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Wang Y, Singh K, Lu C, Suntharalingam K. Anti-Cancer Stem Cell Properties of Square Planar Copper(II) Complexes with Vanillin Schiff Base Ligands. Molecules 2025; 30:1636. [PMID: 40286223 PMCID: PMC11990672 DOI: 10.3390/molecules30071636] [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: 03/04/2025] [Revised: 03/30/2025] [Accepted: 04/02/2025] [Indexed: 04/29/2025] Open
Abstract
Current breast cancer therapies are unable to positively impact the lives of a significant proportion of diagnosed patients (24% based on 10-year survival rate). Breast cancer relapse and metastasis, the leading cause of breast cancer-associated deaths, is linked to the existence of breast cancer stem cells (CSCs). Redox-modulating metal complexes have been used to perturb the redox balance in breast CSCs and effect cell death. Here, we sought to expand this promising class of anti-breast CSC agents. Specifically, we report the synthesis, and anti-breast CSC properties of a series of copper(II) complexes bearing regioisomeric vanillin Schiff base ligands (1-4). X-ray crystallography studies show that the copper(II) complexes 1-4 adopt square planar geometries with the copper(II) centre coordinated to two vanillin Schiff base ligands. The most effective copper(II) complex within the series 4 displays low micromolar potency towards breast CSCs, up to 4.6-fold higher than salinomycin and cisplatin. Mechanistic studies indicate that copper(II) complex 4 elevates reactive oxygen species levels in breast CSCs, leading to activation of the JNK/p38 pathway and caspase-dependent apoptosis. Overall, this work expands the library of anti-breast CSC copper(II) complexes and provides insight into their mode of action.
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Affiliation(s)
- Yihan Wang
- School of Chemistry, University of Leicester, Leicester LE1 7RH, UK; (Y.W.); (K.S.)
| | - Kuldip Singh
- School of Chemistry, University of Leicester, Leicester LE1 7RH, UK; (Y.W.); (K.S.)
| | - Chunxin Lu
- College of Biological, Chemical Sciences and Engineering, Jiaxing University, Jiaxing 314001, China
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Singh MT, Thaggikuppe Krishnamurthy P, Magham SV. Harnessing the synergistic potential of NK1R antagonists and selective COX-2 inhibitors for simultaneous targeting of TNBC cells and cancer stem cells. J Drug Target 2024; 32:258-269. [PMID: 38252517 DOI: 10.1080/1061186x.2024.2309568] [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: 09/26/2023] [Accepted: 01/11/2024] [Indexed: 01/24/2024]
Abstract
Triple-negative breast cancer (TNBC) lacks the expression of oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), rendering it unresponsive to endocrine therapy and HER2 targeted treatments. Though certain chemotherapeutics targeting the cell cycle have shown efficacy to a certain extent, the presence of chemotherapy-resistant cancer stem cells (CSCs) presents a significant challenge in tackling TNBC. Multiple lines of evidence suggest the upregulation of neuropeptide Substance P (SP), its NK-1 receptor (NK1R) and the Cyclooxygenase-2 (COX-2) enzyme in TNBC patients. Upregulation of the SP/NK1R system and COX-2 influences major signalling pathways involved in cell proliferation, growth, survival, angiogenesis, inflammation, metastasis and stem cell activity. The simultaneous activation and crosstalk between the pathways activated by SP/NK1R and COX-2 consequently increase the levels of key regulators of self-renewal pathways in CSCs, promoting stemness. The combination therapy with NK1R antagonists and COX-2 inhibitors can simultaneously target TNBC cells and CSCs, thereby enhancing treatment efficacy and reducing the risk of recurrence and relapse. This review discusses the rationale for combining NK1R antagonists and COX-2 inhibitors for the better management of TNBC and a novel strategy to deliver drug cargo precisely to the tumour site to address the challenges associated with off-target binding.
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Affiliation(s)
- Madhu Tanya Singh
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Praveen Thaggikuppe Krishnamurthy
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
| | - Sai Varshini Magham
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Ooty, The Nilgiris, Tamil Nadu, India
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3
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Lee DHY, Tsang JY, Li JJX, Lau SL, Tam F, Loong TC, Tse GM. Cytokeratin 15 is a novel and independent predictor of poor outcome in luminal B HER2-negative breast carcinomas. Pathology 2024; 56:834-841. [PMID: 38909003 DOI: 10.1016/j.pathol.2024.03.009] [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: 08/28/2023] [Revised: 02/28/2024] [Accepted: 03/18/2024] [Indexed: 06/24/2024]
Abstract
Cytokeratin 15 (CK15) has been described as a stem cell marker in human organs and its expression is seen in breast tissue. CK15 expression is associated with aggressive features in endometrial and oesophageal cancers, but data on the breast are lacking. This study aims to investigate the clinicopathological associations and prognostic significance of CK15 in breast carcinomas. A multi-institute cohort of breast carcinomas were retrieved. Clinicopathological and outcome data were obtained and compared with immunohistochemical expression CK15 and a panel of biomarkers. In total, 1,476 cases were included, with an expression rate of 3.5%, preferentially expressed in luminal subtypes (p=0.024), with luminal B carcinomas being the highest (4.7%), as opposed to basal-like (1%) and HER2-overexpressed carcinomas (0%). Except for nodal stage (p=0.013) and nodal metastasis (p=0.048), oestrogen (p=0.035) and progesterone receptor (p=0.001) positivity, there were no associations with other clinicopathological parameters. A trend was observed with shorter breast cancer specific survival (BCSS) in CK15-positive luminal B carcinomas (p=0.062). On further subgroup multivariate analysis of luminal B HER2-negative carcinomas, CK15 expression exhibited robust correlation with shorter BCSS (HR=9.004, p=0.001) and disease-free survival (HR=7.085, p<0.001). Restricted to luminal breast carcinomas, specifically luminal B HER2-negative, CK15 is demonstrated to be a robust independent predictor of higher risk of recurrence and shorter survival, with potential as a clinical prognostic marker and an exclusive stem cell marker for this subgroup of carcinomas.
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Affiliation(s)
- Dennis H Y Lee
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Julia Y Tsang
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Joshua J X Li
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Sin Leung Lau
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong
| | - Fiona Tam
- Department of Pathology, Kwong Wah Hospital, Hong Kong
| | | | - Gary M Tse
- Department of Anatomical and Cellular Pathology and State Key Laboratory of Translational Oncology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
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Kamalabadi Farahani M, Farjadmehr M, Atashi A, Momeni A, Behzadifard M. Concise review: breast cancer stems cells and their role in metastases. Ann Med Surg (Lond) 2024; 86:5266-5275. [PMID: 39238997 PMCID: PMC11374310 DOI: 10.1097/ms9.0000000000002270] [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: 04/02/2024] [Accepted: 06/04/2024] [Indexed: 09/07/2024] Open
Abstract
Background Breast cancer stem cells (BCSCs) have been suggested to be responsible for the development of Breast cancer (BC). The aim of this study was to evaluate BCSCs and the target organs microenvironment immunophenotyping markers in common BC metastases, and therapeutic targets regarding to the mentioned criteria. Material and methods This narrative review involved searching international databases; PubMed, Google Scholar using predetermined keywords including breast cancer, breast cancer stem cells, breast cancer metastases, immunophenotyping, immunohistochemistry and metastases. The search results were assessed based on the title, abstract, and full text of the articles, and relevant findings were included in the review. Results BCSCs express high amounts of aldehyde dehydrogenase 1 (ALDH1), Ganglioside 2 (GD2), CD44 and CD133 but are negative for CD24 marker. CXCR4 and OPN have high expression in the cells and may contribute in BC metastasis to the bone. Nestin, CK5, prominin-1 (CD133) markers in BCSCs have been reported to correlate with brain metastasis. High expression of CD44 in BCSCs and CXCL12 expression in the liver microenvironment may contribute to BC metastasis to the liver. Aberrantly expressed vascular cell adhesion molecule-1 (VCAM-1) that binds to collagen and elastin fibers on pulmonary parenchyma, and CXCR4 of BCSCs and CXCL12 in lung microenvironment may promote the cells homing and metastasis to lung. Conclusion As in various types of BC metastases different markers that expressed by the cells and target organ microenvironment are responsible, BCSCs immunophenotyping can be used as target markers to predict the disease prognosis and treatment.
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Affiliation(s)
| | | | - Amir Atashi
- Department of Tissue Engineering, School of Medicine, Shahroud University of Medical Sciences
| | - Alireza Momeni
- Department of hematology and Oncology, School of Medicine
| | - Mahin Behzadifard
- Department of Laboratory Sciences, School of Allied Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran
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Kunachowicz D, Kłosowska K, Sobczak N, Kepinska M. Applicability of Quantum Dots in Breast Cancer Diagnostic and Therapeutic Modalities-A State-of-the-Art Review. NANOMATERIALS (BASEL, SWITZERLAND) 2024; 14:1424. [PMID: 39269086 PMCID: PMC11396817 DOI: 10.3390/nano14171424] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 08/27/2024] [Accepted: 08/28/2024] [Indexed: 09/15/2024]
Abstract
The increasing incidence of breast cancers (BCs) in the world population and their complexity and high metastatic ability are serious concerns for healthcare systems. Despite the significant progress in medicine made in recent decades, the efficient treatment of invasive cancers still remains challenging. Chemotherapy, a fundamental systemic treatment method, is burdened with severe adverse effects, with efficacy limited by resistance development and risk of disease recurrence. Also, current diagnostic methods have certain drawbacks, attracting attention to the idea of developing novel, more sensitive detection and therapeutic modalities. It seems the solution for these issues can be provided by nanotechnology. Particularly, quantum dots (QDs) have been extensively evaluated as potential targeted drug delivery vehicles and, simultaneously, sensing and bioimaging probes. These fluorescent nanoparticles offer unlimited possibilities of surface modifications, allowing for the attachment of biomolecules, such as antibodies or proteins, and drug molecules, among others. In this work, we discuss the potential applicability of QDs in breast cancer diagnostics and treatment in light of the current knowledge. We begin with introducing the molecular and histopathological features of BCs, standard therapeutic regimens, and current diagnostic methods. Further, the features of QDs, along with their uptake, biodistribution patterns, and cytotoxicity, are described. Based on the reports published in recent years, we present the progress in research on possible QD use in improving BC diagnostics and treatment efficacy as chemotherapeutic delivery vehicles and photosensitizing agents, along with the stages of their development. We also address limitations and open questions regarding this topic.
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Affiliation(s)
- Dominika Kunachowicz
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Karolina Kłosowska
- Students' Scientific Association at the Department of Pharmaceutical Biochemistry (SKN No. 214), Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Natalia Sobczak
- Students' Scientific Association of Biomedical and Environmental Analyses (SKN No. 85), Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
| | - Marta Kepinska
- Department of Pharmaceutical Biochemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211A, 50-556 Wroclaw, Poland
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Stiff T, Bayraktar S, Dama P, Stebbing J, Castellano L. CRISPR screens in 3D tumourspheres identified miR-4787-3p as a transcriptional start site miRNA essential for breast tumour-initiating cell growth. Commun Biol 2024; 7:859. [PMID: 39003349 PMCID: PMC11246431 DOI: 10.1038/s42003-024-06555-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 07/04/2024] [Indexed: 07/15/2024] Open
Abstract
Our study employs pooled CRISPR screens, integrating 2D and 3D culture models, to identify miRNAs critical in Breast Cancer (BC) tumoursphere formation. These screens combine with RNA-seq experiments allowing identification of miRNA signatures and targets essential for tumoursphere growth. miR-4787-3p exhibits significant up-regulation in BC, particularly in basal-like BCs, suggesting its association with aggressive disease. Surprisingly, despite its location within the 5'UTR of a protein coding gene, which defines DROSHA-independent transcription start site (TSS)-miRNAs, we find it dependant on both DROSHA and DICER1 for maturation. Inhibition of miR-4787-3p hinders tumoursphere formation, highlighting its potential as a therapeutic target in BC. Our study proposes elevated miR-4787-3p expression as a potential prognostic biomarker for adverse outcomes in BC. We find that protein-coding genes positively selected in the CRISPR screens are enriched of miR-4787-3p targets. Of these targets, we select ARHGAP17, FOXO3A, and PDCD4 as known tumour suppressors in cancer and experimentally validate the interaction of miR-4787-3p with their 3'UTRs. Our work illuminates the molecular mechanisms underpinning miR-4787-3p's oncogenic role in BC. These findings advocate for clinical investigations targeting miR-4787-3p and underscore its prognostic significance, offering promising avenues for tailored therapeutic interventions and prognostic assessments in BC.
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Affiliation(s)
- Tom Stiff
- University of Sussex, School of life Sciences, John Maynard Smith Building, Falmer, Brighton, BN1 9QG, UK
| | - Salih Bayraktar
- University of Sussex, School of life Sciences, John Maynard Smith Building, Falmer, Brighton, BN1 9QG, UK
| | - Paola Dama
- University of Sussex, School of life Sciences, John Maynard Smith Building, Falmer, Brighton, BN1 9QG, UK
| | | | - Leandro Castellano
- University of Sussex, School of life Sciences, John Maynard Smith Building, Falmer, Brighton, BN1 9QG, UK.
- Department of Surgery and Cancer, Division of Cancer, Imperial College London, Imperial Centre for Translational and Experimental Medicine (ICTEM), London, W12 0NN, UK.
