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Sankar S, Kalidass B, Indrakumar J, Kodiveri Muthukaliannan G. NSAID-encapsulated nanoparticles as a targeted therapeutic platform for modulating chronic inflammation and inhibiting cancer progression: a review. Inflammopharmacology 2025:10.1007/s10787-025-01760-8. [PMID: 40285986 DOI: 10.1007/s10787-025-01760-8] [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: 03/24/2025] [Accepted: 04/11/2025] [Indexed: 04/29/2025]
Abstract
Recent advancements in nanotechnology have significantly advanced nanocarrier-mediated drug delivery systems, promoting therapeutic outcomes in mitigating chronic inflammation and cancer. Nanomaterials offer significant advantages over traditional small-molecule drugs, including a high surface-area-to-volume ratio, tunable structural features, and extended bloodstream circulation time. Chronic inflammation is a well-established mechanism for malignant initiation, progression, and metastasis, promoting the potent strategy for cancer prevention and therapy. Numerous studies revealed that nonsteroidal anti-inflammatory drugs (NSAIDs) have the therapeutic ability to manage disease progression via amolerating angiogenesis and inducing apoptosis. However, prolonged intake of NSAIDs is often limited by adverse side-effects and systemic toxicities. The encapsulation of NSAIDs in a nanocarrier have materialized as a dynamic approach to mitigate the limitations by improving pharmacokinetics and pharmacodynamics, reducing off-target effects, and enhancing the drug stability. This review encompasses recent progress in the development of NSAID-based nanotherapeutics, focusing on pivotal mechanisms underlying nanoparticle-mediated drug delivery, such as improved tumor-specific targeting and strategies to overcome drug resistance. The ability of these nano-cargoes to accommodate anti-inflammatory strategies with advanced drug delivery platforms is critically evaluated. This review also highlights the transformative potential of NSAID-encapsulated nanoparticles as a multifaceted therapeutic venue for addressing chronic inflammation and mitigating cancer progression.
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Affiliation(s)
- Srivarshini Sankar
- Department of Biotechnology, School of Bioscience and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632 014, India
| | - Bharathi Kalidass
- Department of Biotechnology, School of Bioscience and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632 014, India
| | - Janani Indrakumar
- Department of Biotechnology, School of Bioscience and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632 014, India
| | - Gothandam Kodiveri Muthukaliannan
- Department of Biotechnology, School of Bioscience and Technology, Vellore Institute of Technology, Tamil Nadu, Vellore, 632 014, India.
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2
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Zhang M, Zhang L, Liu J, Zhao J, Mei J, Zou J, Luo Y, Cai C. Mammary stem cells: molecular cues, orchestrated regulatory mechanisms and its implications in breast cancer. J Genet Genomics 2025:S1673-8527(25)00116-X. [PMID: 40254157 DOI: 10.1016/j.jgg.2025.04.007] [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: 01/05/2025] [Revised: 04/03/2025] [Accepted: 04/11/2025] [Indexed: 04/22/2025]
Abstract
Mammary stem cells (MaSCs), endowed with self-renewal and multilineage differentiation capabilities, are crucial for mammary gland development, function, and disease initiation. Recent advances in MaSCs biology research encompass molecular marker identification, regulatory pathway dissection, and microenvironmental crosstalk. This review synthesizes key progress and remaining challenges in MaSC research. Molecular profiling advances have identified key markers recently, such as Procr, Dll1, Bcl11b, and PD-L1. Central to their regulatory logic are evolutionarily conserved pathways, including Wnt, Notch, Hedgehog, and Hippo, which exhibit context-dependent thresholds to balance self-renewal and differentiation. Beyond intrinsic signaling, the dynamic interplay between MaSCs and their microenvironment, such as luminal-derived Wnt4, macrophage-mediated TNF-α signaling, and adrenergic inputs from sympathetic nerves, spatially orchestrates stem cell behavior. In addition, this review also discusses the roles of breast cancer stem cells (BCSCs) in tumorigenesis and therapeutic resistance, focusing on the molecular mechanisms underlying MaSC transformation into BCSCs. Despite progress, challenges remain: human MaSCs functional assays lack standardization, pathway inhibitors risk off-target effects, and delivery systems lack precision. Emerging tools like spatial multi-omics, organoids, and biomimetic scaffolds address these gaps. By integrating MaSCs and BCSCs biology, this review links mechanisms to breast cancer and outlines strategies to target malignancy to accelerate clinical translation.
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Affiliation(s)
- Mengna Zhang
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
| | - Lingxian Zhang
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
| | - Jie Liu
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
| | - Jiahui Zhao
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
| | - Jiayu Mei
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
| | - Jiahua Zou
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China
| | - Yaogan Luo
- Mengniu Institute of Nutrition Science, Shanghai 200124, China
| | - Cheguo Cai
- Key Laboratory of Systems Health Science of Zhejiang Province, School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, Zhejiang 310024, China.
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3
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Ro J, Kim J, Park J, Choi Y, Cho Y. ODSEI Chip: An Open 3D Microfluidic Platform for Studying Tumor Spheroid-Endothelial Interactions. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2410659. [PMID: 39805002 PMCID: PMC11967799 DOI: 10.1002/advs.202410659] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 11/28/2024] [Indexed: 01/16/2025]
Abstract
Current in vitro models of 3D tumor spheroids within the microenvironment have emerged as promising tools for understanding tumor progression and potential drug responses. However, creating spheroids with functional vasculature remains challenging in a controlled and high-throughput manner. Herein, a novel open 3D-microarray platform is presented for a spheroid-endothelium interaction (ODSEI) chip, capable of arraying more than 1000 spheroids on top of the vasculature, compartmentalized for single spheroid-level analysis of drug resistance, and allows for the extraction of specific spheroids for further analysis. As proof of concept, the crosstalk between breast cancer spheroids and vasculature is monitored, validating the roles of endothelial cells in acquired tamoxifen resistance. Cancer spheroids exhibited reduced sensitivity to tamoxifen in the presence of vasculature. Further analysis through single-cell RNA sequencing of extracted spheroids and protein arrays elucidated gene expression profiles and cytokines associated with acquired tamoxifen resistance, particularly involving the TNF-α pathway via NF-κB and mTOR signaling. By targeting the highly expressed cytokines (IL-8, TIMP1) identified, tamoxifen resistance in cancer spheroid can be effectively reversed. In summary, the ODSEI chip allows to study spheroid and endothelial interaction in various contexts, leading to improved insights into tumor biology and therapeutic strategies.
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Affiliation(s)
- Jooyoung Ro
- Department of Biomedical EngineeringUlsan National Institute of Science and Technology (UNIST)Ulsan44919South Korea
- Center for Algorithmic and Robotized SynthesisInstitute for Basic Science (IBS)Ulsan44919South Korea
| | - Junyoung Kim
- Department of Biomedical EngineeringUlsan National Institute of Science and Technology (UNIST)Ulsan44919South Korea
- Center for Algorithmic and Robotized SynthesisInstitute for Basic Science (IBS)Ulsan44919South Korea
| | - Juhee Park
- Center for Algorithmic and Robotized SynthesisInstitute for Basic Science (IBS)Ulsan44919South Korea
| | - Yongjun Choi
- Center for Algorithmic and Robotized SynthesisInstitute for Basic Science (IBS)Ulsan44919South Korea
| | - Yoon‐Kyoung Cho
- Department of Biomedical EngineeringUlsan National Institute of Science and Technology (UNIST)Ulsan44919South Korea
- Center for Algorithmic and Robotized SynthesisInstitute for Basic Science (IBS)Ulsan44919South Korea
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Ryspayeva D, Seyhan AA, MacDonald WJ, Purcell C, Roady TJ, Ghandali M, Verovkina N, El-Deiry WS, Taylor MS, Graff SL. Signaling pathway dysregulation in breast cancer. Oncotarget 2025; 16:168-201. [PMID: 40080721 PMCID: PMC11906143 DOI: 10.18632/oncotarget.28701] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2024] [Accepted: 03/03/2025] [Indexed: 03/15/2025] Open
Abstract
This article provides a comprehensive analysis of the signaling pathways implicated in breast cancer (BC), the most prevalent malignancy among women and a leading cause of cancer-related mortality globally. Special emphasis is placed on the structural dynamics of protein complexes that are integral to the regulation of these signaling cascades. Dysregulation of cellular signaling is a fundamental aspect of BC pathophysiology, with both upstream and downstream signaling cascade activation contributing to cellular process aberrations that not only drive tumor growth, but also contribute to resistance against current treatments. The review explores alterations within these pathways across different BC subtypes and highlights potential therapeutic strategies targeting these pathways. Additionally, the influence of specific mutations on therapeutic decision-making is examined, underscoring their relevance to particular BC subtypes. The article also discusses both approved therapeutic modalities and ongoing clinical trials targeting disrupted signaling pathways. However, further investigation is necessary to fully elucidate the underlying mechanisms and optimize personalized treatment approaches.
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Affiliation(s)
- Dinara Ryspayeva
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Attila A. Seyhan
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
| | - William J. MacDonald
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Connor Purcell
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Tyler J. Roady
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
| | - Maryam Ghandali
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Nataliia Verovkina
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
| | - Wafik S. El-Deiry
- Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Warren Alpert Medical School, Brown University, RI 02903, USA
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
- Department of Medicine, Hematology/Oncology Division, Lifespan Health System and Brown University, RI 02903, USA
| | - Martin S. Taylor
- Department of Pathology and Laboratory Medicine, Warren Alpert Medical School, Brown University, RI 02903, USA
- Joint Program in Cancer Biology, Lifespan Health System and Brown University, RI 02903, USA
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Pathobiology Graduate Program, Brown University, RI 02903, USA
- Brown Center on the Biology of Aging, Brown University, RI 02903, USA
| | - Stephanie L. Graff
- Legorreta Cancer Center at Brown University, RI 02903, USA
- Department of Medicine, Hematology/Oncology Division, Lifespan Health System and Brown University, RI 02903, USA
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Balkrishna A, Kumar S, Malik R, Mehra KS, Chaturvedi H, Okeshwar, Mittal R. Unveiling role of oncogenic signalling pathways in complicating breast cancer. Biomedicine (Taipei) 2025; 15:13-21. [PMID: 40176859 PMCID: PMC11959987 DOI: 10.37796/2211-8039.1640] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 01/11/2024] [Accepted: 01/12/2024] [Indexed: 04/05/2025] Open
Abstract
Heterogeneous nature of breast cancer has significantly affected the overall survival, disease free survival and progression free survival amongst the diseased individuals. Metastasis of cancerous cells to distant sites including bone, lungs, liver, lymph node and others have further exhilarated the adverse effects. However, ER, PR and HER-2 are responsible for normal physiological development of women but in altered conditions they may act as initiator or progressor and so far 5 subtypes of disease have been identified. Alteration of pro-survival, pro-proliferative and anti-apoptotic pathways including JAK/STAT, MAPK, PI3K/AkT/mTOR, NF-κB, BCL2 and several others have induced oncogenic events including epithelial-mesenchymal transition, intra-vasation, extra-vasation and many more. Although several US-FDA approved drugs are available in market to target above mentioned signalling pathways but issues of resistance, side effects have restricted their efficacy. The present review article aims to highlight diverse molecular subtypes and the signalling pathways involved in complicating the disease along with the US-FDA approved drugs to target them. Potential herbal medicine to target the disease have also been emphasized that can be used either as mono-therapeutic approach or in combination with conventional therapeutic regimens to target breast cancer.
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Affiliation(s)
- Acharya Balkrishna
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar,
India
- Department of Yog Science, University of Patanjali, Haridwar,
India
- Department of Sanskrit, University of Patanjali, Haridwar,
India
| | - Sagar Kumar
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar,
India
| | - Rohan Malik
- Department of Yog Science, University of Patanjali, Haridwar,
India
| | | | | | - Okeshwar
- Department of Sanskrit, University of Patanjali, Haridwar,
India
| | - Rashmi Mittal
- Patanjali Herbal Research Department, Patanjali Research Institute, Haridwar,
India
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Jan A, Sofi S, Jan N, Mir MA. An update on cancer stem cell survival pathways involved in chemoresistance in triple-negative breast cancer. Future Oncol 2025; 21:715-735. [PMID: 39936282 PMCID: PMC11881842 DOI: 10.1080/14796694.2025.2461443] [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: 10/29/2024] [Accepted: 01/29/2025] [Indexed: 02/13/2025] Open
Abstract
Triple-negative breast cancer (TNBC) presents a formidable global health challenge, marked by its aggressive behavior and significant treatment resistance. This subtype, devoid of estrogen, progesterone, and HER2 receptors, largely relies on breast cancer stem cells (BCSCs) for its progression, metastasis, and recurrence. BCSCs, characterized by their self-renewal capacity and resistance to conventional therapies, exploit key surface markers and critical signaling pathways like Wnt, Hedgehog, Notch, TGF-β, PI3K/AKT/mTOR and Hippo-YAP/TAZ to thrive. Their adaptability is underscored by mechanisms including drug efflux and enhanced DNA repair, contributing to poor prognosis and high recurrence rates. The tumor microenvironment (TME) further facilitates BCSC survival through complex interactions with stromal and immune cells. Emerging therapeutic strategies targeting BCSCs - ranging from immunotherapy and nanoparticle-based drug delivery systems to gene-editing technologies - aim to disrupt these resistant cells. Additionally, innovative approaches focusing on exosome-mediated signaling and metabolic reprogramming show promise in overcoming chemoresistance. By elucidating the distinct characteristics of BCSCs and their role in TNBC, researchers are paving the way for novel treatments that may effectively eradicate these resilient cells, mitigate metastasis, and ultimately improve patient outcomes. This review highlights the urgent need for targeted strategies that address the unique biology of BCSCs in the pursuit of more effective therapeutic interventions for TNBC.
