, Jia Q, Zhang D, Peng J, Wang C, Xu N, Liao DJ. Evidence for immortality and autonomy in animal cancer models is often not provided, which causes confusion on key issues of cancer biology. J Cancer 2020; 11:2887-2920. [PMID: 32226506 PMCID: PMC7086263 DOI: 10.7150/jca.41324] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2019] [Accepted: 02/08/2020] [Indexed: 11/08/2022] Open
Abstract
Modern research into carcinogenesis has undergone three phases. Surgeons and pathologists started the first phase roughly 250 years ago, establishing morphological traits of tumors for pathologic diagnosis, and setting immortality and autonomy as indispensable criteria for neoplasms. A century ago, medical doctors, biologists and chemists started to enhance "experimental cancer research" by establishing many animal models of chemical-induced carcinogenesis for studies of cellular mechanisms. In this second phase, the two-hit theory and stepwise carcinogenesis of "initiation-promotion" or "initiation-promotion-progression" were established, with an illustrious finding that outgrowths induced in animals depend on the inducers, and thus are not authentically neoplastic, until late stages. The last 40 years are the third incarnation, molecular biologists have gradually dominated the carcinogenesis research fraternity and have established numerous genetically-modified animal models of carcinogenesis. However, evidence has not been provided for immortality and autonomy of the lesions from most of these models. Probably, many lesions had already been collected from animals for analyses of molecular mechanisms of "cancer" before the lesions became autonomous. We herein review the monumental work of many predecessors to reinforce that evidence for immortality and autonomy is essential for confirming a neoplastic nature. We extrapolate that immortality and autonomy are established early during sporadic human carcinogenesis, unlike the late establishment in most animal models. It is imperative to resume many forerunners' work by determining the genetic bases for initiation, promotion and progression, the genetic bases for immortality and autonomy, and which animal models are, in fact, good for identifying such genetic bases.
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Affiliation(s)
- Xixi Dou
- Shandong Provincial Key Laboratory of Transmucosal and Transdermal Drug Delivery, Shandong Freda Pharmaceutical Group Co., Ltd., Jinan 250101, Shandong Province, P.R. China
| | - Pingzhen Tong
- Department of Pathology, The Second Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, P.R. China
| | - Hai Huang
- Center for Clinical Laboratories, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, P.R. China
| | - Lucas Zellmer
- Masonic Cancer Center, University of Minnesota, 435 E. River Road, Minneapolis, MN 55455, USA
| | - Yan He
- Key Lab of Endemic and Ethnic Diseases of The Ministry of Education of China in Guizhou Medical University, Guiyang, Guizhou Province 550004, P. R. China
| | - Qingwen Jia
- Shandong Provincial Key Laboratory of Transmucosal and Transdermal Drug Delivery, Shandong Freda Pharmaceutical Group Co., Ltd., Jinan 250101, Shandong Province, P.R. China
| | - Daizhou Zhang
- Shandong Provincial Key Laboratory of Transmucosal and Transdermal Drug Delivery, Shandong Freda Pharmaceutical Group Co., Ltd., Jinan 250101, Shandong Province, P.R. China
| | - Jiang Peng
- Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, P.R. China
| | - Chenguang Wang
- Department of Orthopaedics, Shandong Provincial Hospital Affiliated to Shandong University, Jinan 250021, Shandong Province, P.R. China
| | - Ningzhi Xu
- Tianjin LIPOGEN Gene Technology Ltd., #238 Baidi Road, Nankai District, Tianjin 300192, P.R. China
| | - Dezhong Joshua Liao
- Department of Pathology, The Second Hospital of Guizhou University of Traditional Chinese Medicine, Guiyang 550001, Guizhou Province, P.R. China
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Chang NC. Autophagy and Stem Cells: Self-Eating for Self-Renewal. Front Cell Dev Biol 2020; 8:138. [PMID: 32195258 PMCID: PMC7065261 DOI: 10.3389/fcell.2020.00138] [Citation(s) in RCA: 106] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Accepted: 02/19/2020] [Indexed: 12/22/2022] Open
Abstract
Autophagy is a fundamental cell survival mechanism that allows cells to adapt to metabolic stress through the degradation and recycling of intracellular components to generate macromolecular precursors and produce energy. The autophagy pathway is critical for development, maintaining cellular and tissue homeostasis, as well as immunity and prevention of human disease. Defects in autophagy have been attributed to cancer, neurodegeneration, muscle and heart disease, infectious disease, as well as aging. While autophagy has classically been viewed as a passive quality control and general house-keeping mechanism, emerging evidence demonstrates that autophagy is an active process that regulates the metabolic status of the cell. Adult stem cells, which are long-lived cells that possess the unique ability to self-renew and differentiate into specialized cells throughout the body, have distinct metabolic requirements. Research in a variety of stem cell types have established that autophagy plays critical roles in stem cell quiescence, activation, differentiation, and self-renewal. Here, we will review the evidence demonstrating that autophagy is a key regulator of stem cell function and how defective stem cell autophagy contributes to degenerative disease, aging and the generation of cancer stem cells. Moreover, we will discuss the merits of targeting autophagy as a regenerative medicine strategy to promote stem cell function and improve stem cell-based therapies.
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Affiliation(s)
- Natasha C Chang
- Department of Biochemistry, Faculty of Medicine, McGill University, Montreal, QC, Canada
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