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Gadwal A, Purohit P, Khokhar M, Vishnoi JR, Pareek P, Choudhary R, Elhence P, Banerjee M, Sharma P. GALNT14 in association with GDF-15 promotes stemness and drug resistance through β-catenin signalling pathway in breast cancer. Mol Biol Rep 2024; 51:691. [PMID: 38796671 DOI: 10.1007/s11033-024-09645-9] [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: 03/11/2024] [Accepted: 05/16/2024] [Indexed: 05/28/2024]
Abstract
BACKGROUND Altered glycosylation plays a role in carcinogenesis. GALNT14 promotes cancer stem-like properties and drug resistance. GDF-15 is known to induces drug resistance and stemness markers for maintenance of breast cancer (BC) stem-like cell state. Currently there is lack of data on association of GDF-15 and GALNTs. In this study, the expression and interaction of GALNT14 and GDF-15 with stemness (OCT4 and SOX2) and drug resistance (ABCC5) markers were evaluated in BC. METHODS We investigated tumour tissue from 30 BC patients and adjacent non-tumour tissues. Expression of serum GALNT14 from BC patients and matched healthy controls was evaluated. Expression of GALNT14, GDF-15, OCT4, SOX2, ABCC5, and β-catenin in BC tissue was determined by RT-PCR. Knockdown of GALNT14 and GDF-15 in the MCF-7 cell line was done through siRNA, gene expression and protein expression of β-catenin by western blot were determined. RESULTS A significant increase in the expression of GALNT14, GDF-15, OCT4, SOX2, ABCC5, and β-catenin was observed in BC tumour tissues compared to adjacent non-tumour tissues. The serum level of GALNT14 was significantly high in BC patients (80.7 ± 65.3 pg/ml) compared to healthy controls (12.2 ± 9.12 pg/ml) (p < 0.000). To further analyse the signalling pathway involved in BC stemness and drug resistance, GALNT14 and GDF-15 were knocked down in the MCF-7 cell line, and it was observed that after knockdown, the expression level of OCT4, SOX2, ABCC5, and β-catenin was decreased, and co-knockdown with GALNT14 and GDF-15 further decreased the expression of genes. CONCLUSION It can be concluded that GALNT14, in association with GDF-15, promotes stemness and intrinsic drug resistance in BC, possibly through the β-catenin signalling pathway.
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Affiliation(s)
- Ashita Gadwal
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India.
| | - Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India
| | - Jeewan Ram Vishnoi
- Department of Oncosurgery, All India Institute of Medical Sciences, Jodhpur, India
| | - Puneet Pareek
- Department of Radiation Oncology, All India Institute of Medical Sciences, Jodhpur, India
| | - Ramkaran Choudhary
- Department of General Surgery, All India Institute of Medical Sciences, Jodhpur, India
| | - Poonam Elhence
- Department of Pathology, All India Institute of Medical Sciences, Jodhpur, India
| | - Mithu Banerjee
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, Rajasthan, 342005, India
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Sharif MS, Mohseni HS, Khanavi M, Ghadami S, Jafarzadeh E, Tavajohi S, Aliebrahimi S, Ostad SN. Exploring the Synergistic Effect of Sildenafil and Green Tea Polyphenols on Breast Cancer Stem Cell-like Cells and their Parental Cells: A Potential Novel Therapeutic Approach. Anticancer Agents Med Chem 2024; 24:304-315. [PMID: 37957912 DOI: 10.2174/0118715206276925231107060329] [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: 08/11/2023] [Revised: 10/17/2023] [Accepted: 10/19/2023] [Indexed: 11/15/2023]
Abstract
BACKGROUND Many cancer studies have intensely focused on the role of diet, among other factors involved in cancer establishment. The positive effect of green tea polyphenols (GTP) on controlling breast cancer cells has been reported in several studies. Cancer stem cell-like cells (CSC-LCs) possessing self-renewal, metastatic, and drug-resistant capacities are considered prominent therapeutic targets. In many tumors, inducible nitric oxide synthase (iNOS) expression levels are high; however, they have a dual effect on breast cancer pathogenesis. OBJECTIVE This study aimed to investigate the cytotoxicity of the iNOS agonist (Sildenafil) and antagonist (LNAME), both alone and in combination with GTP, on MDA-MB-231, CD44+/CD24- CSC-LCs, and their parental cells (MCF-7). METHODS The cell viability assay has been studied using the MTT assay. To analyze drug-drug combinations, CompuSyn and Combenefit software were used. The cytotoxicity mechanism was determined using flow cytometric analysis. RESULTS L-NAME and GTP showed a synergistic effect on MDA-MB-231 and CSC-LCs. Such an effect was not observed on MCF-7. Sildenafil and GTP, on the other hand, showed synergistic cytotoxicity in all the cells mentioned above. Flow cytometric tests resulted in more than 70% apoptosis in MDA-MB-231 and MCF-7. Also, sub-G1 arrest among MCF-7 cells and a considerable decrease in ROS production by MDA-MB-231 cells following treatment with Sildenafil and GTP were observed. CONCLUSION Sildenafil, in combination with flavonoids, may be considered a novel strategy for cancer treatment.
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Affiliation(s)
- Marzie Salari Sharif
- Department of Toxicology and Pharmacology, International Campus, School of Pharmacy, Tehran University of Medical Science, Tehran, Iran
| | - Habibeh Sadat Mohseni
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahnaz Khanavi
- Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Shima Ghadami
- Department of Pharmacognosy, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Emad Jafarzadeh
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Shohreh Tavajohi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Shima Aliebrahimi
- Department of Artificial Intelligence, Smart University of Medical Sciences, Tehran, Iran
| | - Seyed Nasser Ostad
- Toxicology and Poisoning Research Centre, Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
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Guefack MGF, Talukdar D, Mukherjee R, Guha S, Mitra D, Saha D, Das G, Damen F, Kuete V, Murmu N. Hypericum roeperianum bark extract suppresses breast cancer proliferation via induction of apoptosis, downregulation of PI3K/Akt/mTOR signaling cascade and reversal of EMT. JOURNAL OF ETHNOPHARMACOLOGY 2024; 319:117093. [PMID: 37634746 DOI: 10.1016/j.jep.2023.117093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/20/2023] [Accepted: 08/24/2023] [Indexed: 08/29/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Hypericum roeperianum is a medicinal spice traditionally used in West Africa to treat female sterility, fungal infections, and cancer. It has previously been reported that H. roeperianum exhibits cytotoxic potential by reducing the viability of cancer cells involving multidrug-resistant phenotypes, but its underlying molecular mechanism remains unknown. AIM OF THE STUDY The mechanistic involvement of H. roeperianum methanolic crude extract (HRC) in attenuating breast cancer progression by exploring the effects on mitochondrial apoptosis and epithelial-mesenchymal transition (EMT) was investigated. MATERIALS AND METHODS In the present study, we examined the anticancer properties of HRC through MTT assay, colony formation, wound healing assay, spheroid formation, DNA fragmentation and flow cytometry for cell cycle arrest, apoptosis (Annexin V/PI staining) and mitochondrial membrane potential (MMP) (JC-1) detection. In addition, western blot analysis of various proteins and quantitative real time PCR of various genes involved in apoptosis, EMT and the PI3K/Akt/mToR signal transduction pathway were performed. RESULTS This study revealed that HRC treatment significantly decreased breast cancer cell viability, colony forming efficiency and reduced the ability of cell migration and spheroid formation. HRC also induced apoptosis in MDA-MB-231 and MCF-7 via promoting G0/G1 cell cycle arrest, disruption of mitochondrial membrane potential and induction of DNA damage. The crude extract induced apoptosis by activating the intrinsic pathway with a stronger effect that relies on the combined potency of associated molecular markers including Bax, Bad, Bcl-2, cytochrome C, caspase-9, and cleaved-PARP. It was also found that HRC regulates the PI3K/Akt/mToR pathway. In addition, HRC inhibited EMT by expressional alteration of Vimentin and E-cadherin, as well as the regulatory transcription factors such as Snail and Slug. The in vitro findings reflected similar mechanistic approach in 4T1 cell induced syngeneic mice model, indicating the reduction of tumor volume along with the significant expressional alteration of EMT and apoptotic markers. CONCLUSION Taken together the findings concluded that H. roeperianum is a potential source of cytotoxic phytochemicals that exhibit abortifacient effect on breast cancer, both in vitro and in vivo, thus could further be utilized in breast cancer therapy.
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Affiliation(s)
- Michel-Gael F Guefack
- Department of Signal Transduction and Biogenic Amines, 37, S. P. Mukherjee Road, Chittaranjan National Cancer Institute (CNCI), Kolkata, 700026, India; Department of Biochemistry, University of Dschang, Dschang, Cameroon, P.O. Box 67, Dschang, Cameroon.
| | - Debojit Talukdar
- Department of Signal Transduction and Biogenic Amines, 37, S. P. Mukherjee Road, Chittaranjan National Cancer Institute (CNCI), Kolkata, 700026, India.
| | - Rimi Mukherjee
- Department of Signal Transduction and Biogenic Amines, 37, S. P. Mukherjee Road, Chittaranjan National Cancer Institute (CNCI), Kolkata, 700026, India.
| | - Subhabrata Guha
- Department of Signal Transduction and Biogenic Amines, 37, S. P. Mukherjee Road, Chittaranjan National Cancer Institute (CNCI), Kolkata, 700026, India.
| | - Debarpan Mitra
- Department of Signal Transduction and Biogenic Amines, 37, S. P. Mukherjee Road, Chittaranjan National Cancer Institute (CNCI), Kolkata, 700026, India.
| | - Depanwita Saha
- Department of Signal Transduction and Biogenic Amines, 37, S. P. Mukherjee Road, Chittaranjan National Cancer Institute (CNCI), Kolkata, 700026, India.
| | - Gaurav Das
- Department of Signal Transduction and Biogenic Amines, 37, S. P. Mukherjee Road, Chittaranjan National Cancer Institute (CNCI), Kolkata, 700026, India.
| | - François Damen
- Department of Chemistry, University of Dschang, Dschang, Cameroon, P.O. Box 67, Dschang, Cameroon.
| | - Victor Kuete
- Department of Biochemistry, University of Dschang, Dschang, Cameroon, P.O. Box 67, Dschang, Cameroon.
| | - Nabendu Murmu
- Department of Signal Transduction and Biogenic Amines, 37, S. P. Mukherjee Road, Chittaranjan National Cancer Institute (CNCI), Kolkata, 700026, India.
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10
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Ghazimoradi MH, Pakravan K, Khalafizadeh A, Babashah S. TET1 regulates stem cell properties and cell cycle of Cancer stem cells in triple-negative breast cancer via DNA demethylation. Biochem Pharmacol 2024; 219:115913. [PMID: 37995981 DOI: 10.1016/j.bcp.2023.115913] [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: 10/14/2023] [Revised: 11/04/2023] [Accepted: 11/07/2023] [Indexed: 11/25/2023]
Abstract
The role of cancer stem cells in metastasis, recurrence, and resistance to conventional therapies is significant. Addressing these cells could potentially decrease cancer reoccurrences and mortality rates. TET1, a crucial gene involved in stem cell self-renewal and potency, may also play a part in cancer stem cells, which warrants further research. To explore the role of TET1 in cancer stem cells, we conducted experiments involving loss and gain. We then analyzed factors such as migration, invasion, cell cycle, cell viability, mammosphere formation, and the CD44+/CD24- subpopulation of cancer cells. We also investigate the influence of TET1 on CCNB1, CDK1, and OCT4. Our study reveals that TET1 can regulate the phenotype of cancer stem cells via OCT4. Additionally, it can control the cell cycle by increasing CDK1 and CCNB1 levels. These findings suggest that targeting DNA methylation and TET1 could be an effective strategy to overcome obstacles posed by Cancer stem cells. Our research also indicates that TET1 can influence the phenotype of cancer stem cells and the cell cycle of breast cancer cells potentially through OCT4, CCNB1, and CDK1. This highlights the importance of TET1 in breast cancer cases and suggests a potential therapeutic approach through DNA methylation and modulation of TET1.
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Affiliation(s)
- Mohammad H Ghazimoradi
- Department of Molecular Genetics, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Katayoon Pakravan
- Department of Molecular Genetics, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Ali Khalafizadeh
- Department of Molecular Genetics, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Sadegh Babashah
- Department of Molecular Genetics, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.
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11
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Lin J, Feng D, Liu J, Yang Y, Wei X, Lin W, Lin Q. Construction of stemness gene score by bulk and single-cell transcriptome to characterize the prognosis of breast cancer. Aging (Albany NY) 2023; 15:8185-8203. [PMID: 37602872 PMCID: PMC10496995 DOI: 10.18632/aging.204963] [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: 03/15/2023] [Accepted: 07/17/2023] [Indexed: 08/22/2023]
Abstract
Breast cancer (BC) is a heterogeneous disease characterized by significant differences in prognosis and therapy response. Numerous prognostic tools have been developed for breast cancer. Usually these tools are based on bulk RNA-sequencing (RNA-Seq) and ignore tumor heterogeneity. Consequently, the goal of this study was to construct a single-cell level tool for predicting the prognosis of BC patients. In this study, we constructed a stemness-risk gene score (SGS) model based on single-sample gene set enrichment analysis (ssGSEA). Patients were divided into two groups based on the median SGS. Patients with a high SGS scores had a significantly worse prognosis than those with a low SGS, and these groups exhibited differences in several tumor characteristics, such as immune infiltration, gene mutations, and copy number variants. Our results indicate that the SGS is a reliable tool for predicting prognosis and response to immunotherapy in BC patients.