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Affiliation(s)
- Asma Jan
- Cancer Biology Laboratory, Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Shazia Sofi
- Cancer Biology Laboratory, Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Nusrat Jan
- Cancer Biology Laboratory, Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Manzoor Ahmad Mir
- Cancer Biology Laboratory, Department of Bioresources, School of Biological Sciences, University of Kashmir, Srinagar, India
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7
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Xu L, Xu P, Wang J, Ji H, Zhang L, Tang Z. Advancements in clinical research and emerging therapies for triple-negative breast cancer treatment. Eur J Pharmacol 2025; 988:177202. [PMID: 39675457 DOI: 10.1016/j.ejphar.2024.177202] [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: 08/02/2024] [Revised: 11/30/2024] [Accepted: 12/09/2024] [Indexed: 12/17/2024]
Abstract
Triple-negative breast cancer (TNBC), defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) expression, is acknowledged as the most aggressive form of breast cancer (BC), comprising 15%-20% of all primary cases. Despite the prevalence of TNBC, effective and well-tolerated targeted therapies remain limited, with chemotherapy continuing to be the mainstay of treatment. However, the horizon is brightened by recent advancements in immunotherapy and antibody-drug conjugates (ADCs), which have garnered the U.S. Food and Drug Administration (FDA) approval for various stages of TNBC. Poly (ADP-ribose) polymerase inhibitors (PARPi), particularly for TNBC with BRCA mutations, present a promising avenue, albeit with the challenge of resistance that must be addressed. The success of phosphoinositide-3 kinase (PI3K) pathway inhibitors in hormone receptor (HR)-positive BC suggests potential applicability in TNBC, spurring optimism within the research community. This review endeavors to offer a comprehensive synthesis of both established and cutting-edge targeted therapies for TNBC. We delve into the specifics of PARPi, androgen receptor (AR) inhibitors, Cancer stem cells (CSCs), PI3K/Protein Kinase B (AKT)/mammalian target of rapamycin (mTOR), the transforming growth factor-beta (TGF-β), Ntoch, Wnt/β-catenin, hedgehog (Hh) pathway inhibitors, Epigenetic target-mediated drug delivery, ADCs, immune checkpoint inhibitors (ICIs)and novel immunotherapeutic solutions, contextualizing TNBC within current treatment paradigms. By elucidating the mechanisms of these drugs and their prospective clinical applications, we aim to shed light on the challenges and underscore the beacon of hope that translational research and innovative therapies represent for the oncology field.
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Affiliation(s)
- Lili Xu
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing, Zhejiang, 312000, China
| | - Pengtao Xu
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing, Zhejiang, 312000, China
| | - Jingsong Wang
- Department of Pharmacy, Guangyuan Central Hospital, Guangyuan, Sichuan, 628000, China
| | - Hui Ji
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing, Zhejiang, 312000, China
| | - Lin Zhang
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing, Zhejiang, 312000, China
| | - Zhihua Tang
- Department of Pharmacy, Shaoxing People's Hospital, Shaoxing, Zhejiang, 312000, China.
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8
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Kevat S, Mistry A, Oza N, Majmudar M, Patel N, Shah R, Ramachandran AV, Chauhan R, Haque S, Parashar NC, Tuli HS, Parashar G. Cancer Stem Cell Regulation as a Target of Therapeutic Intervention: Insights into Breast, Cervical and Lung Cancer. Cell Biochem Biophys 2025:10.1007/s12013-025-01666-w. [PMID: 39843681 DOI: 10.1007/s12013-025-01666-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2025] [Indexed: 01/24/2025]
Abstract
Cancer Stem Cells (CSCs) play an important role in the development, resistance, and recurrence of many malignancies. These subpopulations of tumor cells have the potential to self-renew, differentiate, and resist conventional therapy, highlighting their importance in cancer etiology. This review explores the regulatory mechanisms of CSCs in breast, cervical, and lung cancers, highlighting their plasticity, self-renewal, and differentiation capabilities. CD44+/CD24- cells are a known marker for breast CSCs. Markers like as CD133 and ALDH have been discovered in cervical cancer CSCs. Similarly, in lung cancer, CSCs identified by CD44, CD133, and ALDH are linked to aggressive tumor behavior and poor therapy results. The commonalities between these tumors highlight the general necessity of targeting CSCs in treatment efforts. However, the intricacies of CSC activity, such as their interaction with the tumor microenvironment and particular signaling pathways differ between cancer types, demanding specialized methods. Wnt/β-catenin, Notch, and Hedgehog pathways are one of the essential signaling pathways, targeting them, may show ameliorative effects on breast, lung and cervical carcinomas and their respective CSCs. Pre-clinical data suggests targeting specific signaling pathways can eliminate CSCs, but ongoing clinical trials are on utilizing signaling pathway inhibitors in patients. In recent studies it has been reported that CAR T based targeting of specific markers may be used as combination therapy. Ongoing research related to nanobiotechnology can also play a significant role in diagnosis and treatment purpose targeting CSCs, as nanomaterials can be used for precise targeting and identification of CSCs. Further research into the targeting of signaling pathways and its precursors could prove to be right step into directing therapies towards CSCs for cancer therapy.
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Affiliation(s)
- Sakshi Kevat
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Archie Mistry
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Naman Oza
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Mohit Majmudar
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Netra Patel
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Rushabh Shah
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - A V Ramachandran
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India
| | - Ritu Chauhan
- Department of Biotechnology, Graphic Era Deemed to be University, Dehradun, Uttarakhand, India
| | - Shafiul Haque
- Research and Scientific Studies Unit, College of Nursing and Health Sciences, Jazan University, Jazan, Saudi Arabia
- School Of Medicine, Universidad Espiritu Santo, Samborondon, Ecuador
| | | | - Hardeep Singh Tuli
- Department of Bio-Sciences and Technology, Maharishi Markandeshwar (Deemed to be University), Ambala, Haryana, India
| | - Gaurav Parashar
- Division of Biomedical and Life Sciences, School of Science, Navrachana University, Vadodara, Gujarat, India.
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9
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Ren X, Liu X, Zhang Q, Yang C, Xu Z. Simultaneous imaging of telomerase activity and protein tyrosine kinase 7 in living cells during epithelial-mesenchymal transformation via a near-infrared light-activatable nanoprobe. Talanta 2025; 282:126993. [PMID: 39383724 DOI: 10.1016/j.talanta.2024.126993] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 09/20/2024] [Accepted: 10/03/2024] [Indexed: 10/11/2024]
Abstract
Exploring the relationship between key regulation molecules (such as telomerase and protein tyrosine kinase 7) during epithelial-mesenchymal transformation of cells is beneficial for studying malignant tumor metastasis. Fluorescence is usually used for real-time monitoring the distribution and expression of regulatory molecules in living cells. However, the recognition function of these classical nanoprobes is "always active" due to the absence of exogenous control, which leads to the amplification of both the background signal and the response signal, making it difficult to distinguish changes in biomolecule expression levels. To improve the fluorescence ratio between tumor and normal cells, we constructed near-infrared light-activatable nanoprobes by engineering the functional units of catalytic hairpin assembly and integrating upconversion luminescence nanoparticles. Under near-infrared light irradiation, the nanoparticles, serving as a near-infrared-to-ultraviolet light transducer, induced the photolysis of the photo-cleavable linkers sealed in hairpins. The recognition function of the nanoprobes can be controlled by near-infrared light, preventing them from recognizing the targets in non-irradiated regions. By employing the nanoprobes, we realized simultaneous imaging of two regulatory molecules in living cells and observed an increase in telomerase activity and a decrease in protein tyrosine kinase 7 expression during drug-induced epithelial-mesenchymal transformation. This work provides a promising method for revealing changes and relationships of regulatory molecules during tumor metastasis.
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Affiliation(s)
- Xiuyan Ren
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Xiaopeng Liu
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Qi Zhang
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Chunguang Yang
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China
| | - Zhangrun Xu
- Research Center for Analytical Sciences, Northeastern University, Shenyang, 110819, PR China.
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10
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Rabani S, Gunes EG, Gunes M, Pellegrino B, Lampert B, David K, Pillai R, Li A, Becker-Herman S, Rosen ST, Shachar I. CD84 as a therapeutic target for breaking immune tolerance in triple-negative breast cancer. Cell Rep 2024; 43:114920. [PMID: 39466774 DOI: 10.1016/j.celrep.2024.114920] [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: 02/01/2024] [Revised: 07/11/2024] [Accepted: 10/14/2024] [Indexed: 10/30/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. The tumor microenvironment (TME) plays a major regulatory role in TNBC progression and is highly infiltrated by suppressive immune cells that reduce anti-tumor immune activity. Although regulatory B cells (Bregs) are a key TME component, knowledge of their function in TNBC is limited. CD84 is a homophilic adhesion molecule that promotes the survival of blood tumors. In the current study, we followed the role of CD84 in the regulation of the TME in TNBC. We demonstrate that CD84 induces a cascade in Bregs that involves the β-catenin and Tcf4 pathway, which induces the transcription of interleukin-10 by binding to its promoter and the promoter of its regulator, AhR. This leads to the expansion of Bregs, which in turn control the activity of other immune cells and immune suppression. Accordingly, we suggest CD84 as a therapeutic target for breaking immune tolerance in TNBC.
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Affiliation(s)
- Stav Rabani
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Emine Gulsen Gunes
- Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA, USA
| | - Martin Gunes
- Judy and Bernard Briskin Center for Multiple Myeloma Research, City of Hope, Duarte, CA, USA
| | - Bianca Pellegrino
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Bar Lampert
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Keren David
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Raju Pillai
- Pathology Core, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | - Aimin Li
- Pathology Core, Beckman Research Institute, City of Hope, Duarte, CA, USA
| | | | - Steven T Rosen
- Department of Hematology and Stem Cell Transplantation, City of Hope and Beckman Research Institute, Duarte, CA, USA
| | - Idit Shachar
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
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11
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Liu Y, Zou Y, Ye Y, Chen Y. Advances in the Understanding of the Pathogenesis of Triple-Negative Breast Cancer. Cancer Med 2024; 13:e70410. [PMID: 39558881 PMCID: PMC11574469 DOI: 10.1002/cam4.70410] [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: 09/02/2024] [Revised: 10/24/2024] [Accepted: 10/30/2024] [Indexed: 11/20/2024] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a heterogeneous disease characterized by high aggressiveness, high malignancy, and poor prognosis compared to other breast cancer subtypes. OBJECTIVE This review aims to explore recent advances in understanding TNBC and to provide new insights and potential references for clinical treatment. METHODS We examined current literature on TNBC to analyze molecular subtypes, genetic mutations, signaling pathways, mechanisms of drug resistance, and emerging therapies. RESULTS Findings highlight key aspects of TNBC's molecular subtypes, relevant mutations, and pathways, alongside emerging treatments that target drug resistance mechanisms. CONCLUSION These insights into TNBC pathogenesis may help guide future therapeutic strategies and improve clinical outcomes for patients with TNBC.
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Affiliation(s)
- Yuhan Liu
- School of Clinical MedicineShandong Second Medical UniversityWeifangChina
| | - Yuhan Zou
- School of Clinical MedicineShandong Second Medical UniversityWeifangChina
| | - Yangli Ye
- College of Life Sciences and TechnologyShandong Second Medical UniversityWeifangChina
| | - Yong Chen
- Key Laboratory of Immune Microenvironment and Inflammatory Disease Research in Universities of Shandong Province, School of Basic Medical SciencesShandong Second Medical UniversityWeifangChina
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12
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Cordani M, Dando I, Ambrosini G, González-Menéndez P. Signaling, cancer cell plasticity, and intratumor heterogeneity. Cell Commun Signal 2024; 22:255. [PMID: 38702718 PMCID: PMC11067149 DOI: 10.1186/s12964-024-01643-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/06/2024] Open
Abstract
Cancer's complexity is in part due to the presence of intratumor heterogeneity and the dynamic nature of cancer cell plasticity, which create substantial obstacles in effective cancer management. Variability within a tumor arises from the existence of diverse populations of cancer cells, impacting the progression, spread, and resistance to treatments. At the core of this variability is the concept of cellular plasticity - the intrinsic ability of cancer cells to alter their molecular and cellular identity in reaction to environmental and genetic changes. This adaptability is a cornerstone of cancer's persistence and progression, making it a formidable target for treatments. Emerging studies have emphasized the critical role of such plasticity in fostering tumor diversity, which in turn influences the course of the disease and the effectiveness of therapeutic strategies. The transformative nature of cancer involves a network of signal transduction pathways, notably those that drive the epithelial-to-mesenchymal transition and metabolic remodeling, shaping the evolutionary path of cancer cells. Despite advancements, our understanding of the precise molecular machinations and signaling networks driving these changes is still evolving, underscoring the necessity for further research. This editorial presents a series entitled "Signaling Cancer Cell Plasticity and Intratumor Heterogeneity" in Cell Communication and Signaling, dedicated to unraveling these complex processes and proposing new avenues for therapeutic intervention.
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Affiliation(s)
- Marco Cordani
- Department of Biochemistry and Molecular Biology, Faculty of Biology, Complutense University, Madrid, 28040, Spain.
- Instituto de Investigaciones Sanitarias San Carlos (IdISSC), Madrid, 28040, Spain.
| | - Ilaria Dando
- Department of Neuroscience, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, Verona, 37134, Italy.
| | - Giulia Ambrosini
- Department of Neuroscience, Biomedicine and Movement Sciences, Biochemistry Section, University of Verona, Verona, 37134, Italy.
| | - Pedro González-Menéndez
- Departamento de Morfología y Biología Celular, School of Medicine, Julián Claveria 6, Oviedo, 33006, Spain.
- Instituto Universitario de Oncología del Principado de Asturias (IUOPA), University of Oviedo, Oviedo, 33006, Spain.
- Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias (HUCA), Oviedo, 33011, Spain.
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13
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Song B, Hou G, Xu M, Chen M. Exosomal miR-122-3p represses the growth and metastasis of MCF-7/ADR cells by targeting GRK4-mediated activation of the Wnt/β-catenin pathway. Cell Signal 2024; 117:111101. [PMID: 38365112 DOI: 10.1016/j.cellsig.2024.111101] [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: 12/12/2023] [Revised: 02/05/2024] [Accepted: 02/13/2024] [Indexed: 02/18/2024]
Abstract
Breast cancer (BC) is a common cancer whose incidence continues to grow while its medical progress has stagnated. miRNAs are vital messengers that facilitate communications among different cancer cells. This study was to reveal the correlation of miR-122-3p expression with BC metastasis and Adriamycin (ADM) resistance and its mechanism of inhibiting BC metastasis. We found that expression of miR-122-3p is negatively correlated with BC metastasis and is lower in MCF-7/ADR cells. Overexpression of miR-122-3p in MCF-7/ADR cancer cells impairs their ability to migrate, invade, and stimulate blood vessel formation. Further research found that miR-122-3p directly binds to the 3' UTR of GRK4, reducing the phosphorylation of LRP6, which activates the Wnt/β-catenin signaling pathway, facilitating BC development and metastasis. In addition, we observed that miR-122-3p is present in MCF-7 cells, and treatment of MCF-7/ADR cells with MCF-7-derived exosomes, but not with exosomes from miR-122-3p-deficient MCF-7 cells, has identical effects to miR-122-3p overexpression. Data from xenograft experiments further suggest that excess miR-122-3p and MCF-7-derived exosomes inhibit the growth and metastasis of MCF-7/ADR cancer cells in vivo. In conclusion our data reveal that exosomal miR-122-3p may negatively regulate BC growth and metastasis, potentially serving as a diagnostic and druggable target for BC treatment.
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Affiliation(s)
- Binbin Song
- Department of Radiotherapy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu, China.; Department of Medical Oncology, The Affiliated Hospital of Jiaxing University, Jiaxing 314001, Zhejiang, China
| | - Guoxin Hou
- Department of Medical Oncology, The Affiliated Hospital of Jiaxing University, Jiaxing 314001, Zhejiang, China
| | - Maoyi Xu
- Department of Medical Oncology, The Affiliated Hospital of Jiaxing University, Jiaxing 314001, Zhejiang, China
| | - Ming Chen
- Department of Radiotherapy, The Second Affiliated Hospital of Soochow University, Suzhou 215004, Jiangsu, China..
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14
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Yang H, Shi Y, Lin A, Qi C, Liu Z, Cheng Q, Miao K, Zhang J, Luo P. PESSA: A web tool for pathway enrichment score-based survival analysis in cancer. PLoS Comput Biol 2024; 20:e1012024. [PMID: 38717988 PMCID: PMC11078417 DOI: 10.1371/journal.pcbi.1012024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2023] [Accepted: 03/26/2024] [Indexed: 05/12/2024] Open
Abstract
The activation levels of biologically significant gene sets are emerging tumor molecular markers and play an irreplaceable role in the tumor research field; however, web-based tools for prognostic analyses using it as a tumor molecular marker remain scarce. We developed a web-based tool PESSA for survival analysis using gene set activation levels. All data analyses were implemented via R. Activation levels of The Molecular Signatures Database (MSigDB) gene sets were assessed using the single sample gene set enrichment analysis (ssGSEA) method based on data from the Gene Expression Omnibus (GEO), The Cancer Genome Atlas (TCGA), The European Genome-phenome Archive (EGA) and supplementary tables of articles. PESSA was used to perform median and optimal cut-off dichotomous grouping of ssGSEA scores for each dataset, relying on the survival and survminer packages for survival analysis and visualisation. PESSA is an open-access web tool for visualizing the results of tumor prognostic analyses using gene set activation levels. A total of 238 datasets from the GEO, TCGA, EGA, and supplementary tables of articles; covering 51 cancer types and 13 survival outcome types; and 13,434 tumor-related gene sets are obtained from MSigDB for pre-grouping. Users can obtain the results, including Kaplan-Meier analyses based on the median and optimal cut-off values and accompanying visualization plots and the Cox regression analyses of dichotomous and continuous variables, by selecting the gene set markers of interest. PESSA (https://smuonco.shinyapps.io/PESSA/ OR http://robinl-lab.com/PESSA) is a large-scale web-based tumor survival analysis tool covering a large amount of data that creatively uses predefined gene set activation levels as molecular markers of tumors.
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Affiliation(s)
- Hong Yang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Haizhu District, Guangzhou, Guangdong, China
- The First School of Clinical Medicine, Southern Medical University, Baiyun District, Guangzhou, Guangdong, China
| | - Ying Shi
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Haizhu District, Guangzhou, Guangdong, China
- The Second School of Clinical Medicine, Southern Medical University, Baiyun District, Guangzhou, Guangdong, China
| | - Anqi Lin
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Haizhu District, Guangzhou, Guangdong, China
| | - Chang Qi
- Institute of Logic and Computation, TU Wien, Austria
| | - Zaoqu Liu
- State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China
- State Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Pathophysiology, Peking Union Medical College, Beijing, China
| | - Quan Cheng
- Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Kai Miao
- Cancer Centre and Institute of Translational Medicine, Faculty of Health Sciences, University of Macau, Macau SAR, China
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Macau SAR, China
| | - Jian Zhang
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Haizhu District, Guangzhou, Guangdong, China
| | - Peng Luo
- Department of Oncology, Zhujiang Hospital, Southern Medical University, Haizhu District, Guangzhou, Guangdong, China
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15
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Gadwal A, Purohit P, Khokhar M, Vishnoi JR, Pareek P, Choudhary R, Elhence P, Banerjee M, Sharma P. GALNT6, GALNT14, and Gal-3 in association with GDF-15 promotes drug resistance and stemness of breast cancer via β-catenin axis. Growth Factors 2024; 42:84-100. [PMID: 38889447 DOI: 10.1080/08977194.2024.2368907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Accepted: 06/12/2024] [Indexed: 06/20/2024]
Abstract
N-acetylgalactosaminyltransferases (GALNTs) are a polypeptide responsible for aberrant glycosylation in breast cancer (BC), but the mechanism is unclear. In this study, expression levels of GALNT6, GALNT14, and Gal-3 were assessed in BC, and their association with GDF-15, β-catenin, stemness (SOX2 and OCT4), and drug resistance marker (ABCC5) was evaluated. Gene expression of GALNT6, GALNT14, Gal-3, GDF-15, OCT4, SOX2, ABCC5, and β-catenin in tumor and adjacent non-tumor tissues (n = 30) was determined. The same was compared with GEO-microarray datasets. A significant increase in the expression of candidate genes was observed in BC tumor compared to adjacent non-tumor tissue; and in pre-therapeutic patients compared to post-therapeutic. GALNT6, GALNT14, Gal-3, and GDF-15 showed positive association with β-catenin, SOX2, OCT4, and ABCC5 and were significantly associated with poor Overall Survival. Our findings were also validated via in silico analysis. Our study suggests that GALNT6, GALNT14, and Gal-3 in association with GDF-15 promote stemness and intrinsic drug resistance in BC, possibly by β-catenin signaling pathway.
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Affiliation(s)
- Ashita Gadwal
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Purvi Purohit
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
| | - Manoj Khokhar
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, 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, India
| | - Praveen Sharma
- Department of Biochemistry, All India Institute of Medical Sciences, Jodhpur, India
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16
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Ilhan M, Hastar N, Kampfrath B, Spierling DN, Jatzlau J, Knaus P. BMP Stimulation Differentially Affects Phosphorylation and Protein Stability of β-Catenin in Breast Cancer Cell Lines. Int J Mol Sci 2024; 25:4593. [PMID: 38731813 PMCID: PMC11083028 DOI: 10.3390/ijms25094593] [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: 02/19/2024] [Revised: 04/18/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
Increased expression and nuclear translocation of β-CATENIN is frequently observed in breast cancer, and it correlates with poor prognosis. Current treatment strategies targeting β-CATENIN are not as efficient as desired. Therefore, detailed understanding of β-CATENIN regulation is crucial. Bone morphogenetic proteins (BMP) and Wingless/Integrated (WNT) pathway crosstalk is well-studied for many cancer types including colorectal cancer, whereas it is still poorly understood for breast cancer. Analysis of breast cancer patient data revealed that BMP2 and BMP6 were significantly downregulated in tumors. Since mutation frequency in genes enhancing β-CATENIN protein stability is relatively low in breast cancer, we aimed to investigate whether decreased BMP ligand expression could contribute to a high protein level of β-CATENIN in breast cancer cells. We demonstrated that downstream of BMP stimulation, SMAD4 is required to reduce β-CATENIN protein stability through the phosphorylation in MCF7 and T47D cells. Consequently, BMP stimulation reduces β-CATENIN levels and prevents its nuclear translocation and target gene expression in MCF7 cells. Conversely, BMP stimulation has no effect on β-CATENIN phosphorylation or stability in MDA-MB-231 and MDA-MB-468 cells. Likewise, SMAD4 modulation does not alter the response of those cells, indicating that SMAD4 alone is insufficient for BMP-induced β-CATENIN phosphorylation. While our data suggest that considering BMP activity may serve as a prognostic marker for understanding β-CATENIN accumulation risk, further investigation is needed to elucidate the differential responsiveness of breast cancer cell lines.
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Affiliation(s)
- Mustafa Ilhan
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Berlin School of Integrative Oncology, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Nurcan Hastar
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Brandenburg School for Regenerative Therapies, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Branka Kampfrath
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
| | - Deniz Neslihan Spierling
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
| | - Jerome Jatzlau
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Brandenburg School for Regenerative Therapies, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Petra Knaus
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Berlin School of Integrative Oncology, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
- Brandenburg School for Regenerative Therapies, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
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17
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MacLean MR, Walker OL, Arun RP, Fernando W, Marcato P. Informed by Cancer Stem Cells of Solid Tumors: Advances in Treatments Targeting Tumor-Promoting Factors and Pathways. Int J Mol Sci 2024; 25:4102. [PMID: 38612911 PMCID: PMC11012648 DOI: 10.3390/ijms25074102] [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: 02/28/2024] [Revised: 03/30/2024] [Accepted: 04/02/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer stem cells (CSCs) represent a subpopulation within tumors that promote cancer progression, metastasis, and recurrence due to their self-renewal capacity and resistance to conventional therapies. CSC-specific markers and signaling pathways highly active in CSCs have emerged as a promising strategy for improving patient outcomes. This review provides a comprehensive overview of the therapeutic targets associated with CSCs of solid tumors across various cancer types, including key molecular markers aldehyde dehydrogenases, CD44, epithelial cellular adhesion molecule, and CD133 and signaling pathways such as Wnt/β-catenin, Notch, and Sonic Hedgehog. We discuss a wide array of therapeutic modalities ranging from targeted antibodies, small molecule inhibitors, and near-infrared photoimmunotherapy to advanced genetic approaches like RNA interference, CRISPR/Cas9 technology, aptamers, antisense oligonucleotides, chimeric antigen receptor (CAR) T cells, CAR natural killer cells, bispecific T cell engagers, immunotoxins, drug-antibody conjugates, therapeutic peptides, and dendritic cell vaccines. This review spans developments from preclinical investigations to ongoing clinical trials, highlighting the innovative targeting strategies that have been informed by CSC-associated pathways and molecules to overcome therapeutic resistance. We aim to provide insights into the potential of these therapies to revolutionize cancer treatment, underscoring the critical need for a multi-faceted approach in the battle against cancer. This comprehensive analysis demonstrates how advances made in the CSC field have informed significant developments in novel targeted therapeutic approaches, with the ultimate goal of achieving more effective and durable responses in cancer patients.
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Affiliation(s)
- Maya R. MacLean
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Olivia L. Walker
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Raj Pranap Arun
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
| | - Wasundara Fernando
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Biology, Acadia University, Wolfville, NS B4P 2R6, Canada
| | - Paola Marcato
- Department of Pathology, Dalhousie University, Halifax, NS B3H 4R2, Canada; (M.R.M.); (O.L.W.); (R.P.A.); (W.F.)
- Department of Microbiology and Immunology, Dalhousie University, Halifax, NS B3H 4R2, Canada
- Nova Scotia Health Authority, Halifax, NS B3H 4R2, Canada
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18
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Gholamzad A, Khakpour N, Khosroshahi EM, Asadi S, Koohpar ZK, Matinahmadi A, Jebali A, Rashidi M, Hashemi M, Sadi FH, Gholamzad M. Cancer stem cells: The important role of CD markers, Signaling pathways, and MicroRNAs. Pathol Res Pract 2024; 256:155227. [PMID: 38490099 DOI: 10.1016/j.prp.2024.155227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 02/23/2024] [Accepted: 02/25/2024] [Indexed: 03/17/2024]
Abstract
For the first time, a subset of small cancer cells identified in acute myeloid leukemia has been termed Cancer Stem Cells (CSCs). These cells are notorious for their robust proliferation, self-renewal abilities, significant tumor-forming potential, spread, and resistance to treatments. CSCs are a global concern, as it found in numerous types of cancer, posing a real-world challenge today. Our review encompasses research on key CSC markers, signaling pathways, and MicroRNA in three types of cancer: breast, colon, and liver. These factors play a critical role in either promoting or inhibiting cancer cell growth. The reviewed studies have shown that as cells undergo malignant transformation, there can be an increase or decrease in the expression of different Cluster of Differentiation (CD) markers on their surface. Furthermore, alterations in essential signaling pathways, such as Wnt and Notch1, may impact CSC proliferation, survival, and movement, while also providing potential targets for cancer therapies. Additionally, some research has focused on MicroRNAs due to their dual role as potential therapeutic biomarkers and their ability to enhance CSCs' response to anti-cancer drugs. MicroRNAs also regulate a wide array of cellular processes, including the self-renewal and pluripotency of CSCs, and influence gene transcription. Thus, these studies indicate that MicroRNAs play a significant role in the malignancy of various tumors. Although the gathered information suggests that specific CSC markers, signaling pathways, and MicroRNAs are influential in determining the destiny of cancer cells and could be advantageous for therapeutic strategies, their precise roles and impacts remain incompletely defined, necessitating further investigation.