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Affiliation(s)
- Jun Lin
- Department of Anesthesiology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Anesthesiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Deyi Feng
- Xiamen University, Xiamen 361100, China
| | - Jie Liu
- Department of Endoscopy, Shengli Clinical Medical College of Fujian Medical University, Fuzhou 350001, China
| | - Ye Yang
- The First Affiliated Hospital of Fujian Medical University, Fuzhou 350005, China
| | - Xujin Wei
- The Graduate School of Fujian Medical University, Fuzhou 350001, China
| | - Wenqian Lin
- Department of Anesthesiology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Anesthesiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
| | - Qun Lin
- Department of Anesthesiology, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
- Department of Anesthesiology, National Regional Medical Center, Binhai Campus of the First Affiliated Hospital, Fujian Medical University, Fuzhou 350212, China
- Anesthesiology Research Institute, The First Affiliated Hospital, Fujian Medical University, Fuzhou 350005, China
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12
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Raute K, Strietz J, Parigiani MA, Andrieux G, Thomas OS, Kistner KM, Zintchenko M, Aichele P, Hofmann M, Zhou H, Weber W, Boerries M, Swamy M, Maurer J, Minguet S. Breast Cancer Stem Cell-Derived Tumors Escape from γδ T-cell Immunosurveillance In Vivo by Modulating γδ T-cell Ligands. Cancer Immunol Res 2023; 11:810-829. [PMID: 37139603 PMCID: PMC10236150 DOI: 10.1158/2326-6066.cir-22-0296] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Revised: 11/09/2022] [Accepted: 03/20/2023] [Indexed: 05/05/2023]
Abstract
There are no targeted therapies for patients with triple-negative breast cancer (TNBC). TNBC is enriched in breast cancer stem cells (BCSC), which play a key role in metastasis, chemoresistance, relapse, and mortality. γδ T cells hold great potential in immunotherapy against cancer and might provide an approach to therapeutically target TNBC. γδ T cells are commonly observed to infiltrate solid tumors and have an extensive repertoire of tumor-sensing mechanisms, recognizing stress-induced molecules and phosphoantigens (pAgs) on transformed cells. Herein, we show that patient-derived triple-negative BCSCs are efficiently recognized and killed by ex vivo expanded γδ T cells from healthy donors. Orthotopically xenografted BCSCs, however, were refractory to γδ T-cell immunotherapy. We unraveled concerted differentiation and immune escape mechanisms: xenografted BCSCs lost stemness, expression of γδ T-cell ligands, adhesion molecules, and pAgs, thereby evading immune recognition by γδ T cells. Indeed, neither promigratory engineered γδ T cells, nor anti-PD-1 checkpoint blockade, significantly prolonged overall survival of tumor-bearing mice. BCSC immune escape was independent of the immune pressure exerted by the γδ T cells and could be pharmacologically reverted by zoledronate or IFNα treatment. These results pave the way for novel combinatorial immunotherapies for TNBC.
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Affiliation(s)
- Katrin Raute
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
- Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany
| | - Juliane Strietz
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
- Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany
| | - Maria Alejandra Parigiani
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
- Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany
| | - Geoffroy Andrieux
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Oliver S. Thomas
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
- Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, Freiburg, Germany
| | - Klaus M. Kistner
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
- Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany
| | - Marina Zintchenko
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
- Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany
| | - Peter Aichele
- Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany
| | - Maike Hofmann
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Houjiang Zhou
- Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom
| | - Wilfried Weber
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
| | - Melanie Boerries
- Institute of Medical Bioinformatics and Systems Medicine, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
- German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Mahima Swamy
- Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom
| | - Jochen Maurer
- Department of Gynecology and Obstetrics, University Hospital RWTH Aachen, Aachen, Germany
| | - Susana Minguet
- Faculty of Biology, University of Freiburg, Freiburg, Germany
- Signalling Research Centres BIOSS and CIBSS, University of Freiburg, Freiburg, Germany
- Center of Chronic Immunodeficiency (CCI) and Institute for Immunodeficiency, University Clinics and Medical Faculty, Freiburg, Germany
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13
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Song L, Yang J, Qin Z, Ou C, Luo R, Yang W, Wang L, Wang N, Ma S, Wu Q, Gong C. Multi-Targeted and On-Demand Non-Coding RNA Regulation Nanoplatform against Metastasis and Recurrence of Triple-Negative Breast Cancer. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2207576. [PMID: 36905244 DOI: 10.1002/smll.202207576] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 02/06/2023] [Indexed: 06/08/2023]
Abstract
Dysregulation of microRNAs (miRs) is the hallmark of triple-negative breast cancer (TNBC), which is closely involved with its growth, metastasis, and recurrence. Dysregulated miRs are promising targets for TNBC therapy, however, targeted and accurate regulation of multiple disordered miRs in tumors is still a great challenge. Here, a multi-targeting and on-demand non-coding RNA regulation nanoplatform (MTOR) is reported to precisely regulate disordered miRs, leading to dramatical suppression of TNBC growth, metastasis, and recurrence. With the assistance of long blood circulation, ligands of urokinase-type plasminogen activator peptide and hyaluronan located in multi-functional shells enable MTOR to actively target TNBC cells and breast cancer stem cell-like cells (BrCSCs). After entering TNBC cells and BrCSCs, MTOR is subjected to lysosomal hyaluronidase-induced shell detachment, leading to an explosion of the TAT-enriched core, thereby enhancing nuclear targeting. Subsequently, MTOR could precisely and simultaneously downregulate microRNA-21 expression and upregulate microRNA-205 expression in TNBC. In subcutaneous xenograft, orthotopic xenograft, pulmonary metastasis, and recurrence TNBC mouse models, MTOR shows remarkably synergetic effects on the inhibition of tumor growth, metastasis, and recurrence due to its on-demand regulation of disordered miRs. This MTOR system opens a new avenue for on-demand regulation of disordered miRs against growth, metastasis, and recurrence of TNBC.
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Affiliation(s)
- Linjiang Song
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Jin Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Zeyi Qin
- Department of Biology, Brandeis University, Waltham, MA, 02453, USA
| | - Chunqing Ou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Rui Luo
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Wen Yang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Li Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Ning Wang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Shuang Ma
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Qinjie Wu
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
| | - Changyang Gong
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, P. R. China
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14
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Pantelaiou-Prokaki G, Reinhardt O, Georges NS, Agorku DJ, Hardt O, Prokakis E, Mieczkowska IK, Deppert W, Wegwitz F, Alves F. Basal-like mammary carcinomas stimulate cancer stem cell properties through AXL-signaling to induce chemotherapy resistance. Int J Cancer 2023; 152:1916-1932. [PMID: 36637144 DOI: 10.1002/ijc.34429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 12/16/2022] [Accepted: 12/19/2022] [Indexed: 01/14/2023]
Abstract
Basal-like breast cancer (BLBC) is the most aggressive and heterogeneous breast cancer (BC) subtype. Conventional chemotherapies represent next to surgery the most frequently employed treatment options. Unfortunately, resistant tumor phenotypes often develop, resulting in therapeutic failure. To identify the early events occurring upon the first drug application and initiating chemotherapy resistance in BLBC, we leveraged the WAP-T syngeneic mammary carcinoma mouse model and we developed a strategy combining magnetic-activated cell sorting (MACS)-based tumor cell enrichment with high-throughput transcriptome analyses. We discovered that chemotherapy induced a massive gene expression reprogramming toward stemness acquisition to tolerate and survive the cytotoxic treatment in vitro and in vivo. Retransplantation experiments revealed that one single cycle of cytotoxic drug combination therapy (Cyclophosphamide, Adriamycin and 5-Fluorouracil) suffices to induce resistant tumor cell phenotypes in vivo. We identified Axl and its ligand Pros1 as highly induced genes driving cancer stem cell (CSC) properties upon chemotherapy in vivo and in vitro. Furthermore, from our analysis of BLBC patient datasets, we found that AXL expression is also strongly correlated with CSC-gene signatures, a poor response to conventional therapies and worse survival outcomes in those patients. Finally, we demonstrate that AXL inhibition sensitized BLBC-cells to cytotoxic treatment in vitro. Together, our data support AXL as a promising therapeutic target to optimize the efficiency of conventional cytotoxic therapies in BLBC.
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Affiliation(s)
- Garyfallia Pantelaiou-Prokaki
- Max Planck Institute for Multidisciplinary Sciences, Translational Molecular Imaging, Göttingen, Germany.,Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany
| | - Oliver Reinhardt
- Max Planck Institute for Multidisciplinary Sciences, Translational Molecular Imaging, Göttingen, Germany
| | - Nadine S Georges
- Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany
| | - David J Agorku
- Miltenyi Biotec B.V. & Co. KG, R&D Reagents, Bergisch Gladbach, Germany
| | - Olaf Hardt
- Miltenyi Biotec B.V. & Co. KG, R&D Reagents, Bergisch Gladbach, Germany
| | - Evangelos Prokakis
- Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany
| | - Iga K Mieczkowska
- Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Wolfgang Deppert
- University Medical Center Hamburg Eppendorf, Institute for Tumor Biology, University of Hamburg, Hamburg, Germany
| | - Florian Wegwitz
- Department of Gynecology and Obstetrics, University Medical Center Göttingen, Göttingen, Germany.,Department of General, Visceral and Pediatric Surgery, University Medical Center Göttingen, Göttingen, Germany
| | - Frauke Alves
- Max Planck Institute for Multidisciplinary Sciences, Translational Molecular Imaging, Göttingen, Germany.,Institute for Diagnostic and Interventional Radiology, University Medical Center Göttingen, Göttingen, Germany.,Clinic for Hematology and Medical Oncology, University Medical Center Göttingen, Göttingen, Germany
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15
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Johnson A, Olelewe C, Kim JH, Northcote-Smith J, Mertens RT, Passeri G, Singh K, Awuah SG, Suntharalingam K. The anti-breast cancer stem cell properties of gold(i)-non-steroidal anti-inflammatory drug complexes. Chem Sci 2023; 14:557-565. [PMID: 36741517 PMCID: PMC9847679 DOI: 10.1039/d2sc04707a] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 12/10/2022] [Indexed: 12/14/2022] Open
Abstract
The anti-breast cancer stem cell (CSC) properties of a series of gold(i) complexes comprising various non-steroidal anti-inflammatory drugs (NSAIDs) and triphenylphosphine 1-8 are reported. The most effective gold(i)-NSAID complex 1, containing indomethacin, exhibits greater potency for breast CSCs than bulk breast cancer cells (up to 80-fold). Furthermore, 1 reduces mammosphere viability to a better extent than a panel of clinically used breast cancer drugs and salinomycin, an established anti-breast CSC agent. Mechanistic studies suggest 1-induced breast CSC death results from breast CSC entry, cytoplasm localisation, an increase in intracellular reactive oxygen species levels, cyclooxygenase-2 downregulation and inhibition, and apoptosis. Remarkably, 1 also significantly inhibits tumour growth in a murine metastatic triple-negative breast cancer model. To the best of our knowledge, 1 is the first gold complex of any geometry or oxidation state to demonstrate anti-breast CSC properties.
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Affiliation(s)
- Alice Johnson
- School of Chemistry, University of LeicesterLeicesterUK,Biomolecular Sciences Research Centre, Sheffield Hallam UniversitySheffieldUK
| | - Chibuzor Olelewe
- Department of Chemistry, University of KentuckyLexingtonKentuckyUSA
| | - Jong Hyun Kim
- Department of Chemistry, University of KentuckyLexingtonKentuckyUSA
| | | | - R. Tyler Mertens
- Department of Chemistry, University of KentuckyLexingtonKentuckyUSA
| | | | - Kuldip Singh
- School of Chemistry, University of LeicesterLeicesterUK
| | - Samuel G. Awuah
- Department of Chemistry, University of KentuckyLexingtonKentuckyUSA,Department of Pharmaceutical Sciences, University of KentuckyLexingtonKentuckyUSA
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16
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Zamfirescu AM, Yatsenko AS, Shcherbata HR. Notch signaling sculpts the stem cell niche. Front Cell Dev Biol 2022; 10:1027222. [PMID: 36605720 PMCID: PMC9810114 DOI: 10.3389/fcell.2022.1027222] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2022] [Accepted: 12/02/2022] [Indexed: 12/24/2022] Open
Abstract
Adult stem cells depend on their niches for regulatory signaling that controls their maintenance, division, and their progeny differentiation. While communication between various types of stem cells and their niches is becoming clearer, the process of stem cell niche establishment is still not very well understood. Model genetic organisms provide simplified systems to address various complex questions, for example, how is a stem cell niche formed? What signaling cascades induce the stem cell niche formation? Are the mechanisms of stem cell niche formation conserved? Notch signaling is an evolutionarily conserved pathway first identified in fruit flies, crucial in fate acquisition and spatiotemporal patterning. While the core logic behind its activity is fairly simple and requires direct cell-cell interaction, it reaches an astonishing complexity and versatility by combining its different modes of action. Subtleties such as equivalency between communicating cells, their physical distance, receptor and ligand processing, and endocytosis can have an effect on the way the events unfold, and this review explores some important general mechanisms of action, later on focusing on its involvement in stem cell niche formation. First, looking at invertebrates, we will examine how Notch signaling induces the formation of germline stem cell niche in male and female Drosophila. In the developing testis, a group of somatic gonadal precursor cells receive Delta signals from the gut, activating Notch signaling and sealing their fate as niche cells even before larval hatching. Meanwhile, the ovarian germline stem cell niche is built later during late larval stages and requires a two-step process that involves terminal filament formation and cap cell specification. Intriguingly, double security mechanisms of Notch signaling activation coordinated by the soma or the germline control both steps to ensure the robustness of niche assembly. Second, in the vast domains of mammalian cellular signaling, there is an emerging picture of Notch being an active player in a variety of tissues in health and disease. Notch involvement has been shown in stem cell niche establishment in multiple organs, including the brain, muscle, and intestine, where the stem cell niches are essential for the maintenance of adult stem cells. But adult stem cells are not the only cells looking for a home. Cancer stem cells use Notch signaling at specific stages to gain an advantage over endogenous tissue and overpower it, at the same time acquiring migratory and invasive abilities to claim new tissues (e.g., bone) as their territory. Moreover, in vitro models such as organoids reveal similar Notch employment when it comes to the developing stem cell niches. Therefore, a better understanding of the processes regulating stem cell niche assembly is key for the fields of stem cell biology and regenerative medicines.