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Affiliation(s)
- Amir Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Niloofar Khakpour
- Department of Bacteriology and Virology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Elaheh Mohandesi Khosroshahi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Saba Asadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran
| | - Zeinab Khazaei Koohpar
- Department of Cell and Molecular Biology, Faculty of Biological Sciences,Tonekabon Branch,Islamic Azad University, Tonekabon, Iran
| | - Arash Matinahmadi
- Department of Cellular and Molecular Biology, Nicolaus Copernicus,Torun,Poland
| | - Ali Jebali
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran; Deprtment of Medical Nanotechnology,Faculty of Advanced Sciences and Technology,Tehran Medical Sciences,Islamic Azad University, Tehran, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran; The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran.
| | - Mehrdad Hashemi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran.
| | | | - Mehrdad Gholamzad
- Department of Microbiology and Immunology, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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19
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Scully MA, Wilhelm R, Wilkins DE, Day ES. Membrane-Cloaked Nanoparticles for RNA Interference of β-Catenin in Triple-Negative Breast Cancer. ACS Biomater Sci Eng 2024; 10:1355-1363. [PMID: 38306303 PMCID: PMC10939768 DOI: 10.1021/acsbiomaterials.4c00160] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2024]
Abstract
There is an outstanding need for targeted therapies for triple-negative breast cancer (TNBC), an aggressive breast cancer subtype. Since TNBC's rapid growth and metastasis are driven by hyperactive Wnt signaling, suppressing the key-pathway mediator β-catenin through RNA interference may improve patient outcomes. However, small interfering ribonucleic acid (siRNA) molecules require a carrier to elicit targeted gene silencing. Here, we show that 4T1 cancer cell membrane wrapped poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) can deliver siRNA into TNBC cells, silence β-catenin expression, and reduce the cells' tumorigenic qualities. Compared to unwrapped and nontargeted NPs, the cancer cell membrane wrapped nanoparticles (CCNPs) exhibit dramatically improved uptake by TNBC cells versus breast epithelial cells and greater gene silencing at mRNA and protein levels. Congruently, β-catenin siRNA-loaded CCNPs significantly activate senescence in 2D cultured TNBC cells and reduce proliferation in 3D spheroids. This work advances the development of nucleic acid carriers for targeted RNA interference therapy.
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Affiliation(s)
- Mackenzie A Scully
- Department of Biomedical Engineering, University of Delaware, Newark, Delaware 19713, United States of America
| | - Ruth Wilhelm
- Department of Biomedical Engineering, University of Delaware, Newark, Delaware 19713, United States of America
| | - Dana E Wilkins
- Department of Biomedical Engineering, University of Delaware, Newark, Delaware 19713, United States of America
| | - Emily S Day
- Department of Biomedical Engineering, University of Delaware, Newark, Delaware 19713, United States of America
- Department of Materials Science and Engineering, University of Delaware, Newark, Delaware 19716, United States of America
- Center for Translational Research, Helen F. Graham Cancer Center and Research Institute, Newark, Delaware 19713, United States of America
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20
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Alitongbieke G, Zhang X, Zhu F, Wu Q, Lin Z, Li X, Xue Y, Lai X, Feng J, Huang R, Pan Y. Glucan from Oudemansiella raphanipes suppresses breast cancer proliferation and metastasis by regulating macrophage polarization and the WNT/β-catenin signaling pathway. J Cancer 2024; 15:1169-1181. [PMID: 38356709 PMCID: PMC10861828 DOI: 10.7150/jca.89873] [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: 09/05/2023] [Accepted: 11/16/2023] [Indexed: 02/16/2024] Open
Abstract
Background: The glucan extract of Oudemansiella raphanipes (Orp) has multiple biological properties, similar to extracts of other natural edible fungi. Drugs traditionally used in cancer treatment are associated with several drawbacks, such as side effects, induction of resistance, and poor prognosis, and many recent studies have focused on polysaccharides extracted from natural sources as alternatives. Our study focuses on the therapeutic role and molecular mechanism of action of Orp in breast cancer progression. Methods: MMTV-PyMT transgenic mice were used as the spontaneous breast cancer mice model. Immunoblotting, hematoxylin-eosin staining, immunohistochemistry, and immunofluorescence were used to evaluate the tumor behaviors in breast cancer. The inflammatory cell model was constructed using TNF-α. Macrophage activation and WNT/β-catenin signaling were assayed using western blotting and immunofluorescence. Results: Orp management significantly inhibited tumor growth and promoted tumor cell apoptosis in MMTV-PyMT transgenic mice. Besides, the Orp challenge also attenuated the ability of breast tumors to metastasize into lung tissues. Mechanistically, Orp treatment restrained the polarization of M1 macrophages to M2 macrophages and suppressed WNT/β-catenin signaling in mouse tumor tissues, which implied that Orp-mediated tumor inhibition partly occurred via regulating the inflammatory response. Findings from in vitro experiments confirmed that Orp inhibited the TNF-α-induced nuclear transportation of β-catenin, thus preventing inflammation signaling and the expression of c-Myc in MCF-7 cells. Conclusion: Orp inhibits breast cancer growth and metastasis by regulating macrophage polarization and the WNT/β-catenin signaling axis. The findings of this study suggest that Orp may be a promising therapeutic strategy for breast cancer.
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Affiliation(s)
- Gulimiran Alitongbieke
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Xiuru Zhang
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Fukai Zhu
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Qici Wu
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Zhichao Lin
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Xiumin Li
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Yu Xue
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Xuebin Lai
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
| | - Jiexin Feng
- Department of Breast Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian 363099, People's Republic of China
| | - Rongjie Huang
- Department of General Surgery, Zhangzhou Affiliated Hospital of Fujian Medical University, Zhangzhou, Fujian 363099, People's Republic of China
| | - Yutian Pan
- Engineering Technological Center of Mushroom Industry, Minnan Normal University, Zhangzhou, Fujian 363000, People's Republic of China
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21
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Mohapatra P, Madhulika S, Behera S, Singh P, Sa P, Prasad P, Swain RK, Sahoo SK. Nimbolide-based nanomedicine inhibits breast cancer stem-like cells by epigenetic reprogramming of DNMTs-SFRP1-Wnt/β-catenin signaling axis. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 34:102031. [PMID: 37771911 PMCID: PMC10523002 DOI: 10.1016/j.omtn.2023.102031] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 09/06/2023] [Indexed: 09/30/2023]
Abstract
Triple-negative breast cancer (TNBC) harbors a high percentage of breast cancer stem-like cells (BCSCs) that significantly contribute to poor prognosis, metastasis, and relapse of the disease. Thus, targeting BCSCs could be a promising approach to combat TNBC. In this context, we investigated nimbolide (Nim), a limonoid triterpenoid that has potent anticancer properties, but poor pharmacokinetics and low bioavailability limit its therapeutic application. So, to enhance the therapeutic potential of Nim, Nim-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Nim NPs) were formulated and the anticancer stem cell (CSC) effects evaluated in vitro and in vivo. In vitro studies suggested that Nim NPs significantly inhibited several inherent characteristics of BCSCs, such as stemness, self-renewability, chemoresistance, epithelial-to-mesenchymal transition (EMT), and migration in comparison to native Nim. Next, the mechanism behind the anti-CSC effect of Nim was explored. Mechanistically, we found that Nim epigenetically restores tumor suppressor gene secreted frizzled-related protein 1 (SFRP1) expression by downregulating DNA methyltransferases (DNMTs), leading to Wnt/β-catenin signaling inhibition. Further, in vivo results demonstrated that Nim NPs showed enhanced anti-tumor and anti-metastatic effects compared to native Nim in two preclinical models without any systemic toxicity. Overall, these findings provide proof of concept that Nim-based phytonanomedicine can inhibit BCSCs by epigenetic reprogramming of the DNMTs-SFRP1-Wnt/β-catenin signaling axis.
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Affiliation(s)
- Priyanka Mohapatra
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
- Regional Centre for Biotechnology, Faridabad 121001, Haryana, India
| | - Swati Madhulika
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
- Regional Centre for Biotechnology, Faridabad 121001, Haryana, India
| | - Somalisa Behera
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
| | - Priya Singh
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
- Regional Centre for Biotechnology, Faridabad 121001, Haryana, India
| | - Pratikshya Sa
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
- Regional Centre for Biotechnology, Faridabad 121001, Haryana, India
| | - Punit Prasad
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
| | - Rajeeb Kumar Swain
- Institute of Life Sciences, Nalco Square, Bhubaneswar 751023, Odisha, India
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22
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Guo Z, Han S. Targeting cancer stem cell plasticity in triple-negative breast cancer. EXPLORATION OF TARGETED ANTI-TUMOR THERAPY 2023; 4:1165-1181. [PMID: 38213533 PMCID: PMC10776602 DOI: 10.37349/etat.2023.00190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2023] [Accepted: 10/15/2023] [Indexed: 01/13/2024] Open
Abstract
Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited treatment options. Cancer stem cells (CSCs) are thought to play a crucial role in TNBC progression and resistance to therapy. CSCs are a small subpopulation of cells within tumors that possess self-renewal and differentiation capabilities and are responsible for tumor initiation, maintenance, and metastasis. CSCs exhibit plasticity, allowing them to switch between states and adapt to changing microenvironments. Targeting CSC plasticity has emerged as a promising strategy for TNBC treatment. This review summarizes recent advances in understanding the molecular mechanisms underlying CSC plasticity in TNBC and discusses potential therapeutic approaches targeting CSC plasticity.
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Affiliation(s)
- Zhengwang Guo
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Shuyan Han
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Integration of Chinese and Western Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China
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23
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Paul S, Das K, Ghosh A, Chatterjee A, Bhoumick A, Basu A, Sen P. Coagulation factor VIIa enhances programmed death-ligand 1 expression and its stability in breast cancer cells to promote breast cancer immune evasion. J Thromb Haemost 2023; 21:3522-3538. [PMID: 37579880 DOI: 10.1016/j.jtha.2023.08.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 08/02/2023] [Accepted: 08/03/2023] [Indexed: 08/16/2023]
Abstract
BACKGROUND Immunotherapy for breast cancer has not gained significant success. Coagulation factor VIIa (FVIIa)-tissue factor (TF) mediated activation of protease-activated receptor 2 (PAR2) is shown to promote metastasis and secretion of the immune-modulatory cytokines but the role of FVIIa in cancer immunology is still not well understood. OBJECTIVES Here, we aim to investigate whether FVIIa protects breast cancer cells from CD8 T-cell-mediated killing. METHODS Peripheral blood mononuclear cell-derived CD8 T cells were cocultured with vehicle or FVIIa pretreated MDAMB468 cells. The proliferation and activity of CD8 T cells were measured by flow cytometry and ELISA. An allograft model, using wild-type or TF/PAR2-deleted 4T1 cells, was employed to determine the effect of FVIIa on breast cancer immune evasion in vivo. RESULTS Here, we demonstrate that TF-FVIIa induces programmed death-ligand 1 (PD-L1) in breast cancer cells by activating PAR2. PAR2 activation triggers large tumor suppressor kinase 1 (LATS1) inactivation leading to loss of yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) phosphorylation and subsequent nuclear localization of YAP/TAZ. YAP/TAZ inhibition reduces PD-L1 expression and increases CD8 T-cell activity. We further demonstrate that, apart from transcriptional induction of PD-L1, PAR2 activation also increases PD-L1 stability by enhancing its glycosylation through N-glycosyltransferases STT3A and STT3B. CONCLUSION In a mouse model of breast cancer, tumor cell-specific PAR2 depletion leads to PD-L1 downregulation and increases anti-PD-1 immunotherapy efficacy. In conclusion, we showed that FVIIa-mediated signaling cascade in cancer cells serves as a tumor intrinsic mechanism of immunosuppression to promote cancer immune evasion.
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Affiliation(s)
- Subhojit Paul
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata, India
| | - Kaushik Das
- Department of Cellular and Molecular Biology, The University of Texas Health Science Center at Tyler, Tyler, Texas
| | - Arnab Ghosh
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata, India
| | - Akash Chatterjee
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata, India
| | - Avinandan Bhoumick
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata, India
| | - Abhimanyu Basu
- Department of General Surgery, Institute of Postgraduate Medical Education and Research, Kolkata, West Bengal, India
| | - Prosenjit Sen
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata, India.
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24
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Kumar H, Gupta NV, Jain R, Madhunapantula SV, Babu CS, Kesharwani SS, Dey S, Jain V. A review of biological targets and therapeutic approaches in the management of triple-negative breast cancer. J Adv Res 2023; 54:271-292. [PMID: 36791960 DOI: 10.1016/j.jare.2023.02.005] [Citation(s) in RCA: 40] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 01/23/2023] [Accepted: 02/09/2023] [Indexed: 02/15/2023] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a heterogeneous, aggressive phenotype of breast cancer with associated chemoresistance. The development of chemo- or radioresistance could be attributed to diverse tumor microenvironments, overexpression of membrane proteins (transporters), epigenetic changes, and alteration of the cell signaling pathways/genes associated with the development of cancer stem cells (CSCs). AIM OF REVIEW Due to the diverse and heterogeneous nature of TNBC, therapeutic response to the existing modalities offers limited scope and thus results in reccurance after therapy. To establish landmark therapeutic efficacy, a number of novel therapeutic modalities have been proposed. In addition, reversal of the resistance that developed during treatment may be altered by employing appropriate therapeutic modalities. This review aims to discuss the plethora of investigations carried out, which will help readers understand and make an appropriate choice of therapy directed toward complete elimination of TNBC. KEY SCIENTIFIC CONCEPTS OF REVIEW This manuscript addresses the major contributory factors from the tumor microenvironment that are responsible for the development of chemoresistance and poor prognosis. The associated cellular events and molecular mechanism-based therapeutic interventions have been explained in detail. Inhibition of ABC transporters, cell signaling pathways associated with CSCs, and epigenetic modification offers promising results in this regard. TNBC progression, invasion, metastasis and recurrence can also be inhibited by blocking multiple cell signaling pathways, targeting specific receptors/epigenetic targets, disrupting bioenergetics and generating reactive oxygen species (ROS).