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Affiliation(s)
| | | | - Halyna R. Shcherbata
- Mount Desert Island Biological Laboratory, Bar Harbor, ME, United States,*Correspondence: Halyna R. Shcherbata,
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17
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Targeting Breast Cancer Stem Cells Using Naturally Occurring Phytoestrogens. Int J Mol Sci 2022; 23:ijms23126813. [PMID: 35743256 PMCID: PMC9224163 DOI: 10.3390/ijms23126813] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/31/2022] [Accepted: 06/09/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer therapies have made significant strides in improving survival for patients over the past decades. However, recurrence and drug resistance continue to challenge long-term recurrence-free and overall survival rates. Mounting evidence supports the cancer stem cell model in which the existence of a small population of breast cancer stem cells (BCSCs) within the tumor enables these cells to evade conventional therapies and repopulate the tumor, giving rise to more aggressive, recurrent tumors. Thus, successful breast cancer therapy would need to target these BCSCs, as well the tumor bulk cells. Since the Women’s Health Initiative study reported an increased risk of breast cancer with the use of conventional hormone replacement therapy in postmenopausal women, many have turned their attention to phytoestrogens as a natural alternative. Phytoestrogens are plant compounds that share structural similarities with human estrogens and can bind to the estrogen receptors to alter the endocrine responses. Recent studies have found that phytoestrogens can also target BCSCs and have the potential to complement conventional therapy eradicating BCSCs. This review summarized the latest findings of different phytoestrogens and their effect on BCSCs, along with their mechanisms of action, including selective estrogen receptor binding and inhibition of molecular pathways used by BCSCs. The latest results of phytoestrogens in clinical trials are also discussed to further evaluate the use of phytoestrogen in the treatment and prevention of breast cancer.
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18
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Gentile P. Breast Cancer Therapy: The Potential Role of Mesenchymal Stem Cells in Translational Biomedical Research. Biomedicines 2022; 10:1179. [PMID: 35625915 PMCID: PMC9138371 DOI: 10.3390/biomedicines10051179] [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: 04/12/2022] [Revised: 05/06/2022] [Accepted: 05/18/2022] [Indexed: 02/04/2023] Open
Abstract
The potential role of mesenchymal stem cells (MSCs) in the treatment of metastatic cancers, including breast cancer, has been investigated for many years leading to encouraging results. The role of fat grafting and the related adipose-derived mesenchymal stem cells (AD-MSCs) has been detailed and described for breast reconstruction purposes confirming the safety of AD-MSCs. MSCs have great potential for delivering anticancer agents, suicide genes, and oncolytic viruses to tumors. Currently, many studies have focused on the products of MSCs, including extracellular vesicles (EVs), as a cell-free therapy. This work aimed to review and discuss the current knowledge on MSCs and their EVs in breast cancer therapy.
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Affiliation(s)
- Pietro Gentile
- Department of Surgical Science, “Tor Vergata” University, 00133 Rome, Italy; ; Tel.: +39-3388-5154-79
- Academy of International Regenerative Medicine & Surgery Societies (AIRMESS), 1201 Geneva, Switzerland
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19
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Firoozbakht F, Rezaeian I, Rueda L, Ngom A. Computationally repurposing drugs for breast cancer subtypes using a network-based approach. BMC Bioinformatics 2022; 23:143. [PMID: 35443626 PMCID: PMC9020161 DOI: 10.1186/s12859-022-04662-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2021] [Accepted: 03/30/2022] [Indexed: 11/22/2022] Open
Abstract
‘De novo’ drug discovery is costly, slow, and with high risk. Repurposing known drugs for treatment of other diseases offers a fast, low-cost/risk and highly-efficient method toward development of efficacious treatments. The emergence of large-scale heterogeneous biomolecular networks, molecular, chemical and bioactivity data, and genomic and phenotypic data of pharmacological compounds is enabling the development of new area of drug repurposing called ‘in silico’ drug repurposing, i.e., computational drug repurposing (CDR). The aim of CDR is to discover new indications for an existing drug (drug-centric) or to identify effective drugs for a disease (disease-centric). Both drug-centric and disease-centric approaches have the common challenge of either assessing the similarity or connections between drugs and diseases. However, traditional CDR is fraught with many challenges due to the underlying complex pharmacology and biology of diseases, genes, and drugs, as well as the complexity of their associations. As such, capturing highly non-linear associations among drugs, genes, diseases by most existing CDR methods has been challenging. We propose a network-based integration approach that can best capture knowledge (and complex relationships) contained within and between drugs, genes and disease data. A network-based machine learning approach is applied thereafter by using the extracted knowledge and relationships in order to identify single and pair of approved or experimental drugs with potential therapeutic effects on different breast cancer subtypes. Indeed, further clinical analysis is needed to confirm the therapeutic effects of identified drugs on each breast cancer subtype.
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Affiliation(s)
- Forough Firoozbakht
- School of Computer Science, University of Windsor, 401 Sunset Ave., Windsor, ON, Canada
| | - Iman Rezaeian
- School of Computer Science, University of Windsor, 401 Sunset Ave., Windsor, ON, Canada.,Rocket Innovation Studio, 156 Chatham St W, Windsor, ON, Canada
| | - Luis Rueda
- School of Computer Science, University of Windsor, 401 Sunset Ave., Windsor, ON, Canada.
| | - Alioune Ngom
- School of Computer Science, University of Windsor, 401 Sunset Ave., Windsor, ON, Canada
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20
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Eini M, Parsi S, Barati M, Bahramali G, Alizadeh Zarei M, Kiani J, Azarnezhad A, Hosseini A. Bioinformatic Investigation of Micro RNA-802 Target Genes, Protein Networks, and Its Potential Prognostic Value in Breast Cancer. Avicenna J Med Biotechnol 2022; 14:154-164. [PMID: 35633990 PMCID: PMC9077654 DOI: 10.18502/ajmb.v14i2.8882] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 01/22/2022] [Indexed: 11/24/2022] Open
Abstract
Background An increasing number of studies have suggested that unveiling the molecular network of miRNAs may provide novel therapeutic targets or biomarkers. In this study, we investigated the probable molecular functions that are related to microRNA-802 (miR-802) and evaluated its prognostic value in breast cancer utilizing bioinformatics tools. Methods PPI network, pathway enrichment and transcription factor analysis were applied to obtain hub genes among overlapping genes of four miRNA target prediction databases. Prognosis value assessments and expression analysis of hub genes using bioinformatics tools, as well as their literature validation were performed. Results Our results showed a significant correlation of the miR-802 overexpression with poor patient survival rate (BC, p=2.7e-5). We determined 247 target genes significant for GO and KEGG terms. Analysis of TFs by TRUST showed that RUNX3, FOXO3, and E2F1 are possible TFs that regulate the miR-802 expression and target genes network. According to our analysis; 21 genes might have an important function in miR-802 molecular processes and regulatory networks. The result shows that among these 21 genes, 8 genes (CASC3, ITGA4, AGO3, TARDBP, MED13L, SF1, SNRPE and CRNKL1) are positively correlated with patient survival. Therefore these genes could be considered and experimentally evaluated as a prognostic biomarker for breast cancer. Conclusion The comprehensive bioinformatics study on miR-802 target genes provided insight into miR-802 mediated pathways and processes. Furthermore, representing candidate target genes by prognostic values indicates the potential clinical application of miR-802 in breast cancer.
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Affiliation(s)
- Maryam Eini
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Sepideh Parsi
- Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School Worcester, MA, USA
| | - Mahmood Barati
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | | | | | - Jafar Kiani
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Assad Azarnezhad
- Liver and Digestive Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Arshad Hosseini
- Department of Biotechnology, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
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21
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The Role of Circulating Tumor Cells in the Prognosis of Metastatic Triple-Negative Breast Cancers: A Systematic Review of the Literature. Biomedicines 2022; 10:biomedicines10040769. [PMID: 35453519 PMCID: PMC9025371 DOI: 10.3390/biomedicines10040769] [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: 02/15/2022] [Revised: 03/20/2022] [Accepted: 03/22/2022] [Indexed: 12/24/2022] Open
Abstract
Breast cancer is one of the leading causes of death in women worldwide. One subtype of breast cancer is the triple-negative, which accounts for 15% of total breast cancer cases and is known for its poor prognosis. The main cause of death is due to metastasis. Circulating tumor cells (CTCs) play a key role in the metastatic process. CTCs arise either by detaching from the primary tumor or from cancer stem cells undergoing an epithelial-to-mesenchymal transition (EMT). This review aims to present up-to-date data concerning the role of CTC numbers in relation to the prognostic and treatment response in metastatic triple-negative breast cancer (mTNBC) patients, and also to discuss the methods used for CTCs’ identification. A search in the MEDLINE database was performed. A total of 234 articles were identified. The results of the 24 eligible studies showed that positive CTC status is associated with shorter overall survival (OS) and progression-free survival (PFS) in mTNBC patients. Furthermore, a decrease in number of CTCs during therapy seems to be a favorable prognostic factor, making CTCs’ detection an important prognostic tool before and during therapy in mTNBC patients. The methods used for CTC detection are still developing and need further improvement.
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22
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Wan Q, Zeng Z, Qi J, Chen Z, Liu X, Zu Y. Aptamer-armed nanostructures improve the chemotherapy outcome of triple-negative breast cancer. Mol Ther 2022; 30:2242-2256. [PMID: 35143958 DOI: 10.1016/j.ymthe.2022.02.004] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2021] [Revised: 11/10/2021] [Accepted: 02/04/2022] [Indexed: 11/17/2022] Open
Abstract
Triple-negative breast cancer is an aggressive subtype of breast cancer that is primarily treated using systemic chemotherapy due to the lack of a specific cell surface marker for drug delivery. Cancer cell-specific aptamer-mediated drug delivery is a promising targeted chemotherapy for marker-unknown cancers. Using a poorly differentiated carcinoma cell-specific DNA aptamer (PDGC21T), we formed a self-assembling circinate DNA nanoparticle (Apt21TNP) that binds triple-negative breast cancer cells. Using our previously designed pH-sensitive dendrimer-conjugated doxorubicin (DDOX) as the payload, we found that each nanoparticle loaded 30 doxorubicin molecules to form an Apt21TNP-DDOX nanomedicine that is stable in human plasma. Upon cell binding, Apt21TNP-DDOX is internalized by triple-negative breast cancer cells through the macropinocytosis pathway. Once inside cells, the low pH microenvironment in lysosomes induces doxorubicin drug payload release from Apt21TNP-DDOX. Our in vitro studies demonstrate that Apt21TNP-DDOX can preferentially bind triple-negative breast cancer cells to induce cell death. Further, we show that Apt21TNP-DDOX can accumulate in subcutaneous MDA-MB-231 tumors in mice following systemic administration to reduce tumor burden, minimize side effects, and improve animal survival. Together, our results demonstrate that Apt21TNP-mediated doxorubicin delivery is a potent, targeted chemotherapy for triple-negative breast cancer that may alleviate side effects in patients.
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Affiliation(s)
- Quanyuan Wan
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Zihua Zeng
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Jianjun Qi
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Zhenghu Chen
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Xiaohui Liu
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Youli Zu
- Department of Pathology and Genomic Medicine, Houston Methodist Hospital, Houston, TX 77030, USA.
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23
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Integration of Genomic Profiling and Organoid Development in Precision Oncology. Int J Mol Sci 2021; 23:ijms23010216. [PMID: 35008642 PMCID: PMC8745679 DOI: 10.3390/ijms23010216] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 11/26/2022] Open
Abstract
Precision oncology involves an innovative personalized treatment strategy for each cancer patient that provides strategies and options for cancer treatment. Currently, personalized cancer medicine is primarily based on molecular matching. Next-generation sequencing and related technologies, such as single-cell whole-transcriptome sequencing, enable the accurate elucidation of the genetic landscape in individual cancer patients and consequently provide clinical benefits. Furthermore, advances in cancer organoid models that represent genetic variations and mutations in individual cancer patients have direct and important clinical implications in precision oncology. This review aimed to discuss recent advances, clinical potential, and limitations of genomic profiling and the use of organoids in breast and ovarian cancer. We also discuss the integration of genomic profiling and organoid models for applications in cancer precision medicine.
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24
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Yu W, Hu C, Gao H. Advances of nanomedicines in breast cancer metastasis treatment targeting different metastatic stages. Adv Drug Deliv Rev 2021; 178:113909. [PMID: 34352354 DOI: 10.1016/j.addr.2021.113909] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2021] [Revised: 07/20/2021] [Accepted: 07/28/2021] [Indexed: 02/07/2023]
Abstract
Breast cancer is the most common tumor in women, and the metastasis further increases the malignancy with extremely high mortality. However, there is almost no effective method in the clinic to completely inhibit breast cancer metastasis due to the dynamic multistep process with complex pathways and scattered occurring site. Nowadays, nanomedicines have been evidenced with great potential in treating cancer metastasis. In this review, we summarize the latest research advances of nanomedicines in anti-metastasis treatment. Strategies are categorized according to the metastasis dynamics, including primary tumor, circulating tumor cells, pre-metastatic niches and secondary tumor. In each different stage of metastasis process, nanomedicines are designed specifically with different functions. At the end of the review, we give our perspectives on current limitations and future directions in anti-metastasis therapy. We expect the review provides comprehensive understandings of anti-metastasis therapy for breast cancer, and boosts the clinical translation in the future to improve women's health.