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Affiliation(s)
- Hitesh Kumar
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | - N Vishal Gupta
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | - Rupshee Jain
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | - SubbaRao V Madhunapantula
- Department of Biochemistry, Centre of Excellence in Molecular Biology & Regenerative Medicine, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | - C Saravana Babu
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India
| | | | - Surajit Dey
- Roseman University of Health Sciences, College of Pharmacy, Henderson, NV, USA
| | - Vikas Jain
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, India.
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25
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Mubtasim N, Gollahon L. The Effect of Adipocyte-Secreted Factors in Activating Focal Adhesion Kinase-Mediated Cell Signaling Pathway towards Metastasis in Breast Cancer Cells. Int J Mol Sci 2023; 24:16605. [PMID: 38068928 PMCID: PMC10706115 DOI: 10.3390/ijms242316605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 11/07/2023] [Accepted: 11/17/2023] [Indexed: 12/18/2023] Open
Abstract
Obesity-associated perturbations in the normal secretion of adipocytokines from white adipocytes can drive the metastatic progression of cancer. However, the association between obesity-induced changes in secretory factors of white adipocytes and subsequent transactivation of the downstream effector proteins impacting metastasis in breast cancer cells remains unclear. Focal adhesion kinase, a cytoplasmic signal transducer, regulates the biological phenomenon of metastasis by activating downstream targets such as beta-catenin and MMP9. Thus, the possible role of phosphorylated FAK in potentiating cancer cell migration was investigated. To elucidate this potential relationship, MCF7 (ER+), MDA-MB-231 (Triple Negative) breast cancer cells, and MCF-10A non-tumorigenic breast cells were exposed to in vitro murine adipocyte-conditioned medium derived from 3T3-L1 MBX cells differentiated to obesity with fatty acid supplementation. Our results show that the conditioned medium derived from these obese adipocytes enhanced motility and invasiveness of breast cancer cells. Importantly, no such changes were observed in the non-tumorigenic breast cells. Our results also show that increased FAK autophosphorylation was followed by increased expression of beta-catenin and MMP9 in the breast cancer cells when exposed to obese adipocyte-conditioned medium, but not in the MCF10A cells. These results indicate that adipocyte-derived secretory factors induced FAK activation through phosphorylation. This in turn increased breast cancer cell migration and invasion by activating its downstream effector proteins beta-catenin and MMP9.
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Affiliation(s)
- Noshin Mubtasim
- Department of Biological Sciences, Texas Tech University, 2500 Broadway, Lubbock, TX 79409, USA;
| | - Lauren Gollahon
- Department of Biological Sciences, Texas Tech University, 2500 Broadway, Lubbock, TX 79409, USA;
- Obesity Research Institute, Texas Tech University, 2500 Broadway, Lubbock, TX 79409, USA
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26
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Zeng Z, Fu M, Hu Y, Wei Y, Wei X, Luo M. Regulation and signaling pathways in cancer stem cells: implications for targeted therapy for cancer. Mol Cancer 2023; 22:172. [PMID: 37853437 PMCID: PMC10583419 DOI: 10.1186/s12943-023-01877-w] [Citation(s) in RCA: 51] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Accepted: 10/05/2023] [Indexed: 10/20/2023] Open
Abstract
Cancer stem cells (CSCs), initially identified in leukemia in 1994, constitute a distinct subset of tumor cells characterized by surface markers such as CD133, CD44, and ALDH. Their behavior is regulated through a complex interplay of networks, including transcriptional, post-transcriptional, epigenetic, tumor microenvironment (TME), and epithelial-mesenchymal transition (EMT) factors. Numerous signaling pathways were found to be involved in the regulatory network of CSCs. The maintenance of CSC characteristics plays a pivotal role in driving CSC-associated tumor metastasis and conferring resistance to therapy. Consequently, CSCs have emerged as promising targets in cancer treatment. To date, researchers have developed several anticancer agents tailored to specifically target CSCs, with some of these treatment strategies currently undergoing preclinical or clinical trials. In this review, we outline the origin and biological characteristics of CSCs, explore the regulatory networks governing CSCs, discuss the signaling pathways implicated in these networks, and investigate the influential factors contributing to therapy resistance in CSCs. Finally, we offer insights into preclinical and clinical agents designed to eliminate CSCs.
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Affiliation(s)
- Zhen Zeng
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Minyang Fu
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuan Hu
- Department of Pediatric Nephrology Nursing, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Yuquan Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Xiawei Wei
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China
| | - Min Luo
- Laboratory of Aging Research and Cancer Agent Target, State Key Laboratory of Biotherapy, Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, No. 17, Block 3, Southern Renmin Road, Chengdu, Sichuan, 610041, P.R. China.
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27
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Pérez-González A, Bévant K, Blanpain C. Cancer cell plasticity during tumor progression, metastasis and response to therapy. NATURE CANCER 2023; 4:1063-1082. [PMID: 37537300 PMCID: PMC7615147 DOI: 10.1038/s43018-023-00595-y] [Citation(s) in RCA: 110] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 06/01/2023] [Indexed: 08/05/2023]
Abstract
Cell plasticity represents the ability of cells to be reprogrammed and to change their fate and identity, enabling homeostasis restoration and tissue regeneration following damage. Cell plasticity also contributes to pathological conditions, such as cancer, enabling cells to acquire new phenotypic and functional features by transiting across distinct cell states that contribute to tumor initiation, progression, metastasis and resistance to therapy. Here, we review the intrinsic and extrinsic mechanisms driving cell plasticity that promote tumor growth and proliferation as well as metastasis and drug tolerance. Finally, we discuss how cell plasticity could be exploited for anti-cancer therapy.
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Affiliation(s)
- Andrea Pérez-González
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Kevin Bévant
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium
| | - Cédric Blanpain
- Laboratory of Stem Cells and Cancer, Université Libre de Bruxelles (ULB), Brussels, Belgium.
- WELBIO, ULB, Bruxelles, Belgium.
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28
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Ordaz-Ramos A, Tellez-Jimenez O, Vazquez-Santillan K. Signaling pathways governing the maintenance of breast cancer stem cells and their therapeutic implications. Front Cell Dev Biol 2023; 11:1221175. [PMID: 37492224 PMCID: PMC10363614 DOI: 10.3389/fcell.2023.1221175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 06/28/2023] [Indexed: 07/27/2023] Open
Abstract
Breast cancer stem cells (BCSCs) represent a distinct subpopulation of cells with the ability to self-renewal and differentiate into phenotypically diverse tumor cells. The involvement of CSC in treatment resistance and cancer recurrence has been well established. Numerous studies have provided compelling evidence that the self-renewal ability of cancer stem cells is tightly regulated by specific signaling pathways, which exert critical roles to maintain an undifferentiated phenotype and prevent the differentiation of CSCs. Signaling pathways such as Wnt/β-catenin, NF-κB, Notch, Hedgehog, TGF-β, and Hippo have been implicated in the promotion of self-renewal of many normal and cancer stem cells. Given the pivotal role of BCSCs in driving breast cancer aggressiveness, targeting self-renewal signaling pathways holds promise as a viable therapeutic strategy for combating this disease. In this review, we will discuss the main signaling pathways involved in the maintenance of the self-renewal ability of BCSC, while also highlighting current strategies employed to disrupt the signaling molecules associated with stemness.
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Affiliation(s)
- Alejandro Ordaz-Ramos
- Innovation in Precision Medicine Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, México
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Circuito de Posgrados, Ciudad Universitaria, Coyoacán, México
| | - Olivia Tellez-Jimenez
- Innovation in Precision Medicine Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, México
- Posgrado en Ciencias Biológicas, Unidad de Posgrado, Circuito de Posgrados, Ciudad Universitaria, Coyoacán, México
| | - Karla Vazquez-Santillan
- Innovation in Precision Medicine Laboratory, Instituto Nacional de Medicina Genómica, Mexico City, México
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29
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Lučić I, Kurtović M, Mlinarić M, Piteša N, Čipak Gašparović A, Sabol M, Milković L. Deciphering Common Traits of Breast and Ovarian Cancer Stem Cells and Possible Therapeutic Approaches. Int J Mol Sci 2023; 24:10683. [PMID: 37445860 DOI: 10.3390/ijms241310683] [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: 05/06/2023] [Revised: 06/21/2023] [Accepted: 06/23/2023] [Indexed: 07/15/2023] Open
Abstract
Breast cancer (BC) and ovarian cancer (OC) are among the most common and deadly cancers affecting women worldwide. Both are complex diseases with marked heterogeneity. Despite the induction of screening programs that increase the frequency of earlier diagnosis of BC, at a stage when the cancer is more likely to respond to therapy, which does not exist for OC, more than 50% of both cancers are diagnosed at an advanced stage. Initial therapy can put the cancer into remission. However, recurrences occur frequently in both BC and OC, which are highly cancer-subtype dependent. Therapy resistance is mainly attributed to a rare subpopulation of cells, named cancer stem cells (CSC) or tumor-initiating cells, as they are capable of self-renewal, tumor initiation, and regrowth of tumor bulk. In this review, we will discuss the distinctive markers and signaling pathways that characterize CSC, their interactions with the tumor microenvironment, and the strategies they employ to evade immune surveillance. Our focus will be on identifying the common features of breast cancer stem cells (BCSC) and ovarian cancer stem cells (OCSC) and suggesting potential therapeutic approaches.
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Affiliation(s)
- Ivan Lučić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Matea Kurtović
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Monika Mlinarić
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Nikolina Piteša
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Ana Čipak Gašparović
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Maja Sabol
- Laboratory for Hereditary Cancer, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
| | - Lidija Milković
- Laboratory for Oxidative Stress, Division of Molecular Medicine, Ruđer Bošković Institute, 10000 Zagreb, Croatia
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30
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Salemme V, Vedelago M, Sarcinella A, Moietta F, Piccolantonio A, Moiso E, Centonze G, Manco M, Guala A, Lamolinara A, Angelini C, Morellato A, Natalini D, Calogero R, Incarnato D, Oliviero S, Conti L, Iezzi M, Tosoni D, Bertalot G, Freddi S, Tucci FA, De Sanctis F, Frusteri C, Ugel S, Bronte V, Cavallo F, Provero P, Gai M, Taverna D, Turco E, Pece S, Defilippi P. p140Cap inhibits β-Catenin in the breast cancer stem cell compartment instructing a protective anti-tumor immune response. Nat Commun 2023; 14:2350. [PMID: 37169737 PMCID: PMC10175288 DOI: 10.1038/s41467-023-37824-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 04/03/2023] [Indexed: 05/13/2023] Open
Abstract
The p140Cap adaptor protein is a tumor suppressor in breast cancer associated with a favorable prognosis. Here we highlight a function of p140Cap in orchestrating local and systemic tumor-extrinsic events that eventually result in inhibition of the polymorphonuclear myeloid-derived suppressor cell function in creating an immunosuppressive tumor-promoting environment in the primary tumor, and premetastatic niches at distant sites. Integrative transcriptomic and preclinical studies unravel that p140Cap controls an epistatic axis where, through the upstream inhibition of β-Catenin, it restricts tumorigenicity and self-renewal of tumor-initiating cells limiting the release of the inflammatory cytokine G-CSF, required for polymorphonuclear myeloid-derived suppressor cells to exert their local and systemic tumor conducive function. Mechanistically, p140Cap inhibition of β-Catenin depends on its ability to localize in and stabilize the β-Catenin destruction complex, promoting enhanced β-Catenin inactivation. Clinical studies in women show that low p140Cap expression correlates with reduced presence of tumor-infiltrating lymphocytes and more aggressive tumor types in a large cohort of real-life female breast cancer patients, highlighting the potential of p140Cap as a biomarker for therapeutic intervention targeting the β-Catenin/ Tumor-initiating cells /G-CSF/ polymorphonuclear myeloid-derived suppressor cell axis to restore an efficient anti-tumor immune response.
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Affiliation(s)
- Vincenzo Salemme
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
| | - Mauro Vedelago
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Alessandro Sarcinella
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Federico Moietta
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Alessio Piccolantonio
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
| | - Enrico Moiso
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Giorgia Centonze
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
| | - Marta Manco
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Andrea Guala
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Alessia Lamolinara
- Immuno-Oncology Laboratory, Center for Advanced Studies and Technology (CAST), Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University of Chieti-Pescara, Chieti-Pescara, Italy
| | - Costanza Angelini
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Alessandro Morellato
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
| | - Dora Natalini
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Raffaele Calogero
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
| | - Danny Incarnato
- Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, the Netherlands
| | - Salvatore Oliviero
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
- Department of Life Sciences and Systems Biology, University of Turin, Torino, Italy and IIGM, Candiolo, Italy
| | - Laura Conti
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
| | - Manuela Iezzi
- Immuno-Oncology Laboratory, Center for Advanced Studies and Technology (CAST), Department of Neuroscience, Imaging and Clinical Sciences, G. d'Annunzio University of Chieti-Pescara, Chieti-Pescara, Italy
| | - Daniela Tosoni
- European Institute of Oncology IRCCS, 20141, Milan, Italy
| | | | - Stefano Freddi
- European Institute of Oncology IRCCS, 20141, Milan, Italy
| | - Francesco A Tucci
- European Institute of Oncology IRCCS, 20141, Milan, Italy
- School of Pathology, University of Milan, Milan, Italy
| | - Francesco De Sanctis
- Immunology Section, Department of Medicine, University of Verona, 37134, Verona, Italy
| | - Cristina Frusteri
- Immunology Section, Department of Medicine, University of Verona, 37134, Verona, Italy
| | - Stefano Ugel
- Immunology Section, Department of Medicine, University of Verona, 37134, Verona, Italy
| | - Vincenzo Bronte
- Immunology Section, Department of Medicine, University of Verona, 37134, Verona, Italy
- Istituto Oncologico Veneto, IRCCS, 35128, Padova, Italy
| | - Federica Cavallo
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
| | - Paolo Provero
- Neuroscience Department "Rita Levi Montalcini", University of Torino, Via Cherasco 15, 10126, Torino, Italy
| | - Marta Gai
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Daniela Taverna
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy
| | - Emilia Turco
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy
| | - Salvatore Pece
- European Institute of Oncology IRCCS, 20141, Milan, Italy.
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, 20142, Milano, Italy.
| | - Paola Defilippi
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, 10126, Torino, Italy.
- Molecular Biotechnology Center (MBC) "Guido Tarone", Via Nizza, 52, 10126, Turin, Italy.
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Almatroudi A, Allemailem KS, Alwanian WM, Alharbi BF, Alrumaihi F, Khan AA, Almatroodi SA, Rahmani AH. Effects and Mechanisms of Kaempferol in the Management of Cancers through Modulation of Inflammation and Signal Transduction Pathways. Int J Mol Sci 2023; 24:8630. [PMID: 37239974 PMCID: PMC10218111 DOI: 10.3390/ijms24108630] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 05/04/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Cancer is the principal cause of death and its incidence is increasing continuously worldwide. Various treatment approaches are in practice to treat cancer, but these treatment strategies may be associated with severe side effects and also produce drug resistance. However, natural compounds have established their role in cancer management with minimal side effects. In this vista, kaempferol, a natural polyphenol, mainly found in vegetables and fruits, has been revealed to have many health-promoting effects. Besides its health-promoting potential, its anti-cancer potential has also been described in in vivo as well as in in vitro studies. The anti-cancer potential of kaempferol has been proven through modulation of cell signaling pathways in addition to the induction of apoptosis and cell cycle arrest in cancer cells. It leads to the activation of tumor suppressor genes, inhibition of angiogenesis, PI3K/AKT pathways, STAT3, transcription factor AP-1, Nrf2 and other cell signaling molecules. Poor bioavailability of this compound is one of the major limitations for its proper and effective disease management actions. Recently, some novel nanoparticle-based formulations have been used to overcome these limitations. The aim of this review is to provide a clear picture regarding the mechanism of action of kaempferol in different cancers through the modulation of cell signaling molecules. Besides this, strategies to improve the efficacy and synergistic effects of this compound have also been described. However, more studies are needed based on clinical trials to fully explore the therapeutic role of this compound, especially in cancer treatment.
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Affiliation(s)
- Ahmad Almatroudi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.A.)
| | - Khaled S. Allemailem
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.A.)
| | - Wanian M. Alwanian
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.A.)
| | - Basmah F. Alharbi
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
| | - Faris Alrumaihi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.A.)
| | - Amjad Ali Khan
- Department of Basic Health Sciences, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia
| | - Saleh A. Almatroodi
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.A.)
| | - Arshad Husain Rahmani
- Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, Buraydah 51452, Saudi Arabia; (A.A.)
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Mustafa Karim A, Eun Kwon J, Ali T, Jang J, Ullah I, Lee YG, Won Park D, Park J, Woo Jeang J, Chan Kang S. Triple-negative breast cancer: epidemiology, molecular mechanisms, and modern vaccine-based treatment strategies. Biochem Pharmacol 2023; 212:115545. [PMID: 37044296 DOI: 10.1016/j.bcp.2023.115545] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 04/03/2023] [Accepted: 04/04/2023] [Indexed: 04/14/2023]
Abstract
Long-standing scarcity of efficacious treatments and tumor heterogeneity have contributed to triple-negative breast cancer (TNBC), a subtype with a poor prognosis and aggressive behavior that accounts for 10-15% of all new cases of breast cancer. TNBC is characterized by the absence of progesterone and estrogen receptor expression and lacks gene amplification or overexpression of HER2. Genomic sequencing has detected that the unique mutational profile of both the somatic and germline modifications in TNBC is staggeringly dissimilar from other breast tumor subtypes. The clinical utility of sequencing germline BRCA1/2 genes has been well established in TNBC. Nevertheless, reports regarding the penetrance and risk of other susceptibility genes are relatively scarce. Recurring mutations (e.g., TP53 and PI3KCA mutations) occur together with rare mutations in TNBC, and the shared effects of genomic modifications drive its progression. Given the heterogeneity and complexity of this disease, a clinical understanding of the genomic modifications in TNBC can pave an innovative way toward its therapy. In this review, we summarized the most recent discoveries associated with the underlying biology of developmental signaling pathways in TNBC. We also summarize the recent advancements in genetics and epidemiology and discuss state-of-the-art vaccine-based therapeutic strategies for TNBC that will enable tailored therapeutics.
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Affiliation(s)
- Asad Mustafa Karim
- Department of Oriental Medicine and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, 17104, Republic of Korea.
| | - Jeong Eun Kwon
- Department of Oriental Medicine and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, 17104, Republic of Korea
| | - Tanveer Ali
- Department of Host Defense, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan
| | - Jinsoo Jang
- Department of Oriental Medicine and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, 17104, Republic of Korea
| | - Irfan Ullah
- Department of Internal Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT 06520, USA
| | - Yeong-Geun Lee
- Department of Oriental Medicine and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, 17104, Republic of Korea
| | - Dae Won Park
- Department of Oriental Medicine and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, 17104, Republic of Korea
| | - Juha Park
- Department of Oriental Medicine and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, 17104, Republic of Korea
| | - Jin Woo Jeang
- Department of Oriental Medicine and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, 17104, Republic of Korea
| | - Se Chan Kang
- Department of Oriental Medicine and Biotechnology, College of Life Sciences, Kyung Hee University, Yongin-si, 17104, Republic of Korea.
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Hashemi M, Hasani S, Hajimazdarany S, Ghadyani F, Olyaee Y, Khodadadi M, Ziyarani MF, Dehghanpour A, Salehi H, Kakavand A, Goharrizi MASB, Aref AR, Salimimoghadam S, Akbari ME, Taheriazam A, Hushmandi K, Entezari M. Biological functions and molecular interactions of Wnt/β-catenin in breast cancer: Revisiting signaling networks. Int J Biol Macromol 2023; 232:123377. [PMID: 36702226 DOI: 10.1016/j.ijbiomac.2023.123377] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/27/2022] [Accepted: 01/15/2023] [Indexed: 01/24/2023]
Abstract
Changes in lifestyle such as physical activity and eating habits have been one of the main reasons for development of various diseases in modern world, especially cancer. However, role of genetic factors in initiation of cancer cannot be ignored and Wnt/β-catenin signaling is such factor that can affect tumor progression. Breast tumor is the most malignant tumor in females and it causes high mortality and morbidity around the world. The survival and prognosis of patients are not still desirable, although there have been advances in introducing new kinds of therapies and diagnosis. The present review provides an update of Wnt/β-catenin function in breast cancer malignancy. The upregulation of Wnt is commonly observed during progression of breast tumor and confirms that tumor cells are dependent on this pathway Wnt/β-catenin induction prevents apoptosis that is of importance for mediating drug resistance. Furthermore, Wnt/β-catenin signaling induces DNA damage repair in ameliorating radio-resistance. Wnt/β-catenin enhances proliferation and metastasis of breast tumor. Wnt/β-catenin induces EMT and elevates MMP expression. Furthermore, Wnt/β-catenin participates in tumor microenvironment remodeling and due to its tumor-promoting factor, drugs for its suppression have been developed. Different kinds of upstream mediators Wnt/β-catenin signaling in breast cancer have been recognized that their targeting is a therapeutic approach. Finally, Wnt/β-catenin can be considered as a biomarker in clinical trials.
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Affiliation(s)
- Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Sahar Hasani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Shima Hajimazdarany
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Fatemeh Ghadyani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Yeganeh Olyaee
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Marzieh Khodadadi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Fallah Ziyarani
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amir Dehghanpour
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Hasti Salehi
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Amirabbas Kakavand
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | | | - Amir Reza Aref
- Belfer Center for Applied Cancer Science, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA; Translational Sciences, Xsphera Biosciences Inc., 6 Tide Street, Boston, MA 02210, USA
| | - Shokooh Salimimoghadam
- Department of Biochemistry and Molecular Biology, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz, Iran
| | | | - Afshin Taheriazam
- Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Department of Orthopedics, Faculty of Medicine, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology & Zoonoses, Faculty of Veterinary Medicine, University of Tehran, Tehran, Iran.
| | - Maliheh Entezari
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran; Farhikhtegan Medical Convergence Sciences Research Center, Farhikhtegan Hospital Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
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Preclinical and Clinical Trials of New Treatment Strategies Targeting Cancer Stem Cells in Subtypes of Breast Cancer. Cells 2023; 12:cells12050720. [PMID: 36899854 PMCID: PMC10001180 DOI: 10.3390/cells12050720] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/01/2023] [Accepted: 02/09/2023] [Indexed: 02/26/2023] Open
Abstract
Breast cancer (BC) can be classified into various histological subtypes, each associated with different prognoses and treatment options, including surgery, radiation, chemotherapy, and endocrine therapy. Despite advances in this area, many patients still face treatment failure, the risk of metastasis, and disease recurrence, which can ultimately lead to death. Mammary tumors, like other solid tumors, contain a population of small cells known as cancer stem-like cells (CSCs) that have high tumorigenic potential and are involved in cancer initiation, progression, metastasis, tumor recurrence, and resistance to therapy. Therefore, designing therapies specifically targeting at CSCs could help to control the growth of this cell population, leading to increased survival rates for BC patients. In this review, we discuss the characteristics of CSCs, their surface biomarkers, and the active signaling pathways associated with the acquisition of stemness in BC. We also cover preclinical and clinical studies that focus on evaluating new therapy systems targeted at CSCs in BC through various combinations of treatments, targeted delivery systems, and potential new drugs that inhibit the properties that allow these cells to survive and proliferate.
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Liang L, Kaufmann AM. The Significance of Cancer Stem Cells and Epithelial-Mesenchymal Transition in Metastasis and Anti-Cancer Therapy. Int J Mol Sci 2023; 24:ijms24032555. [PMID: 36768876 PMCID: PMC9917228 DOI: 10.3390/ijms24032555] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 01/25/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
Cancer stem cells (CSCs) have been identified and characterized in both hematopoietic and solid tumors. Their existence was first predicted by Virchow and Cohnheim in the 1870s. Later, many studies showed that CSCs can be identified and isolated by their expression of specific cell markers. The significance of CSCs with respect to tumor biology and anti-cancer treatment lies in their ability to maintain quiescence with very slow proliferation, indefinite self-renewal, differentiation, and trans-differentiation such as epithelial-mesenchymal transition (EMT) and its reverse process mesenchymal-epithelial transition (MET). The ability for detachment, migration, extra- and intravasation, invasion and thereby of completing all necessary steps of the metastatic cascade highlights their significance for metastasis. CSCs comprise the cancer cell populations responsible for tumor growth, resistance to therapies and cancer metastasis. In this review, the history of the CSC theory, their identification and characterization and their biology are described. The contribution of the CSC ability to undergo EMT for cancer metastasis is discussed. Recently, novel strategies for drug development have focused on the elimination of the CSCs specifically. The unique functional and molecular properties of CSCs are discussed as possible therapeutic vulnerabilities for the development of novel anti-metastasis treatments. Prospectively, this may provide precise personalized anti-cancer treatments with improved therapeutic efficiency with fewer side effects and leading to better prognosis.
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Zhang H, Liu C, Zhu D, Zhang Q, Li J. Medicinal Chemistry Strategies for the Development of Inhibitors Disrupting β-Catenin's Interactions with Its Nuclear Partners. J Med Chem 2023; 66:1-31. [PMID: 36583662 DOI: 10.1021/acs.jmedchem.2c01016] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Dysregulation of the Wnt/β-catenin signaling pathway is strongly associated with various aspects of cancer, including tumor initiation, proliferation, and metastasis as well as antitumor immunity, and presents a promising opportunity for cancer therapy. Wnt/β-catenin signaling activation increases nuclear dephosphorylated β-catenin levels, resulting in β-catenin binding to TCF and additional cotranscription factors, such as BCL9, CBP, and p300. Therefore, directly disrupting β-catenin's interactions with these nuclear partners holds promise for the effective and selective suppression of the aberrant activation of Wnt/β-catenin signaling. Herein, we summarize recent advances in biochemical techniques and medicinal chemistry strategies used to identify potent peptide-based and small-molecule inhibitors that directly disrupt β-catenin's interactions with its nuclear binding partners. We discuss the challenges involved in developing drug-like inhibitors that target the interactions of β-catenin and its nuclear binding partner into therapeutic agents.
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Affiliation(s)
- Hao Zhang
- School of Pharmacy, Fudan University, Shanghai 201203, China
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Chenglong Liu
- School of Pharmacy, Fudan University, Shanghai 201203, China
| | - Di Zhu
- School of Pharmacy, Fudan University, Shanghai 201203, China
- Department of Pharmacology, School of Basic Medical Science, Fudan University, Shanghai 201100, China
| | - Qingwei Zhang
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
| | - Jianqi Li
- Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai 201203, China
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Sadeghi M, Gholizadeh M, Safataj N, Tahmasebivand M, Mohajeri G, Lotfi H, Bostanabad SY, Safar B, Salehi M. GLIS2 and CCND1 expression levels in breast cancer patients. Breast Dis 2023; 42:251-259. [PMID: 37574724 DOI: 10.3233/bd-220068] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/15/2023]
Abstract
BACKGROUND Breast cancer (BC) is the most prevalent cancer in women, with increasing incidence and death rates in recent years. Disruptions of different signaling pathways partially cause breast cancer. Hence, different genes through particular pathways are involved in BC tumorigenesis. METHODS In this study, we evaluated the expression level of GLIS2 and CCND1 genes in 50 patients. Also, in-silico analyses were used to enrich related signaling pathways involving the mentioned genes. RESULTS The results showed an increased expression level of Cyclin D1 and decreased expression level of GLIS2 in BC patients. Moreover, a relationship between aberrant expression levels of GLIS2 and CCND1 and BC development was determined. CONCLUSION These observations could help uncover new therapeutic targets for treating patients with BC in the progressive stage.