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25
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Scioli MG, Terriaca S, Fiorelli E, Storti G, Fabbri G, Cervelli V, Orlandi A. Extracellular Vesicles and Cancer Stem Cells in Tumor Progression: New Therapeutic Perspectives. Int J Mol Sci 2021; 22:10572. [PMID: 34638913 PMCID: PMC8508599 DOI: 10.3390/ijms221910572] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 09/27/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
Tumor burden is a complex microenvironment where different cell populations coexist and have intense cross-talk. Among them, a heterogeneous population of tumor cells with staminal features are grouped under the definition of cancer stem cells (CSCs). CSCs are also considered responsible for tumor progression, drug resistance, and disease relapse. Furthermore, CSCs secrete a wide variety of extracellular vesicles (EVs) with different cargos, including proteins, lipids, ssDNA, dsDNA, mRNA, siRNA, or miRNA. EVs are internalized by other cells, orienting the microenvironment toward a protumorigenic and prometastatic one. Given their importance in tumor growth and metastasis, EVs could be exploited as a new therapeutic target. The inhibition of biogenesis, release, or uptake of EVs could represent an efficacious strategy to impair the cross-talk between CSCs and other cells present in the tumor microenvironment. Moreover, natural or synthetic EVs could represent suitable carriers for drugs or bioactive molecules to target specific cell populations, including CSCs. This review will discuss the role of CSCs and EVs in tumor growth, progression, and metastasis and how they affect drug resistance and disease relapse. Furthermore, we will analyze the potential role of EVs as a target or vehicle of new therapies.
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Affiliation(s)
- Maria Giovanna Scioli
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, University of Rome Tor Vergata, 00133 Roma, Italy; (M.G.S.); (S.T.); (E.F.); (G.F.)
| | - Sonia Terriaca
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, University of Rome Tor Vergata, 00133 Roma, Italy; (M.G.S.); (S.T.); (E.F.); (G.F.)
| | - Elena Fiorelli
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, University of Rome Tor Vergata, 00133 Roma, Italy; (M.G.S.); (S.T.); (E.F.); (G.F.)
| | - Gabriele Storti
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Roma, Italy; (G.S.); (V.C.)
| | - Giulia Fabbri
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, University of Rome Tor Vergata, 00133 Roma, Italy; (M.G.S.); (S.T.); (E.F.); (G.F.)
| | - Valerio Cervelli
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, University of Rome Tor Vergata, 00133 Roma, Italy; (G.S.); (V.C.)
| | - Augusto Orlandi
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, University of Rome Tor Vergata, 00133 Roma, Italy; (M.G.S.); (S.T.); (E.F.); (G.F.)
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26
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Neagu AN, Whitham D, Buonanno E, Jenkins A, Alexa-Stratulat T, Tamba BI, Darie CC. Proteomics and its applications in breast cancer. Am J Cancer Res 2021; 11:4006-4049. [PMID: 34659875 PMCID: PMC8493401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Accepted: 07/05/2021] [Indexed: 06/13/2023] Open
Abstract
Breast cancer is an individually unique, multi-faceted and chameleonic disease, an eternal challenge for the new era of high-integrated precision diagnostic and personalized oncomedicine. Besides traditional single-omics fields (such as genomics, epigenomics, transcriptomics and metabolomics) and multi-omics contributions (proteogenomics, proteotranscriptomics or reproductomics), several new "-omics" approaches and exciting proteomics subfields are contributing to basic and advanced understanding of these "multiple diseases termed breast cancer": phenomics/cellomics, connectomics and interactomics, secretomics, matrisomics, exosomics, angiomics, chaperomics and epichaperomics, phosphoproteomics, ubiquitinomics, metalloproteomics, terminomics, degradomics and metadegradomics, adhesomics, stressomics, microbiomics, immunomics, salivaomics, materiomics and other biomics. Throughout the extremely complex neoplastic process, a Breast Cancer Cell Continuum Concept (BCCCC) has been modeled in this review as a spatio-temporal and holistic approach, as long as the breast cancer represents a complex cascade comprising successively integrated populations of heterogeneous tumor and cancer-associated cells, that reflect the carcinoma's progression from a "driving mutation" and formation of the breast primary tumor, toward the distant secondary tumors in different tissues and organs, via circulating tumor cell populations. This BCCCC is widely sustained by a Breast Cancer Proteomic Continuum Concept (BCPCC), where each phenotype of neoplastic and tumor-associated cells is characterized by a changing and adaptive proteomic profile detected in solid and liquid minimal invasive biopsies by complex proteomics approaches. Such a profile is created, beginning with the proteomic landscape of different neoplastic cell populations and cancer-associated cells, followed by subsequent analysis of protein biomarkers involved in epithelial-mesenchymal transition and intravasation, circulating tumor cell proteomics, and, finally, by protein biomarkers that highlight the extravasation and distant metastatic invasion. Proteomics technologies are producing important data in breast cancer diagnostic, prognostic, and predictive biomarkers discovery and validation, are detecting genetic aberrations at the proteome level, describing functional and regulatory pathways and emphasizing specific protein and peptide profiles in human tissues, biological fluids, cell lines and animal models. Also, proteomics can identify different breast cancer subtypes and specific protein and proteoform expression, can assess the efficacy of cancer therapies at cellular and tissular level and can even identify new therapeutic target proteins in clinical studies.
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Affiliation(s)
- Anca-Narcisa Neagu
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
- Laboratory of Animal Histology, Faculty of Biology, “Alexandru Ioan Cuza” University of IașiCarol I bvd. No. 22, Iași 700505, Romania
| | - Danielle Whitham
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
| | - Emma Buonanno
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
| | - Avalon Jenkins
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
| | - Teodora Alexa-Stratulat
- Department of Medical Oncology-Radiotherapy, “Grigore T. Popa” University of Medicine and PharmacyIndependenței bvd. No. 16-18, Iași 700021, Romania
| | - Bogdan Ionel Tamba
- Advanced Center for Research and Development in Experimental Medicine (CEMEX), “Grigore T. Popa” University of Medicine and PharmacyMihail Kogălniceanu Street No. 9-13, Iași 700454, Romania
| | - Costel C Darie
- Biochemistry & Proteomics Group, Department of Chemistry and Biomolecular Science, Clarkson UniversityPotsdam, NY 13699-5810, USA
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27
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Storti G, Scioli MG, Kim BS, Terriaca S, Fiorelli E, Orlandi A, Cervelli V. Mesenchymal Stem Cells in Adipose Tissue and Extracellular Vesicles in Ovarian Cancer Patients: A Bridge toward Metastatic Diffusion or a New Therapeutic Opportunity? Cells 2021; 10:cells10082117. [PMID: 34440886 PMCID: PMC8392703 DOI: 10.3390/cells10082117] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/09/2021] [Accepted: 08/16/2021] [Indexed: 12/24/2022] Open
Abstract
Ovarian cancer is one of the deadliest malignancies among women. Approximately 75% of the patients with ovarian cancer are diagnosed with advanced disease that already has metastasis, particularly to the omentum. The omentum constitutes the ideal soil for ovarian cancer metastasis due to a complex intraperitoneal milieu that favors and supports the whole metastatic process. Adipose-derived stem/stromal cells (ADSCs) are part of this microenvironment and foster tumor progression via sustained paracrine secretion, including extracellular vesicles (EVs). Nonetheless, the preferential relationship between ADSCs, ADSC-derived EVs, and ovarian cancer cells could be exploited to use ADSCs and EVs as a vehicle for anti-cancer therapies. This review will analyze the strict relations between tumor progression, metastatic disease, and adipose tissue with its staminal components. In addition, we will describe the crosstalk and biologic relationship between ADSCs and tumor cells, the role of EVs in intercellular communication, the establishment of drug resistance, metastatic capacity, and ovarian cancer progression. We will analyze the new therapeutic opportunities in treating ovarian cancer offered by ADSCs and EVs as a vehicle for therapeutic molecules to target precisely tumor cells and limit the systemic adverse effects. Finally, we will discuss the limitations of these therapeutic approaches.
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Affiliation(s)
- Gabriele Storti
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University of Rome, 00133 Rome, Italy;
- Correspondence: ; Tel.: +39-06-23188514; Fax: +39-06-23188466
| | - Maria Giovanna Scioli
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, Tor Vergata University of Rome, 00133 Rome, Italy; (M.G.S.); (S.T.); (E.F.); (A.O.)
| | - Bong-Sung Kim
- Department of Plastic Surgery and Hand Surgery, University Hospital Zurich, 8091 Zurich, Switzerland;
| | - Sonia Terriaca
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, Tor Vergata University of Rome, 00133 Rome, Italy; (M.G.S.); (S.T.); (E.F.); (A.O.)
| | - Elena Fiorelli
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, Tor Vergata University of Rome, 00133 Rome, Italy; (M.G.S.); (S.T.); (E.F.); (A.O.)
| | - Augusto Orlandi
- Department of Biomedicine and Prevention, Anatomic Pathology Institute, Tor Vergata University of Rome, 00133 Rome, Italy; (M.G.S.); (S.T.); (E.F.); (A.O.)
| | - Valerio Cervelli
- Plastic and Reconstructive Surgery, Department of Surgical Sciences, Tor Vergata University of Rome, 00133 Rome, Italy;
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28
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Khan S, Suryavanshi M, Kaur J, Nayak D, Khurana A, Manchanda RK, Tandon C, Tandon S. Stem cell therapy: A paradigm shift in breast cancer treatment. World J Stem Cells 2021; 13:841-860. [PMID: 34367480 PMCID: PMC8316873 DOI: 10.4252/wjsc.v13.i7.841] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 04/30/2021] [Accepted: 06/17/2021] [Indexed: 02/07/2023] Open
Abstract
As per the latest Globocan statistics, the high prevalence rate of breast cancer in low- and middle-income countries has led to it becoming the most common cancer to be diagnosed, hence posing a major public health challenge. As per this data, more than 11.7% of the estimated new cancer cases in 2020 were due to breast cancer. A small but significant subpopulation of cells with self- renewing ability are present in the tumor stroma and have been given the nomenclature of cancer stem cells (CSCs). These cells display a high degree of plasticity owing to their ability to transition from the slowly cycling quiescent phase to the actively proliferating phenotype. This attribute of CSCs allows them to differentiate into various cell types having diverse functions. Breast CSCs have a pivotal role in development, metastasis, treatment resistance and relapse of breast cancers. This review focuses on the pathways regulating breast CSC maintenance and the current strategies that are being explored for directing the development of novel, targeted, therapeutic approaches for limiting and eradicating this aberrant stem cell population.
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Affiliation(s)
- Sabiha Khan
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India
| | - Moushumi Suryavanshi
- Department of Pathology, Rajiv Gandhi Cancer Institute and Research Centre, New Delhi 110085, India
| | - Jasamrit Kaur
- Department of Chemistry, Goswami Ganesh Dutta Sanatan Dharma College, Chandigarh 160030, India
| | - Debadatta Nayak
- Central Council for Research in Homeopathy, New Delhi 110058, India
| | - Anil Khurana
- Central Council for Research in Homeopathy, New Delhi 110058, India
| | | | - Chanderdeep Tandon
- Amity Institute of Biotechnology, Amity University, Noida 201313, Uttar Pradesh, India
| | - Simran Tandon
- Amity Institute of Molecular Medicine and Stem Cell Research, Amity University, Noida 201313, Uttar Pradesh, India
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Liaghati P, Momeni P, Esfandi F, Kholghi Oskooei V, Sattari A, Ghafouri-Fard S, Taheri M. Expression analysis of CD24 and CD44 transcripts in Iranian breast cancer patients. Breast Dis 2021; 39:143-148. [PMID: 33427725 DOI: 10.3233/bd-200441] [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: 11/15/2022]
Abstract
BACKGROUND The importance of cancer stem cells (CSCs) in initiation and progression of breast cancer has been well established. This population of cells is characterized by high expression of CD44 and low expression of CD24. OBJECTIVE However, the relative abundance of CD24 and CD44 transcripts in breast cancer tissues and adjacent non-cancerous tissues (ANCTs) has not been quantified yet. METHODS In the present investigation, we assessed expression of CD24 and CD44 at transcript level in breast cancer tissues and ANCTs in association with clinical determinants of patients' outcome and parameters that predict response to therapeutic options. RESULTS There was no significant difference in expression of CD24 and CD44 in breast cancer tissues compared with ANCTs (Expression ratios: 1.03 and 0.84, P values: 0.92 and 0.61, respectively). However, CD44 expression was associated with tumor size in a way this gene was up-regulated in all of small sized (≤2 cm) tumors compared with the corresponding ANCTs (P value = 0.04). Besides, CD44 expression was significantly higher in tumors with extracapsular nodal extension compared with those without extension (P = 0.04). Expression of CD24 was higher in grade 3 tumors compared with grade 2 tumors (P = 0.04). CONCLUSION Expression levels of CD24 and CD44 were correlated with each other in ANCTs but not in tumoral tissues. The current study shows another aspect of CSC markers in the development of breast cancer.