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Affiliation(s)
- Minoosh Sadeghi
- Department of Genetics, Faculty of Science, Shahrekord University, Shahrekord, Iran
| | - Majid Gholizadeh
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Neda Safataj
- Department of Genetics, Islamic Azad University, Shahrekord Branch, Shahrekord, Iran
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Mahsa Tahmasebivand
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Gholamreza Mohajeri
- Department of Surgery, Alzahra University Hospital, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Hajie Lotfi
- Cellular and Molecular Research Center, Research Institute for Prevention of Non-Communicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Saber Yari Bostanabad
- Department of Pharmacology, Faculty of Pharmacy, Istanbul Health and Technology University, Istanbul, Turkey
| | - Behnaz Safar
- Department of Genetics, Faculty of Science, Shahrekord University, Shahrekord, Iran
| | - Mansoor Salehi
- Cellular, Molecular and Genetics Research Center, Isfahan University of Medical Sciences, Isfahan, Iran
- Medical Genetics Research Center of Genome, Isfahan University of Medical Sciences, Isfahan, Iran
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Andrade de Oliveira K, Sengupta S, Yadav AK, Clarke R. The complex nature of heterogeneity and its roles in breast cancer biology and therapeutic responsiveness. Front Endocrinol (Lausanne) 2023; 14:1083048. [PMID: 36909339 PMCID: PMC9997040 DOI: 10.3389/fendo.2023.1083048] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 02/02/2023] [Indexed: 02/25/2023] Open
Abstract
Heterogeneity is a complex feature of cells and tissues with many interacting components. Depending on the nature of the research context, interacting features of cellular, drug response, genetic, molecular, spatial, temporal, and vascular heterogeneity may be present. We describe the various forms of heterogeneity with examples of their interactions and how they play a role in affecting cellular phenotype and drug responses in breast cancer. While cellular heterogeneity may be the most widely described and invoked, many forms of heterogeneity are evident within the tumor microenvironment and affect responses to the endocrine and cytotoxic drugs widely used in standard clinical care. Drug response heterogeneity is a critical determinant of clinical response and curative potential and also is multifaceted when encountered. The interactive nature of some forms of heterogeneity is readily apparent. For example, the process of metastasis has the properties of both temporal and spatial heterogeneity within the host, whereas each individual metastatic deposit may exhibit cellular, genetic, molecular, and vascular heterogeneity. This review describes the many forms of heterogeneity, their integrated activities, and offers some insights into how heterogeneity may be understood and studied in the future.
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Affiliation(s)
- Karla Andrade de Oliveira
- The Hormel Institute, University of Minnesota, Austin, MN, United States
- Department of Biochemistry and Pharmacology, Universidade Federal do Piaui, Piauí, Brazil
| | - Surojeet Sengupta
- The Hormel Institute, University of Minnesota, Austin, MN, United States
| | - Anil Kumar Yadav
- The Hormel Institute, University of Minnesota, Austin, MN, United States
| | - Robert Clarke
- The Hormel Institute, University of Minnesota, Austin, MN, United States
- *Correspondence: Robert Clarke,
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Yuan Y, Yao H, Zhou M, Ma X, Zhou Y, Xu J, Niu M, Yin J, Zheng L, Xu S. Identification of a Novel Potent CYP4Z1 Inhibitor Attenuating the Stemness of Breast Cancer Cells through Lead Optimization. J Med Chem 2022; 65:15749-15769. [PMID: 36414390 DOI: 10.1021/acs.jmedchem.2c01320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
Pharmacological targeting cancer stem cells are emerging as a novel therapeutic modality for cancer treatment and prevention. Human cytochrome P450 enzyme CYP4Z1 represents a promising target for its potential role in attenuating the stemness of breast cancer cells. In order to develop potent and selective CYP4Z1 inhibitors, a series of novel N-hydroxyphenylformamidines were rationally designed and synthesized from a pan-CYP inhibitor HET0016. CYP4Z1 inhibitory activities of the newly synthesized derivatives were evaluated, and the structure-activity relationships (SARs) were summarized. Among them, compound 7c exhibited the best inhibitory activity with an IC50 value of 41.8 nM. Furthermore, it was found that 7c decreased the expression of stemness markers, spheroid formation, and metastatic ability as well as tumor-initiation capability in a concentration-dependent manner in vitro and in vivo. Altogether, compound 7c might be a potential lead compound to develop CYP4Z1 inhibitor with more favorable druggability for clinical application to treat breast cancer.
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Affiliation(s)
- Yin Yuan
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China
| | - Hong Yao
- Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China
| | - Manzhen Zhou
- Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China
| | - Xiaoqian Ma
- Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China
| | - Yi Zhou
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China
| | - Jinyi Xu
- Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China
| | - Miaomiao Niu
- Key Laboratory of Drug Quality Control and Pharmacovigilance, Jiangsu Key Laboratory of Drug Design and Optimization, Ministry of Education, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China
| | - Jun Yin
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China
| | - Lufeng Zheng
- School of Life Science and Technology, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China
| | - Shengtao Xu
- Department of Medicinal Chemistry, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, P. R. China
- Department of Hepatobiliary Surgery, The First People's Hospital of Kunshan, Suzhou 215132, P. R. China
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Yang P, Zhu Y, Zheng Q, Meng S, Wu Y, Shuai W, Sun Q, Wang G. Recent advances of β-catenin small molecule inhibitors for cancer therapy: Current development and future perspectives. Eur J Med Chem 2022; 243:114789. [DOI: 10.1016/j.ejmech.2022.114789] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2022] [Revised: 09/17/2022] [Accepted: 09/18/2022] [Indexed: 11/28/2022]
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Ku SC, Liu HL, Su CY, Yeh IJ, Yen MC, Anuraga G, Ta HDK, Chiao CC, Xuan DTM, Prayugo FB, Wang WJ, Wang CY. Comprehensive analysis of prognostic significance of cadherin (CDH) gene family in breast cancer. Aging (Albany NY) 2022; 14:8498-8567. [PMID: 36315446 PMCID: PMC9648792 DOI: 10.18632/aging.204357] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 09/23/2022] [Indexed: 11/07/2022]
Abstract
Breast cancer is one of the leading deaths in all kinds of malignancies; therefore, it is important for early detection. At the primary tumor site, tumor cells could take on mesenchymal properties, termed the epithelial-to-mesenchymal transition (EMT). This process is partly regulated by members of the cadherin (CDH) family of genes, and it is an essential step in the formation of metastases. There has been a lot of study of the roles of some of the CDH family genes in cancer; however, a holistic approach examining the roles of distinct CDH family genes in the development of breast cancer remains largely unexplored. In the present study, we used a bioinformatics approach to examine expression profiles of CDH family genes using the Oncomine, Gene Expression Profiling Interactive Analysis 2 (GEPIA2), cBioPortal, MetaCore, and Tumor IMmune Estimation Resource (TIMER) platforms. We revealed that CDH1/2/4/11/12/13 messenger (m)RNA levels are overexpressed in breast cancer cells compared to normal cells and were correlated with poor prognoses in breast cancer patients’ distant metastasis-free survival. An enrichment analysis showed that high expressions of CDH1/2/4/11/12/13 were significantly correlated with cell adhesion, the extracellular matrix remodeling process, the EMT, WNT/beta-catenin, and interleukin-mediated immune responses. Collectively, CDH1/2/4/11/12/13 are thought to be potential biomarkers for breast cancer progression and metastasis.
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Affiliation(s)
- Su-Chi Ku
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
- Department of General Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan
| | - Hsin-Liang Liu
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Che-Yu Su
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - I-Jeng Yeh
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Meng-Chi Yen
- Department of Emergency Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Gangga Anuraga
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
- Department of Statistics, Faculty of Science and Technology, Universitas PGRI Adi Buana, Surabaya 60234, Indonesia
| | - Hoang Dang Khoa Ta
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Chung-Chieh Chiao
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
| | - Do Thi Minh Xuan
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
| | - Fidelia Berenice Prayugo
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- International Master/PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Wei-Jan Wang
- Department of Biological Science and Technology, Research Center for Cancer Biology, China Medical University, Taichung 406040, Taiwan
- Research Center for Cancer Biology, China Medical University, Taichung 40676, Taiwan
| | - Chih-Yang Wang
- Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan
- Ph.D. Program for Cancer Molecular Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University and Academia Sinica, Taipei 11031, Taiwan
- TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan
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Cámara-Sánchez P, Díaz-Riascos ZV, García-Aranda N, Gener P, Seras-Franzoso J, Giani-Alonso M, Royo M, Vázquez E, Schwartz S, Abasolo I. Selectively Targeting Breast Cancer Stem Cells by 8-Quinolinol and Niclosamide. Int J Mol Sci 2022; 23:ijms231911760. [PMID: 36233074 PMCID: PMC9570236 DOI: 10.3390/ijms231911760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 09/19/2022] [Accepted: 09/26/2022] [Indexed: 12/01/2022] Open
Abstract
Cancer maintenance, metastatic dissemination and drug resistance are sustained by cancer stem cells (CSCs). Triple negative breast cancer (TNBC) is the breast cancer subtype with the highest number of CSCs and the poorest prognosis. Here, we aimed to identify potential drugs targeting CSCs to be further employed in combination with standard chemotherapy in TNBC treatment. The anti-CSC efficacy of up to 17 small drugs was tested in TNBC cell lines using cell viability assays on differentiated cancer cells and CSCs. Then, the effect of 2 selected drugs (8-quinolinol -8Q- and niclosamide -NCS-) in the cancer stemness features were evaluated using mammosphere growth, cell invasion, migration and anchorage-independent growth assays. Changes in the expression of stemness genes after 8Q or NCS treatment were also evaluated. Moreover, the potential synergism of 8Q and NCS with PTX on CSC proliferation and stemness-related signaling pathways was evaluated using TNBC cell lines, CSC-reporter sublines, and CSC-enriched mammospheres. Finally, the efficacy of NCS in combination with PTX was analyzed in vivo using an orthotopic mouse model of MDA-MB-231 cells. Among all tested drug candidates, 8Q and NCS showed remarkable specific anti-CSC activity in terms of CSC viability, migration, invasion and anchorage independent growth reduction in vitro. Moreover, specific 8Q/PTX and NCS/PTX ratios at which both drugs displayed a synergistic effect in different TNBC cell lines were identified. The sole use of PTX increased the relative presence of CSCs in TNBC cells, whereas the combination of 8Q and NCS counteracted this pro-CSC activity of PTX while significantly reducing cell viability. In vivo, the combination of NCS with PTX reduced tumor growth and limited the dissemination of the disease by reducing circulating tumor cells and the incidence of lung metastasis. The combination of 8Q and NCS with PTX at established ratios inhibits both the proliferation of differentiated cancer cells and the viability of CSCs, paving the way for more efficacious TNBC treatments.
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Affiliation(s)
- Patricia Cámara-Sánchez
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Zamira V. Díaz-Riascos
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Functional Validation & Preclinical Research (FVPR), Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Natalia García-Aranda
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Functional Validation & Preclinical Research (FVPR), Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Petra Gener
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Joaquin Seras-Franzoso
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Micaela Giani-Alonso
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
| | - Miriam Royo
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Institute for Advanced Chemistry (IQAC-CSIC), Jordi Girona 18-26, 08034 Barcelona, Spain
| | - Esther Vázquez
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Institut de Biotecnologia i de Biomedicina, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
- Departament de Genètica i de Microbiologia, Universitat Autònoma de Barcelona, 08193 Barcelona, Spain
| | - Simó Schwartz
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
| | - Ibane Abasolo
- Drug Delivery and Targeting Group, Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain
- Functional Validation & Preclinical Research (FVPR), Vall d’Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona (UAB), 08035 Barcelona, Spain
- Correspondence:
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Nguyen TTP, Suman KH, Nguyen TB, Nguyen HT, Do DN. The Role of miR-29s in Human Cancers—An Update. Biomedicines 2022; 10:biomedicines10092121. [PMID: 36140219 PMCID: PMC9495592 DOI: 10.3390/biomedicines10092121] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Revised: 08/22/2022] [Accepted: 08/24/2022] [Indexed: 11/25/2022] Open
Abstract
MicroRNAs (miRNAs) are small non-coding RNAs that directly bind to the 3’ untranslated region (3’-UTR) of the target mRNAs to inhibit their expression. The miRNA-29s (miR-29s) are suggested to be either tumor suppressors or oncogenic miRNAs that are strongly dysregulated in various types of cancer. Their dysregulation alters the expression of their target genes, thereby exerting influence on different cellular pathways including cell proliferation, apoptosis, migration, and invasion, thereby contributing to carcinogenesis. In the present review, we aimed to provide an overview of the current knowledge on the miR-29s biological network and its functions in cancer, as well as its current and potential applications as a diagnostic and prognostic biomarker and/or a therapeutic target in major types of human cancer.
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Affiliation(s)
- Thuy T. P. Nguyen
- Division of Radiation and Genome Stability, Department of Radiation Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
| | - Kamrul Hassan Suman
- Department of Fisheries, Ministry of Fisheries and Livestock, Dhaka 1205, Bangladesh
| | - Thong Ba Nguyen
- Department of Anatomy, Biochemistry, and Physiology, John A. Burns School of Medicine, University of Hawaii at Manoa, Honolulu, HI 96813, USA
| | - Ha Thi Nguyen
- Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam
- Center for Molecular Biology, College of Medicine and Pharmacy, Duy Tan University, Danang 550000, Vietnam
- Correspondence: (H.T.N.); (D.N.D.)
| | - Duy Ngoc Do
- Department of Animal Science and Aquaculture, Dalhousie University, Truro, NS B2N 5E3, Canada
- Correspondence: (H.T.N.); (D.N.D.)
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Znhit1 and HIF-2α are correlated with cancer stem cell markers in breast cancer patients. Sci Rep 2022; 12:13918. [PMID: 35978075 PMCID: PMC9385614 DOI: 10.1038/s41598-022-18133-8] [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: 05/03/2022] [Accepted: 08/05/2022] [Indexed: 11/23/2022] Open
Abstract
Epigenetic alterations have emerged as fundamental players in development and progression of breast cancer (BC). A hypoxic tumour microenvironment regulates the stemness phenotype in breast cancer stem cells (BCSCs). The aim of this study was to investigate Znhit1 and HIF-2α gene expression in breast cancer tissues as well as their relation to CSCs markers LGR5, ALDH1A1 and β-catenin in tissue and serum of BC patients. The present study included 160 females divided into two groups, group I: 80 healthy females served as control group and group II: 80 breast cancer patients. Gene expression of tissue Znhit1 and HIF-2α was determined by qRT-PCR. Tissue and serum ALDH1A1, LGR5 and β-catenin levels were determined by ELISA. We found that gene expression of Znhit1 was significantly downregulated in BC tissues. Moreover, it was significantly negatively correlated with clinical stage and β-catenin levels in BC patients. Regarding HIF-2α, gene expression of HIF-2α was significantly upregulated in BC tissues. Moreover, it was significantly positively correlated with Her-2/neu expression and β-catenin levels in BC patients. Based upon our results, Znhit1 and HIF-2α may serve as novel therapeutic targets for BC therapy. Additionally, each of serum ALDH1A1, LGR5 and β-catenin may play a crucial role in non-invasive detection of BC with a high specificity and sensitivity.