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Affiliation(s)
- Pegah Liaghati
- Department of Cellular and Molecular Biology-Molecular Cellular Science, Faculty of Basic Science, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | - Parto Momeni
- Department of Cellular and Molecular Biology-Molecular Cellular Science, Faculty of Basic Science, Central Tehran Branch, Islamic Azad University, Tehran, Iran
| | | | - Vahid Kholghi Oskooei
- Department of Laboratory Sciences, School of Paramedical Sciences, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran.,Neuroscience Research Center, Torbat Heydariyeh University of Medical Sciences, Torbat Heydariyeh, Iran
| | - Ali Sattari
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Taheri
- Urogenital Stem Cell Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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30
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Enciso-Benavides J, Alfaro L, Castañeda-Altamirano C, Rojas N, González-Cabeza J, Enciso N, Riesco F, Castillo M, Enciso J. Biological characteristics of a sub-population of cancer stem cells from two triple-negative breast tumour cell lines. Heliyon 2021; 7:e07273. [PMID: 34235281 PMCID: PMC8247099 DOI: 10.1016/j.heliyon.2021.e07273] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 04/21/2021] [Accepted: 06/07/2021] [Indexed: 12/29/2022] Open
Abstract
Triple-negative breast tumours (TNBTs) make up 15-20% of all breast tumours. There is no treatment for them, and the role that cancer stem cells (CSCs) have in carcinogenesis is still unclear, so finding markers and therapeutic targets in CSC exosomes requires these cells to exist as a homogeneous cell population. The objective of this work was to determine differences in ultrastructural morphology, proliferative capacity, and mouse-xenotransplantation characteristics of the MDA-MB-231 and MDA-MB-436 TNBT cell lines with the CD44 high /CD24 low phenotype in order to study their exosomes. The results show that the CD44 high /CD24 low MBA-MB-231 cells had a population doubling time of 41.56 h, compared to 44.79 h in the MDA-MB-436 cell line. After magnetic immunoseparation, 18.75% and 14.56% of the stem cell population of the MDA-MB-231 and MDA-MB-436 cell lines, respectively, were of the CD44 high /CD24 low phenotype, which were expanded to reach purities of 80.4% and 87.6%. The same expanded lineage in both cell lines was shown to possess the pluripotency markers Nanog and Oct4. Under a scanning electron microscope, the CD44 high /CD24 low lineage of the MBA-MD-231 cell line formed groups of more interconnected cells than this lineage of the MBA-MD-436 line. A total of 16% of the mice inoculated with the CD44 high /CD24 low lineage of either cell line presented tumours of the breast, lung, and submandibular ganglia, in whose tissues variable numbers of inoculated cells were found 30 days post-inoculation. By magnetic immunoselection, it was possible to isolate in similar quantities and characterize, expand, and xenotransplant the CD44 high /CD24 low lineage of the MDA-MB-231 and MDA-MB-436 cell lines. The former cell line has greater proliferative capacity, the two lines differ under scanning electron microscopy in how they intercommunicate, and both cell lines induce new tumours in mice and persist at least 30 days post-inoculation in the transplanted animal so their exosomes would also be different.
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Affiliation(s)
| | - Luis Alfaro
- Grupo de Medicina Regenerativa, Universidad Científica del Sur, Lima, Peru
| | | | - Nancy Rojas
- Laboratorio de Microscopia Electrónica, Instituto de Patología, UNMSM, Lima, Peru
| | | | - Nathaly Enciso
- Dirección General de Investigación, Desarrollo e Innovación, Universidad Científica del Sur, Lima, Peru
| | - Fernando Riesco
- Laboratorio de Microscopia Electrónica, Instituto de Patología, UNMSM, Lima, Peru
| | | | - Javier Enciso
- Grupo de Medicina Regenerativa, Universidad Científica del Sur, Lima, Peru
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31
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Wang X, Wang C, Guan J, Chen B, Xu L, Chen C. Progress of Breast Cancer basic research in China. Int J Biol Sci 2021; 17:2069-2079. [PMID: 34131406 PMCID: PMC8193257 DOI: 10.7150/ijbs.60631] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 04/28/2021] [Indexed: 12/15/2022] Open
Abstract
Breast cancer is the most commonly diagnosed and the most lethal cancer in females both in China and worldwide. Currently, the origin of cancer stem cells, the heterogeneity of cancer cells, the mechanism of cancer metastasis and drug resistance are the most important issues that need to be addressed. Chinese investigators have recently made new discoveries in basic breast cancer researches, especially regarding cancer stem cells, cancer metabolism, and microenvironments. These efforts have led to a deeper understanding of drug resistance and metastasis and have also indicated new biomarkers and therapeutic targets. These findings emphasized the importance of the cancer stem cells for targeted therapy. In this review, we summarized the latest important findings in this field in China.
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Affiliation(s)
- Xuerong Wang
- Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Chao Wang
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, China
| | - Jiaheng Guan
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Baoan Chen
- Department of Hematology and Oncology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, China
| | - Lin Xu
- Department of Thoracic Surgery, Jiangsu Cancer Hospital, Nanjing Medical University Affiliated Cancer Hospital, Nanjing, Jiangsu 210009, China
| | - Ceshi Chen
- Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China
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32
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A novel Lnc408 maintains breast cancer stem cell stemness by recruiting SP3 to suppress CBY1 transcription and increasing nuclear β-catenin levels. Cell Death Dis 2021; 12:437. [PMID: 33934099 PMCID: PMC8088435 DOI: 10.1038/s41419-021-03708-6] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 04/01/2021] [Accepted: 04/02/2021] [Indexed: 12/26/2022]
Abstract
Tumor initiation, development, and relapse may be closely associated with cancer stem cells (CSCs). The complicated mechanisms underlying the maintenance of CSCs are keeping in illustration. Long noncoding RNAs (lncRNAs), due to their multifunction in various biological processes, have been indicated to play a crucial role in CSC renewal and stemness maintenance. Using lncRNA array, we identified a novel lncRNA (named lnc408) in epithelial-mesenchymal transition-related breast CSCs (BCSCs). The lnc408 is high expressed in BCSCs in vitro and in vivo. The enhanced lnc408 is critical to BCSC characteristics and tumorigenesis. Lnc408 can recruit transcript factor SP3 to CBY1 promoter to serve as an inhibitor in CBY1 transcription in BCSCs. The high expressed CBY1 in non-BCSC interacts with 14-3-3 and β-catenin to form a ternary complex, which leads a translocation of the ternary complex into cytoplasm from nucleus and degradation of β-catenin in phosphorylation-dependent pattern. The lnc408-mediated decrease of CBY1 in BCSCs impairs the formation of 14-3-3/β-catenin/CBY1 complex, and keeps β-catenin in nucleus to promote CSC-associated CD44, SOX2, Nanog, Klf4, and c-Myc expressions and contributes to mammosphere formation; however, restoration of CBY1 expression in tumor cells reduces BCSC and its enrichment, thus lnc408 plays an essential role in maintenance of BCSC stemness. In shortly, these findings highlight that the novel lnc408 functions as an oncogenic factor by recruiting SP3 to inhibit CBY1 expression and β-catenin accumulation in nucleus to maintain stemness properties of BCSCs. Lnc408-CBY1-β-catenin signaling axis might serve as a new diagnostic and therapeutic target for breast cancer.
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Song K, Farzaneh M. Signaling pathways governing breast cancer stem cells behavior. Stem Cell Res Ther 2021; 12:245. [PMID: 33863385 PMCID: PMC8052733 DOI: 10.1186/s13287-021-02321-w] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2021] [Accepted: 03/31/2021] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is the second common cancer and the leading cause of malignancy among females overall. Breast cancer stem cells (BCSCs) are a small population of breast cancer cells that play a critical role in the metastasis of breast cancer to other organs in the body. BCSCs have both self-renewal and differentiation capacities, which are thought to contribute to the aggressiveness of metastatic lesions. Therefore, targeting BCSCs can be a suitable approach for the treatment and metastasis of breast cancer. Growing evidence has indicated that the Wnt, NFκB, Notch, BMP2, STAT3, and hedgehog (Hh) signaling pathways govern epithelial-to-mesenchymal transition (EMT) activation, growth, and tumorigenesis of BCSCs in the primary regions. miRNAs as the central regulatory molecules also play critical roles in BCSC self-renewal, metastasis, and drug resistance. Hence, targeting these pathways might be a novel therapeutic approach for breast cancer diagnosis and therapy. This review discusses known signaling mechanisms involved in the stimulation or prevention of BCSC self-renewal, metastasis, and tumorigenesis.
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Affiliation(s)
- Kai Song
- Xuzhou Vocational College of Bioengineering, Xuzhou, 221006, Jiangsu, China.
| | - Maryam Farzaneh
- Fertility, Infertility and Perinatology Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
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Zhang R, Tu J, Liu S. Novel molecular regulators of breast cancer stem cell plasticity and heterogeneity. Semin Cancer Biol 2021; 82:11-25. [PMID: 33737107 DOI: 10.1016/j.semcancer.2021.03.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 11/19/2020] [Accepted: 03/11/2021] [Indexed: 12/12/2022]
Abstract
Tumors consist of heterogeneous cell populations, and tumor heterogeneity plays key roles in regulating tumorigenesis, metastasis, recurrence and resistance to anti-tumor therapies. More and more studies suggest that cancer stem cells (CSCs) promote tumorigenesis, metastasis, recurrence and drug resistance as well as are the major source for heterogeneity of cancer cells. CD24-CD44+ and ALDH+ are the most common markers for breast cancer stem cells (BCSCs). Previous studies showed that different BCSC markers label different BCSC populations, indicating the heterogeneity of BCSCs. Therefore, defining the regulation mechanisms of heterogeneous BCSCs is essential for precisely targeting BCSCs and treating breast cancer. In this review, we summarized the novel regulators existed in BCSCs and their niches for BCSC heterogeneity which has been discovered in recent years, and discussed their regulation mechanisms and the latest corresponding cancer treatments, which will extend our understanding on BCSC heterogeneity and plasticity, and provide better prognosis prediction and more efficient novel therapeutic strategies for breast cancer.
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Affiliation(s)
- Rui Zhang
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Juchuanli Tu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Suling Liu
- Fudan University Shanghai Cancer Center & Institutes of Biomedical Sciences, Cancer Institutes, Key Laboratory of Breast Cancer in Shanghai, The Shanghai Key Laboratory of Medical Epigenetics, The International Co-laboratory of Medical Epigenetics and Metabolism, Ministry of Science and Technology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
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All-trans retinoic acid and protein kinase C α/β1 inhibitor combined treatment targets cancer stem cells and impairs breast tumor progression. Sci Rep 2021; 11:6044. [PMID: 33723318 PMCID: PMC7961031 DOI: 10.1038/s41598-021-85344-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 02/28/2021] [Indexed: 01/08/2023] Open
Abstract
Breast cancer is the leading cause of cancer death among women worldwide. Blocking a single signaling pathway is often an ineffective therapy, especially in the case of aggressive or drug-resistant tumors. Since we have previously described the mechanism involved in the crosstalk between Retinoic Acid system and protein kinase C (PKC) pathway, the rationale of our study was to evaluate the effect of combining all-trans-retinoic acid (ATRA) with a classical PCK inhibitor (Gö6976) in preclinical settings. Employing hormone-independent mammary cancer models, Gö6976 and ATRA combined treatment induced a synergistic reduction in proliferative potential that correlated with an increased apoptosis and RARs modulation towards an anti-oncogenic profile. Combined treatment also impairs growth, self-renewal and clonogenicity potential of cancer stem cells and reduced tumor growth, metastatic spread and cancer stem cells frequency in vivo. An in-silico analysis of “Kaplan–Meier plotter” database indicated that low PKCα together with high RARα mRNA expression is a favorable prognosis factor for hormone-independent breast cancer patients. Here we demonstrate that a classical PKC inhibitor potentiates ATRA antitumor effects also targeting cancer stem cells growth, self-renewal and frequency.
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Sun Q, Wang Y, Fu Q, Ouyang A, Liu S, Wang Z, Su Z, Song J, Zhang Q, Zhang P, Lu D. Sulfur‐Coordinated Organoiridium(III) Complexes Exert Breast Anticancer Activity via Inhibition of Wnt/β‐Catenin Signaling. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202015009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Qi Sun
- Guangdong Key Laboratory for Genome Stability & Disease Prevention International Cancer Center Department of Pharmacology Shenzhen University Health Science Center Shenzhen 518060 China
| | - Yi Wang
- College of Chemistry and Environmental Engineering Shenzhen University Shenzhen 518060 P. R. China
- Key Laboratory for Advanced Materials of MOE School of Chemistry & Molecular Engineering East China University of Science and Technology Shanghai 200237 P. R. China
| | - Qiuxia Fu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention International Cancer Center Department of Pharmacology Shenzhen University Health Science Center Shenzhen 518060 China
| | - Ai Ouyang
- College of Chemistry and Environmental Engineering Shenzhen University Shenzhen 518060 P. R. China
| | - Shanshan Liu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention International Cancer Center Department of Pharmacology Shenzhen University Health Science Center Shenzhen 518060 China
| | - Zhongyuan Wang
- Guangdong Key Laboratory for Genome Stability & Disease Prevention International Cancer Center Department of Pharmacology Shenzhen University Health Science Center Shenzhen 518060 China
| | - Zijie Su
- Guangdong Key Laboratory for Genome Stability & Disease Prevention International Cancer Center Department of Pharmacology Shenzhen University Health Science Center Shenzhen 518060 China
| | - Jiaxing Song
- Guangdong Key Laboratory for Genome Stability & Disease Prevention International Cancer Center Department of Pharmacology Shenzhen University Health Science Center Shenzhen 518060 China
| | - Qianling Zhang
- College of Chemistry and Environmental Engineering Shenzhen University Shenzhen 518060 P. R. China
| | - Pingyu Zhang
- College of Chemistry and Environmental Engineering Shenzhen University Shenzhen 518060 P. R. China
| | - Desheng Lu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention International Cancer Center Department of Pharmacology Shenzhen University Health Science Center Shenzhen 518060 China
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Lisencu LA, Bonci EA, Irimie A, Balacescu O, Lisencu C. The Role of Circulating Tumor Cells in Chemoresistant Metastatic Breast Cancer. J Clin Med 2021; 10:jcm10040684. [PMID: 33578862 PMCID: PMC7916545 DOI: 10.3390/jcm10040684] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/28/2021] [Accepted: 02/08/2021] [Indexed: 12/13/2022] Open
Abstract
Breast cancer is the most frequent form of cancer among women and is one of the leading causes of death. Two routes of the metastatic process have been described: linear and parallel progression. A key factor is represented by circulating tumor cells (CTCs). CTCs detach from the primary tumor or develop from cancer stem cells (CSCs) that undergo epithelial-to-mesenchymal transition (EMT). CTCs migrate to the distant site where the reverse process occurs and a new tumor arises. One of the key problems of metastatic disease is chemoresistance, which leads to treatment failure and, eventually, death. The aim of this review is to present up-to-date data regarding the role of CTCs in chemoresistance in metastatic breast cancer (MBC) patients. A search in Cochrane Library and MEDLINE databases was performed. A total of 125 articles were identified. The results of the final 12 eligible studies revealed that CTCs having stem cell features and those with mesenchymal features are aggressive subtypes of cells that survive chemotherapy, being responsible for chemoresistance and thus for disease progression in MBC patients. The hemodynamic shear stress, alongside dynamic changes among CTCs during the disease, is also an important disease progression factor.
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Affiliation(s)
- Lorena Alexandra Lisencu
- 11th Department of Oncological Surgery and Gynecological Oncology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (L.A.L.); (A.I.); (C.L.)
| | - Eduard-Alexandru Bonci
- 11th Department of Oncological Surgery and Gynecological Oncology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (L.A.L.); (A.I.); (C.L.)
- Department of Surgical Oncology, “Prof. Dr. Ion Chiricuță” Institute of Oncology, 400015 Cluj-Napoca, Romania
- Correspondence:
| | - Alexandru Irimie
- 11th Department of Oncological Surgery and Gynecological Oncology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (L.A.L.); (A.I.); (C.L.)
- Department of Surgical Oncology, “Prof. Dr. Ion Chiricuță” Institute of Oncology, 400015 Cluj-Napoca, Romania
| | - Ovidiu Balacescu
- Department of Functional Genomics, Proteomics and Experimental Pathology, “Prof. Dr. Ion Chiricuță” Institute of Oncology, 400015 Cluj-Napoca, Romania;
- 11th Department of Medical Oncology, “Iuliu Hațieganu”, University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania
| | - Cosmin Lisencu
- 11th Department of Oncological Surgery and Gynecological Oncology, “Iuliu Hațieganu” University of Medicine and Pharmacy, 400012 Cluj-Napoca, Romania; (L.A.L.); (A.I.); (C.L.)
- Department of Surgical Oncology, “Prof. Dr. Ion Chiricuță” Institute of Oncology, 400015 Cluj-Napoca, Romania
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Aramini B, Masciale V, Grisendi G, Banchelli F, D'Amico R, Maiorana A, Morandi U, Dominici M, Haider KH. Cancer stem cells and macrophages: molecular connections and future perspectives against cancer. Oncotarget 2021; 12:230-250. [PMID: 33613850 PMCID: PMC7869576 DOI: 10.18632/oncotarget.27870] [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: 05/11/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Cancer stem cells (CSCs) have been considered the key drivers of cancer initiation and progression due to their unlimited self-renewal capacity and their ability to induce tumor formation. Macrophages, particularly tumor-associated macrophages (TAMs), establish a tumor microenvironment to protect and induce CSCs development and dissemination. Many studies in the past decade have been performed to understand the molecular mediators of CSCs and TAMs, and several studies have elucidated the complex crosstalk that occurs between these two cell types. The aim of this review is to define the complex crosstalk between these two cell types and to highlight potential future anti-cancer strategies.
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Affiliation(s)
- Beatrice Aramini
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Valentina Masciale
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Giulia Grisendi
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Federico Banchelli
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Roberto D'Amico
- Center of Statistic, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Antonino Maiorana
- Institute of Pathology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Uliano Morandi
- Division of Thoracic Surgery, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
| | - Massimo Dominici
- Division of Oncology, Department of Medical and Surgical Sciences, University of Modena and Reggio Emilia, Modena, Italy
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Sun Q, Wang Y, Fu Q, Ouyang A, Liu S, Wang Z, Su Z, Song J, Zhang Q, Zhang P, Lu D. Sulfur-Coordinated Organoiridium(III) Complexes Exert Breast Anticancer Activity via Inhibition of Wnt/β-Catenin Signaling. Angew Chem Int Ed Engl 2021; 60:4841-4848. [PMID: 33244858 DOI: 10.1002/anie.202015009] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Indexed: 12/12/2022]
Abstract
The sulfur-coordinated organoiridium(III) complexes pbtIrSS and ppyIrSS, which contain C,N and S,S (dithione) chelating ligands, were found to inhibit breast cancer tumorigenesis and metastasis by targeting Wnt/β-catenin signaling for the first time. Treatment with pbtIrSS and ppyIrSS induces the degradation of LRP6, thereby decreasing the protein levels of DVL2, β-catenin and activated β-catenin, resulting in downregulation of Wnt target genes CD44 and survivin. Additionally, pbtIrSS and ppyIrSS can suppress cell migration and invasion of breast cancer cells. Furthermore, both complexes show the ability to inhibit sphere formation and mediate the stemness properties of breast cancer cells. Importantly, pbtIrSS exerts potent anti-tumor and anti-metastasis effects in mouse xenograft models through the blockage of Wnt/β-catenin signaling. Taken together, our results indicate that pbtIrSS has great potential to be developed as a breast cancer therapeutic agent with a novel mechanism.
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Affiliation(s)
- Qi Sun
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Yi Wang
- College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518060, P. R. China
- Key Laboratory for Advanced Materials of MOE, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, P. R. China
| | - Qiuxia Fu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Ai Ouyang
- College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518060, P. R. China
| | - Shanshan Liu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Zhongyuan Wang
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Zijie Su
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Jiaxing Song
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Qianling Zhang
- College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518060, P. R. China
| | - Pingyu Zhang
- College of Chemistry and Environmental Engineering, Shenzhen University, Shenzhen, 518060, P. R. China
| | - Desheng Lu
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, International Cancer Center, Department of Pharmacology, Shenzhen University Health Science Center, Shenzhen, 518060, China
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40
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Dahn ML, Marcato P. Targeting the Roots of Recurrence: New Strategies for Eliminating Therapy-Resistant Breast Cancer Stem Cells. Cancers (Basel) 2020; 13:cancers13010054. [PMID: 33379132 PMCID: PMC7795348 DOI: 10.3390/cancers13010054] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Accepted: 12/24/2020] [Indexed: 12/26/2022] Open
Affiliation(s)
- Margaret L. Dahn
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
| | - Paola Marcato
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada;
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Correspondence: ; Tel.: +1-(902)-494-4239
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Font-Díaz J, Jiménez-Panizo A, Caelles C, Vivanco MDM, Pérez P, Aranda A, Estébanez-Perpiñá E, Castrillo A, Ricote M, Valledor AF. Nuclear receptors: Lipid and hormone sensors with essential roles in the control of cancer development. Semin Cancer Biol 2020; 73:58-75. [PMID: 33309851 DOI: 10.1016/j.semcancer.2020.12.007] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/04/2020] [Accepted: 12/04/2020] [Indexed: 12/15/2022]
Abstract
Nuclear receptors (NRs) are a superfamily of ligand-activated transcription factors that act as biological sensors and use a combination of mechanisms to modulate positively and negatively gene expression in a spatial and temporal manner. The highly orchestrated biological actions of several NRs influence the proliferation, differentiation, and apoptosis of many different cell types. Synthetic ligands for several NRs have been the focus of extensive drug discovery efforts for cancer intervention. This review summarizes the roles in tumour growth and metastasis of several relevant NR family members, namely androgen receptor (AR), estrogen receptor (ER), glucocorticoid receptor (GR), thyroid hormone receptor (TR), retinoic acid receptors (RARs), retinoid X receptors (RXRs), peroxisome proliferator-activated receptors (PPARs), and liver X receptors (LXRs). These studies are key to develop improved therapeutic agents based on novel modes of action with reduced side effects and overcoming resistance.
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Affiliation(s)
- Joan Font-Díaz
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona, 08028, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08028, Spain
| | - Alba Jiménez-Panizo
- Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08028, Spain; Department of Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, 08028, Spain
| | - Carme Caelles
- Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08028, Spain; Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, University of Barcelona, Barcelona, 08028, Spain
| | - María dM Vivanco
- CIC bioGUNE, Basque Research Technology Alliance, BRTA, Bizkaia Technology Park, Derio, 48160, Spain
| | - Paloma Pérez
- Instituto de Biomedicina de Valencia (IBV)-CSIC, Valencia, 46010, Spain
| | - Ana Aranda
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, 28029, Spain
| | - Eva Estébanez-Perpiñá
- Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08028, Spain; Department of Biochemistry and Molecular Biomedicine, School of Biology, University of Barcelona, Barcelona, 08028, Spain
| | - Antonio Castrillo
- Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas and Universidad Autónoma de Madrid, Madrid, 28029, Spain; Unidad de Biomedicina, (Unidad Asociada al CSIC), Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM), Universidad de Las Palmas, Gran Canaria, 35001, Spain
| | - Mercedes Ricote
- Area of Myocardial Pathophysiology, Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, 28029, Spain
| | - Annabel F Valledor
- Department of Cell Biology, Physiology and Immunology, School of Biology, University of Barcelona, Barcelona, 08028, Spain; Institute of Biomedicine of the University of Barcelona (IBUB), Barcelona, 08028, Spain.
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Cancer Stem Cell-Associated Pathways in the Metabolic Reprogramming of Breast Cancer. Int J Mol Sci 2020; 21:ijms21239125. [PMID: 33266219 PMCID: PMC7730588 DOI: 10.3390/ijms21239125] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Revised: 11/25/2020] [Accepted: 11/26/2020] [Indexed: 02/07/2023] Open
Abstract
Metabolic reprogramming of cancer is now considered a hallmark of many malignant tumors, including breast cancer, which remains the most commonly diagnosed cancer in women all over the world. One of the main challenges for the effective treatment of breast cancer emanates from the existence of a subpopulation of tumor-initiating cells, known as cancer stem cells (CSCs). Over the years, several pathways involved in the regulation of CSCs have been identified and characterized. Recent research has also shown that CSCs are capable of adopting a metabolic flexibility to survive under various stressors, contributing to chemo-resistance, metastasis, and disease relapse. This review summarizes the links between the metabolic adaptations of breast cancer cells and CSC-associated pathways. Identification of the drivers capable of the metabolic rewiring in breast cancer cells and CSCs and the signaling pathways contributing to metabolic flexibility may lead to the development of effective therapeutic strategies. This review also covers the role of these metabolic adaptation in conferring drug resistance and metastasis in breast CSCs.
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Repurposing of Fluvastatin as an Anticancer Agent against Breast Cancer Stem Cells via Encapsulation in a Hyaluronan-Conjugated Liposome. Pharmaceutics 2020; 12:pharmaceutics12121133. [PMID: 33255298 PMCID: PMC7760927 DOI: 10.3390/pharmaceutics12121133] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2020] [Revised: 11/21/2020] [Accepted: 11/23/2020] [Indexed: 02/07/2023] Open
Abstract
Fluvastatin (FLUVA), which is a common anti-hypercholesterolemia drug, exhibits potential anticancer activity as it suppresses the proliferation, angiogenesis, and metastasis of breast cancer cells via inhibiting 3-hydroxy-methyl glutaryl-coenzyme A (HMG-CoA) reductase. In this study, hyaluronan-conjugated FLUVA-encapsulating liposomes (HA-L-FLUVA) were evaluated for their anticancer efficacy in vitro and in vivo. The particle size, zeta potential, and encapsulation efficiency of HA-L-FLUVA were 158.36 ± 1.78 nm, −24.85 ± 6.26 mV, and 35%, respectively. Growth inhibition of breast cancer stem cells (BCSCs) by HA-L-FLUVA was more effective than that by free FLUVA. The half maximal inhibitory concentration (IC50) values of FLUVA, L-FLVUA, and HA-L-FLUVA were 0.16, 0.17, and 0.09 μM, respectively. The in vivo anticancer effect of HA-L-FLUVA in combination with doxorubicin (DOX) was more effective than that of free FLUVA, free DOX, and HA-L-FLUVA. The longest survival of mice was achieved by treatment with FLUVA (15 mg/kg) and HA-L-FLUVA (15 mg/kg) + DOX (3 mg/kg), followed by HA-L-FLUVA (15 mg/kg), Dulbecco’s phosphate buffered saline, and DOX (3 mg/kg). No more than 10% body weight loss was observed in the mice injected with FLUVA, indicating that the drug was not toxic. Taken together, these results indicate that HA-L-FLUVA could serve as an effective anticancer drug by inhibiting the growth of both breast cancer cells and cancer stem cells.
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Wang N, Weng J, Xia J, Zhu Y, Chen Q, Hu D, Zhang X, Sun R, Feng J, Minato N, Gong Y, Su L. SIPA1 enhances SMAD2/3 expression to maintain stem cell features in breast cancer cells. Stem Cell Res 2020; 49:102099. [PMID: 33296812 DOI: 10.1016/j.scr.2020.102099] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2020] [Revised: 09/30/2020] [Accepted: 11/18/2020] [Indexed: 02/06/2023] Open
Abstract
SIPA1, a GTPase activating protein that negatively regulates Ras-related protein (Rap), is a potential modulator of tumor metastasis and recurrence. In this study, we first showed that SIPA1 facilitated the stemness features of breast cancer cells, such as of tumorsphere formation capability and the expression of stemness marker CD44. In addition, SIPA1 promoted the expression of four stemness-associated transcription factors through increasing the expression of SMAD2 and SMAD3 in vitro and in vivo. The stemness features were abolished by blocking the phosphorylation of SMAD3 with its specific inhibitor SIS3. Furthermore, SIPA1 decreased the breast cancer cell sensitivity to chemotherapy drugs. This effect was, however, competitively reversed by blocking the SMAD3 phosphorylation by SIS3 treatment in breast cancer cells. Taken together, SIPA1 promotes and sustains the stemness of breast cancer cells and their resistance to chemotherapy by increasing the expression of SMAD2 and SMAD3, and blocking SMAD3 phosphorylation could suppress the cancer cell stemness and increase the sensitivity to chemotherapy in breast cancer cells expressing a high level of SIPA1.