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Zhou LQ, Shen JX, Zhou T, Li CL, Hu Y, Xiao HJ. The prognostic significance of β-Catenin expression in patients with nasopharyngeal carcinoma: A systematic review and meta-analysis. Front Genet 2022; 13:953739. [PMID: 36035172 PMCID: PMC9400172 DOI: 10.3389/fgene.2022.953739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 06/30/2022] [Indexed: 11/13/2022] Open
Abstract
Background:β-Catenin has been recently identified as a promising novel therapeutic target and prognostic marker in different types of cancer. Here, we conduct a meta-analysis to better clarify the correlation between β-Catenin expression and survival outcomes in nasopharyngeal carcinoma (NPC) patients.Patients/methods: Following the Preferred Reporting Items or Systematic Reviews Meta Analyses (PRISMA) 2020 guidelines, the PubMed, Embase, Web of Science, Cochrane Library, Chinese National Knowledge Infrastructure (CNKI) and Wanfang databases were systematically searched for relevant studies to explore the prognostic significance of β-Catenin in NPC. Pooled hazards ratios (HRs) and 95% confidence intervals (CIs) were used to estimate the association of β-Catenin expression with survival outcomes in NPC patients. Odd ratios (ORs) and 95% CIs for clinicopathological characteristics were also statistically analyzed.Results: Eight studies involving 1,179 patients with NPC were ultimately included in the meta-analysis. Pooled analysis indicated that elevated β-Catenin expression was significantly associated with poor OS (HR = 2.45, 95% CIs: 1.45–4.16, p = 0.001) and poor DFS/PFS (HR 1.79, 95% CIs: 1.29–2.49, p = 0.000). Furthermore, β-cadherin was signifcantly associated with higher TMN stages (OR = 5.10, 95% CIs 2.93–8.86, p = 0.000), clinical stages (OR = 5.10, 95% CIs 2.93–8.86, p = 0.000) and lymph node metastasis (LNM) (OR = 5.01, 95% CIs 2.40–10.44, p = 0.000).Conclusions: This study demonstrated that for NPC, patients with elevated β-Catenin expression are more likely to have poor survival.
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Affiliation(s)
- Liu-Qing Zhou
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jin-Xiong Shen
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tao Zhou
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chun-Li Li
- Department of Otorhinolaryngology, Wuhan First Hospital/Wuhan Hospital of Traditional Chinese and Western Medicine, Wuhan, China
- *Correspondence: Chun-Li Li, ; Yao Hu, ; Hong-Jun Xiao,
| | - Yao Hu
- Department of Otorhinolaryngology, The Central Hospital of Wuhan, Wuhan, China
- *Correspondence: Chun-Li Li, ; Yao Hu, ; Hong-Jun Xiao,
| | - Hong-Jun Xiao
- Department of Otorhinolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Chun-Li Li, ; Yao Hu, ; Hong-Jun Xiao,
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Wang L, Jin Z, Master RP, Maharjan CK, Carelock ME, Reccoppa TBA, Kim MC, Kolb R, Zhang W. Breast Cancer Stem Cells: Signaling Pathways, Cellular Interactions, and Therapeutic Implications. Cancers (Basel) 2022; 14:3287. [PMID: 35805056 PMCID: PMC9265870 DOI: 10.3390/cancers14133287] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/02/2022] [Accepted: 07/02/2022] [Indexed: 02/01/2023] Open
Abstract
Breast cancer stem cells (BCSCs) constitute a small population of cells within breast cancer and are characterized by their ability to self-renew, differentiate, and recapitulate the heterogeneity of the tumor. Clinically, BCSCs have been correlated with cancer progression, metastasis, relapse, and drug resistance. The tumorigenic roles of BCSCs have been extensively reviewed and will not be the major focus of the current review. Here, we aim to highlight how the crucial intrinsic signaling pathways regulate the fate of BCSCs, including the Wnt, Notch, Hedgehog, and NF-κB signaling pathways, as well as how different cell populations crosstalk with BCSCs within the TME, including adipocytes, endothelial cells, fibroblasts, and immune cells. Based on the molecular and cellular activities of BCSCs, we will also summarize the targeting strategies for BCSCs and related clinical trials. This review will highlight that BCSC development in breast cancer is impacted by both BCSC endogenous signaling and external factors in the TME, which provides an insight into how to establish a comprehensively therapeutic strategy to target BCSCs for breast cancer treatments.
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Affiliation(s)
- Lei Wang
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Immunology Concentration, Biomedical Graduate Program, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Zeng Jin
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Cancer Biology Concentration, Biomedical Graduate Program, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Rohan P. Master
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
| | - Chandra K. Maharjan
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
| | - Madison E. Carelock
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Cancer Biology Concentration, Biomedical Graduate Program, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Tiffany B. A. Reccoppa
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- Department of Biology, College of Liberal Arts & Sciences, University of Florida, Gainesville, FL 32610, USA
| | - Myung-Chul Kim
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
| | - Ryan Kolb
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA
| | - Weizhou Zhang
- Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; (L.W.); (Z.J.); (R.P.M.); (C.K.M.); (M.E.C.); (T.B.A.R.); (M.-C.K.); (R.K.)
- UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA
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Karami Fath M, Azargoonjahromi A, Kiani A, Jalalifar F, Osati P, Akbari Oryani M, Shakeri F, Nasirzadeh F, Khalesi B, Nabi-Afjadi M, Zalpoor H, Mard-Soltani M, Payandeh Z. The role of epigenetic modifications in drug resistance and treatment of breast cancer. Cell Mol Biol Lett 2022; 27:52. [PMID: 35764927 PMCID: PMC9238060 DOI: 10.1186/s11658-022-00344-6] [Citation(s) in RCA: 53] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Accepted: 05/24/2022] [Indexed: 02/08/2023] Open
Abstract
Background Breast cancer is defined as a biological and molecular heterogeneous disorder that originates from breast cells. Genetic predisposition is the most important factor giving rise to this malignancy. The most notable mutations in breast cancer occur in the BRCA1 and BRCA2 genes. Owing to disease heterogeneity, lack of therapeutic target, anti-cancer drug resistance, residual disease, and recurrence, researchers are faced with challenges in developing strategies to treat patients with breast cancer. Results It has recently been reported that epigenetic processes such as DNA methylation and histone modification, as well as microRNAs (miRNAs), have potently contributed to the pathophysiology, diagnosis, and treatment of breast cancer. These observations have persuaded researchers to move their therapeutic approaches beyond the genetic framework toward the epigenetic concept. Conclusion Herein we discuss the molecular and epigenetic mechanisms underlying breast cancer progression and resistance as well as various aspects of epigenetic-based therapies as monotherapy and combined with immunotherapy.
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Affiliation(s)
- Mohsen Karami Fath
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | | | - Arash Kiani
- Student Research Committee, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Fateme Jalalifar
- School of Medicine, Jiroft University of Medical Sciences, Jiroft, Iran
| | - Parisa Osati
- Chemical Engineering Department, Fouman Faculty of Engineering, College of Engineering, University of Tehran, Fouman, Iran
| | - Mahsa Akbari Oryani
- Department of Pathology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fateh Shakeri
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Farhad Nasirzadeh
- Department of Cellular and Molecular Biology, Faculty of Biological Sciences, Kharazmi University, Tehran, Iran
| | - Behman Khalesi
- Department of Research and Production of Poultry Viral Vaccine, Razi Vaccine and Serum Research Institute, Agricultural Research Education and Extension Organization, Karaj, Iran
| | - Mohsen Nabi-Afjadi
- Department of Biochemistry, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran
| | - Hamidreza Zalpoor
- Shiraz Neuroscience Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maysam Mard-Soltani
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Dezful University of Medical Sciences, Dezful, Iran.
| | - Zahra Payandeh
- Department Medical Biochemistry and Biophysics, Division Medical Inflammation Research, Karolinska Institute, Stockholm, Sweden.
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Hu X, Zhang Q, Xing W, Wang W. Role of microRNA/lncRNA Intertwined With the Wnt/β-Catenin Axis in Regulating the Pathogenesis of Triple-Negative Breast Cancer. Front Pharmacol 2022; 13:814971. [PMID: 35814205 PMCID: PMC9263262 DOI: 10.3389/fphar.2022.814971] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Accepted: 05/17/2022] [Indexed: 12/12/2022] Open
Abstract
Objective (s): In this mini-review, we aimed to discuss the Wnt/β-catenin signaling pathway modulation in triple-negative breast cancer, particularly the contribution of lncRNAs and miRNAs in its regulation and their possible entwining role in breast cancer pathogenesis, proliferation, migration, or malignancy.Background: Malignant tumor formation is very high for breast cancer in women and is a leading cause of death all over the globe. Among breast cancer subtypes, triple-negative breast cancer is rife in premenopausal women, most invasive, and prone to metastasis. Complex pathways are involved in this cancer’s pathogenesis, advancement, and malignancy, including the Wnt/β-catenin signaling pathway. This pathway is conserved among vertebrates and is necessary for sustaining cell homeostasis. It is regulated by several elements such as transcription factors, enhancers, non-coding RNAs (lncRNAs and miRNAs), etc.Methods: We evaluated lncRNAs and miRNAs differentially expressed in triple-negative breast cancer (TNBC) from the cDNA microarray data set literature survey. Using in silico analyses combined with a review of the current literature, we anticipated identifying lncRNAs and miRNAs that might modulate the Wnt/β-catenin signaling pathway.Result: The miRNAs and lncRNAs specific to triple-negative breast cancer have been identified based on literature and database searches. Tumorigenesis, metastasis, and EMT were all given special attention. Apart from cross-talk being essential for TNBC tumorigenesis and treatment outcomes, our results indicated eight upregulated and seven downregulated miRNAs and 19 upregulated and three downregulated lncRNAs that can be used as predictive or diagnostic markers. This consolidated information could be useful in the clinic and provide a combined literature resource for TNBC researchers working on the Wnt/β-catenin miRNA/lncRNA axis.Conclusion: In conclusion, because the Wnt pathway and miRNAs/lncRNAs can modulate TNBC, their intertwinement results in a cascade of complex reactions that affect TNBC and related processes. Their function in TNBC pathogenesis has been highlighted in molecular processes underlying the disease progression.
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Affiliation(s)
- Xue Hu
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Qiang Zhang
- Department of Breast Surgery, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, China
| | - Wanying Xing
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
| | - Wan Wang
- Department of Breast Surgery, China-Japan Union Hospital of Jilin University, Changchun, China
- *Correspondence: Wan Wang,
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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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Chen X, Yang M, Yin J, Li P, Zeng S, Zheng G, He Z, Liu H, Wang Q, Zhang F, Chen D. Tumor-associated macrophages promote epithelial-mesenchymal transition and the cancer stem cell properties in triple-negative breast cancer through CCL2/AKT/β-catenin signaling. Cell Commun Signal 2022; 20:92. [PMID: 35715860 PMCID: PMC9205034 DOI: 10.1186/s12964-022-00888-2] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Accepted: 04/23/2022] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer with poor prognosis and limited treatment. As a major component of the tumor microenvironment, tumor-associated macrophages (TAMs) play an important role in facilitating the aggressive behavior of TNBC. This study aimed to explore the novel mechanism of TAMs in the regulation of epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) properties in TNBC. METHODS Expression of the M2-like macrophage marker CD163 was evaluated by immunohistochemistry in human breast cancer tissues. The phenotype of M2 macrophages polarized from Tohoku-Hospital-Pediatrics-1 (THP1) cells was verified by flow cytometry. Transwell assays, wound healing assays, western blotting, flow cytometry, ELISA, quantitative polymerase chain reaction (qPCR), luciferase reporter gene assays, and immunofluorescence assays were conducted to investigate the mechanism by which TAMs regulate EMT and CSC properties in BT549 and HCC1937 cells. RESULTS Clinically, we observed a high infiltration of M2-like tumor-associated macrophages in TNBC tissues and confirmed that TAMs were associated with unfavorable prognosis in TNBC patients. Moreover, we found that conditioned medium from M2 macrophages (M2-CM) markedly promoted EMT and CSC properties in BT549 and HCC1937 cells. Mechanistically, we demonstrated that chemokine (C-C motif) ligand 2 (CCL2) secretion by TAMs activated Akt signaling, which in turn increased the expression and nuclear localization of β-catenin. Furthermore, β-catenin knockdown reversed TAM-induced EMT and CSC properties. CONCLUSIONS This study provides a novel mechanism by which TAMs promote EMT and enhance CSC properties in TNBC via activation of CCL2/AKT/β-catenin signaling, which may offer new strategies for the diagnosis and treatment of TNBC. Video Abstract.
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Affiliation(s)
- Xiangzhou Chen
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Mingqiang Yang
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Jiang Yin
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Pan Li
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Shanshan Zeng
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Guopei Zheng
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Zhimin He
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Hao Liu
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China
| | - Qian Wang
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China.
| | - Fan Zhang
- Department of Pharmacy, Renmin Hospital of Wuhan University, No.99 Zhangzhidong Road, Wuhan, 430000, Hubei, China.
| | - Danyang Chen
- Guangzhou Key Laboratory of "Translational Medicine on Malignant Tumor Treatment", Affiliated Cancer Hospital & Institute of Guangzhou Medical University, No.78 Hengzhigang Road, Guangzhou, 510095, Guangdong, China.
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