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Affiliation(s)
- Ning Wang
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Jun Weng
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Jing Xia
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Yangjin Zhu
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Qiongrong Chen
- Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan 430071, China
| | - Die Hu
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China
| | - Xue Zhang
- Department of Breast Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, China
| | - Rui Sun
- Department of Oncology, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430034, China
| | - Jueping Feng
- Department of Oncology, Puai Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430034, China
| | - Nagahiro Minato
- Department of Immunology and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
| | - Yiping Gong
- Department of Breast Surgery, Renmin Hospital of Wuhan University, Wuhan University, Wuhan 430060, China; Department of Breast Surgery, Hubei Cancer Hospital, Wuhan 430079, China.
| | - Li Su
- Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China.
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45
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Sen U, Chaudhury D, Shenoy P S, Bose B. Differential sensitivities of triple-negative breast cancer stem cell towards various doses of vitamin C: An insight into the internal antioxidant systems. J Cell Biochem 2020; 122:349-366. [PMID: 33135276 DOI: 10.1002/jcb.29863] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 09/01/2020] [Accepted: 10/05/2020] [Indexed: 12/14/2022]
Abstract
Cancer stem cells (CSCs) are quiescent and self-renewing, having low levels of reactive oxygen species (ROS), and are responsible for cancer recurrence after chemotherapy and radiotherapy. However, the interplay between the ROS production and scavenging from the oxidative stress has never been studied in breast CSCs. In this present study, we have investigated the cellular energetics of two triple-negative breast cancer stem cells (MDA-MB-231 and MDA-MB-468) treated with two pharmacological doses of vitamin C (10 and 20 mM) that generated ROS. Our results indicate a differential behavior of ROS scavenging by both the CSCs. MDA-MB-468 CSCs exhibited higher resistance to ROS induced damage owing to the higher antioxidant activity, lower mitochondrial damage, and less decrease in membrane potential (ΔΨm ) as compared with MDA-MB-231 CSCs. Moreover, MDA-MB-231 CSCs exhibited an intrinsic apoptosis pathway by activating the cytochrome c, caspase-9, 3, 7, and cleaved PARP upon treatment with vitamin C. This data suggests a possible strategy for targeting breast CSCs using vitamin C. Taken together, the CSCs from MDA-MB-231 could be easily targeted by high/pharmacological doses of vitamin C (≥20 mM) thereby indicating a less robust internal antioxidant machinery.
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Affiliation(s)
- Utsav Sen
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Debajit Chaudhury
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Sudheer Shenoy P
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
| | - Bipasha Bose
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya (Deemed to be University), Mangalore, Karnataka, India
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Zhang Y, Zeng F, Han X, Weng J, Gao Y. Lineage tracing: technology tool for exploring the development, regeneration, and disease of the digestive system. Stem Cell Res Ther 2020; 11:438. [PMID: 33059752 PMCID: PMC7559019 DOI: 10.1186/s13287-020-01941-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Accepted: 09/17/2020] [Indexed: 12/15/2022] Open
Abstract
Lineage tracing is the most widely used technique to track the migration, proliferation, and differentiation of specific cells in vivo. The currently available gene-targeting technologies have been developing for decades to study organogenesis, tissue injury repairing, and tumor progression by tracing the fates of individual cells. Recently, lineage tracing has expanded the platforms available for disease model establishment, drug screening, cell plasticity research, and personalized medicine development in a molecular and cellular biology perspective. Lineage tracing provides new views for exploring digestive organ development and regeneration and techniques for digestive disease causes and progression. This review focuses on the lineage tracing technology and its application in digestive diseases.
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Affiliation(s)
- Yue Zhang
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Fanhong Zeng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Xu Han
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China.,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China
| | - Jun Weng
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. .,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China.
| | - Yi Gao
- Department of Hepatobiliary Surgery II, Guangdong Provincial Research Center for Artificial Organ and Tissue Engineering, Guangzhou Clinical Research and Transformation Center for Artificial Liver, Institute of Regenerative Medicine, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China. .,State Key Laboratory of Organ Failure Research, Southern Medical University, Guangzhou, China.
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47
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Ko CCH, Chia WK, Selvarajah GT, Cheah YK, Wong YP, Tan GC. The Role of Breast Cancer Stem Cell-Related Biomarkers as Prognostic Factors. Diagnostics (Basel) 2020; 10:721. [PMID: 32961774 PMCID: PMC7555329 DOI: 10.3390/diagnostics10090721] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/13/2020] [Accepted: 09/16/2020] [Indexed: 02/06/2023] Open
Abstract
Breast cancer is one of the leading causes of cancer-related deaths in women worldwide, and its incidence is on the rise. A small fraction of cancer stem cells was identified within the tumour bulk, which are regarded as cancer-initiating cells, possess self-renewal and propagation potential, and a key driver for tumour heterogeneity and disease progression. Cancer heterogeneity reduces the overall efficacy of chemotherapy and contributes to treatment failure and relapse. The cell-surface and subcellular biomarkers related to breast cancer stem cell (BCSC) phenotypes are increasingly being recognised. These biomarkers are useful for the isolation of BCSCs and can serve as potential therapeutic targets and prognostic tools to monitor treatment responses. Recently, the role of noncoding microRNAs (miRNAs) has extensively been explored as novel biomarker molecules for breast cancer diagnosis and prognosis with high specificity and sensitivity. An in-depth understanding of the biological roles of miRNA in breast carcinogenesis provides insights into the pathways of cancer development and its utility for disease prognostication. This review gives an overview of stem cells, highlights the biomarkers expressed in BCSCs and describes their potential role as prognostic indicators.
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Affiliation(s)
- Clarence Ching Huat Ko
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
- Department of Biomedical Science, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia;
| | - Wai Kit Chia
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
| | - Gayathri Thevi Selvarajah
- Department of Veterinary Clinical Studies, Faculty of Veterinary Medicine, Universiti Putra Malaysia, 43400 Serdang, Malaysia;
- Institute of Biosciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Malaysia
| | - Yoke Kqueen Cheah
- Department of Biomedical Science, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Malaysia;
- Institute of Biosciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Malaysia
| | - Yin Ping Wong
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
| | - Geok Chin Tan
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia; (C.C.H.K.); (W.K.C.)
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48
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Ding S, Chen X, Shen K. Single-cell RNA sequencing in breast cancer: Understanding tumor heterogeneity and paving roads to individualized therapy. Cancer Commun (Lond) 2020; 40:329-344. [PMID: 32654419 PMCID: PMC7427308 DOI: 10.1002/cac2.12078] [Citation(s) in RCA: 153] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2020] [Revised: 06/27/2020] [Accepted: 06/29/2020] [Indexed: 12/18/2022] Open
Abstract
Single‐cell RNA sequencing (scRNA‐seq) is a novel technology that allows transcriptomic analyses of individual cells. During the past decade, scRNA‐seq sensitivity, accuracy, and efficiency have improved due to innovations including more sensitive, automated, and cost‐effective single‐cell isolation methods with higher throughput as well as ongoing technological development of scRNA‐seq protocols. Among the variety of current approaches with distinct features, researchers can choose the most suitable method to carry out their research. By profiling single cells in a complex population mix, scRNA‐seq presents great advantages over traditional sequencing methods in dissecting heterogeneity in cell populations hidden in bulk analysis and exploring rare cell types associated with tumorigenesis and metastasis. scRNA‐seq studies in recent years in the field of breast cancer research have clustered breast cancer cell populations with different molecular subtypes to identify distinct populations that may correlate with poor prognosis and drug resistance. The technology has also been used to explain tumor microenvironment heterogeneity by identifying distinct immune cell subsets that may be associated with immunosurveillance and are potential immunotherapy targets. Moreover, scRNA‐seq has diverse applications in breast cancer research besides exploring heterogeneity, including the analysis of cell‐cell communications, regulatory single‐cell states, immune cell distributions, and more. scRNA‐seq is also a promising tool that can facilitate individualized therapy due to its ability to define cell subsets with potential treatment targets. Although scRNA‐seq studies of therapeutic selection in breast cancer are currently limited, the application of this technology in this field is prospective. Joint efforts and original ideas are needed to better implement scRNA‐seq technologies in breast cancer research to pave the way for individualized treatment management. This review provides a brief introduction on the currently available scRNA‐seq approaches along with their corresponding strengths and weaknesses and may act as a reference for the selection of suitable methods for research. We also discuss the current applications of scRNA‐seq in breast cancer research for tumor heterogeneity analysis, individualized therapy, and the other research directions mentioned above by reviewing corresponding published studies. Finally, we discuss the limitations of current scRNA‐seq technologies and technical problems that remain to be overcome.
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Affiliation(s)
- Shuning Ding
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Xiaosong Chen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
| | - Kunwei Shen
- Department of General Surgery, Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China
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Hii LW, Chung FFL, Mai CW, Yee ZY, Chan HH, Raja VJ, Dephoure NE, Pyne NJ, Pyne S, Leong CO. Sphingosine Kinase 1 Regulates the Survival of Breast Cancer Stem Cells and Non-stem Breast Cancer Cells by Suppression of STAT1. Cells 2020; 9:886. [PMID: 32260399 PMCID: PMC7226795 DOI: 10.3390/cells9040886] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 04/01/2020] [Accepted: 04/03/2020] [Indexed: 02/05/2023] Open
Abstract
Cancer stem cells (CSCs) represent rare tumor cell populations capable of self-renewal, differentiation, and tumor initiation and are highly resistant to chemotherapy and radiotherapy. Thus, therapeutic approaches that can effectively target CSCs and tumor cells could be the key to efficient tumor treatment. In this study, we explored the function of SPHK1 in breast CSCs and non-CSCs. We showed that RNAi-mediated knockdown of SPHK1 inhibited cell proliferation and induced apoptosis in both breast CSCs and non-CSCs, while ectopic expression of SPHK1 enhanced breast CSC survival and mammosphere forming efficiency. We identified STAT1 and IFN signaling as key regulatory targets of SPHK1 and demonstrated that an important mechanism by which SPHK1 promotes cancer cell survival is through the suppression of STAT1. We further demonstrated that SPHK1 inhibitors, FTY720 and PF543, synergized with doxorubicin in targeting both breast CSCs and non-CSCs. In conclusion, we provide important evidence that SPHK1 is a key regulator of cell survival and proliferation in breast CSCs and non-CSCs and is an attractive target for the design of future therapies.
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Affiliation(s)
- Ling-Wei Hii
- Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (L.-W.H.); (C.W.M.); (Z.Y.Y.); (H.H.C.)
- School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia
- School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Felicia Fei-Lei Chung
- Mechanisms of Carcinogenesis Section (MCA), Epigenetics Group (EGE) International Agency for Research on Cancer, World Health Organization, 69372 Lyon, France;
| | - Chun Wai Mai
- Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (L.-W.H.); (C.W.M.); (Z.Y.Y.); (H.H.C.)
- School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Zong Yang Yee
- Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (L.-W.H.); (C.W.M.); (Z.Y.Y.); (H.H.C.)
- School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Hong Hao Chan
- Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (L.-W.H.); (C.W.M.); (Z.Y.Y.); (H.H.C.)
- School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia
| | - Vijay Joseph Raja
- Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA; (V.J.R.); (N.E.D.)
| | - Noah Elias Dephoure
- Department of Biochemistry, Weill Cornell Medical College, New York, NY 10021, USA; (V.J.R.); (N.E.D.)
| | - Nigel J. Pyne
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland, UK; (N.J.P.); (S.P.)
| | - Susan Pyne
- Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow G4 0RE, Scotland, UK; (N.J.P.); (S.P.)
| | - Chee-Onn Leong
- Centre for Cancer and Stem Cell Research, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia; (L.-W.H.); (C.W.M.); (Z.Y.Y.); (H.H.C.)
- School of Pharmacy, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia
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50
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Hass R, von der Ohe J, Ungefroren H. Potential Role of MSC/Cancer Cell Fusion and EMT for Breast Cancer Stem Cell Formation. Cancers (Basel) 2019; 11:1432. [PMID: 31557960 PMCID: PMC6826868 DOI: 10.3390/cancers11101432] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2019] [Revised: 09/20/2019] [Accepted: 09/24/2019] [Indexed: 02/06/2023] Open
Abstract
Solid tumors comprise of maturated cancer cells and self-renewing cancer stem-like cells (CSCs), which are associated with various other nontumorigenic cell populations in the tumor microenvironment. In addition to immune cells, endothelial cells, fibroblasts, and further cell types, mesenchymal stroma/stem-like cells (MSC) represent an important cell population recruited to tumor sites and predominantly interacting with the different cancer cells. Breast cancer models were among the first to reveal distinct properties of CSCs, however, the cellular process(es) through which these cells are generated, maintained, and expanded within neoplastic tissues remains incompletely understood. Here, we discuss several possible scenarios that are not mutually exclusive but may even act synergistically: fusion of cancer cells with MSC to yield hybrid cells and/or the induction of epithelial-mesenchymal transition (EMT) in breast cancer cells by MSC, which can relay signals for retrodifferentiation and eventually, the generation of breast CSCs (BCSCs). In either case, the consequences may be promotion of self-renewal capacity, tumor cell plasticity and heterogeneity, an increase in the cancer cells' invasive and metastatic potential, and the acquisition of resistance mechanisms towards chemo- or radiotherapy. While specific signaling mechanisms involved in each of these properties remain to be elucidated, the present review article focusses on a potential involvement of cancer cell fusion and EMT in the development of breast cancer stem cells.
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Affiliation(s)
- Ralf Hass
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Juliane von der Ohe
- Biochemistry and Tumor Biology Lab, Department of Obstetrics and Gynecology, Hannover Medical School, 30625 Hannover, Germany.
| | - Hendrik Ungefroren
- First Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, 23538 Lübeck, Germany.
- Department of General Surgery, Visceral, Thoracic, Transplantation and Pediatric Surgery, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
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