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1
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Sindeeva OA, Kozyreva ZV, Abdurashitov AS, Sukhorukov GB. Engineering colloidal systems for cell manipulation, delivery, and tracking. Adv Colloid Interface Sci 2025; 340:103462. [PMID: 40037017 DOI: 10.1016/j.cis.2025.103462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Revised: 02/22/2025] [Accepted: 02/23/2025] [Indexed: 03/06/2025]
Abstract
Men-made colloidal systems are widely presented across various aspects of biomedical science. There is a strong demand for engineering colloids to tailor their functions and properties to meet the requirements of biological and medical tasks. These requirements are not only related to size, shape, capacity to carry bioactive compounds as drug delivery systems, and the ability to navigate via chemical and physical targeting. Today, the more challenging aspects of colloid design are how the colloidal particles interact with biological cells, undergo internalization by cells, how they reside in the cell interior, and whether we can explore cells with colloids, intervene with biochemical processes, and alter cell functionality. Cell tracking, exploitation of cells as natural transporters of internalized colloidal carriers loaded with drugs, and exploring physical methods as external triggers of cell functions are ongoing topics in the research agenda. In this review, we summarize recent advances in these areas, focusing on how colloidal particles interact and are taken up by mesenchymal stem cells, dendritic cells, neurons, macrophages, neutrophils and lymphocytes, red blood cells, and platelets. The engineering of colloidal vesicles with cell membrane fragments and exosomes facilitates their application. The perspectives of different approaches in colloid design, their limitations, and obstacles on the biological side are discussed.
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Affiliation(s)
- Olga A Sindeeva
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Moscow 121205, Russia.
| | - Zhanna V Kozyreva
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Moscow 121205, Russia
| | - Arkady S Abdurashitov
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Moscow 121205, Russia; Life Improvement by Future Technologies (LIFT) Center, Bolshoy Boulevard 30, Moscow 121205, Russia
| | - Gleb B Sukhorukov
- Skolkovo Institute of Science and Technology, Bolshoy Boulevard 30, Moscow 121205, Russia.
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2
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Conte M, Tomaciello M, De Feo MS, Frantellizzi V, Marampon F, De Cristofaro F, De Vincentis G, Filippi L. The Tight Relationship Between the Tumoral Microenvironment and Radium-223. Biomedicines 2025; 13:456. [PMID: 40002869 PMCID: PMC11853176 DOI: 10.3390/biomedicines13020456] [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: 01/19/2025] [Revised: 02/04/2025] [Accepted: 02/09/2025] [Indexed: 02/27/2025] Open
Abstract
Radium-223 (223Ra) was the first radioactive isotope approved for treating castration-resistant prostate cancer (CRPC) with symptomatic bone metastases without visceral metastatic disease. To better understand the action of 223Ra, its role in the tumor microenvironment represents a crucial aspect. A literature search was conducted using the PubMed/MEDLINE database and studies regarding the relationship between 223Ra and the tumoral microenvironment were considered. The tumoral microenvironment is a complex setting in which complex interactions between cells and molecules occur. Radium-223, as an alpha-emitter, induces double-stranded DNA breaks; to potentiate this effect, it could be used in patients with genetic instability but also in combination with therapies which inhibit DNA repair, modulate the immune response, or control tumor growth. In conclusion, a few studies have taken into consideration the tumoral microenvironment in association with 223Ra. However, its understanding is a priority to better comprehend how to effectively exploit 223Ra and its action mechanism.
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Affiliation(s)
- Miriam Conte
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Miriam Tomaciello
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Maria Silvia De Feo
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Viviana Frantellizzi
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Francesco Marampon
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Flaminia De Cristofaro
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Giuseppe De Vincentis
- Department of Radiological Sciences, Oncology and Anatomical Pathology, Sapienza, “Sapienza” University of Rome, 00161 Rome, Italy; (M.C.); (M.T.); (M.S.D.F.); (V.F.); (F.M.); (F.D.C.); (G.D.V.)
| | - Luca Filippi
- Department of Biomedicine and Prevention, University of Rome “Tor Vergata”, Via Montpellier 1, 00133 Rome, Italy
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Liu Y, Sun X, Wei C, Guo S, Song C, Zhang J, Bai J. Targeted Drug Nanodelivery and Immunotherapy for Combating Tumor Resistance. Comb Chem High Throughput Screen 2025; 28:561-581. [PMID: 38676501 DOI: 10.2174/0113862073296206240416060154] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Revised: 03/05/2024] [Accepted: 03/09/2024] [Indexed: 04/29/2024]
Abstract
Chemotherapy resistance is a common cause of tumor treatment failure. Various molecular responses, such as increased expression of efflux transporter proteins, including Pglycoprotein (P-gp), changes in the tumor microenvironment (TME), the role of platelets, and the effects of cancer stem cells (CSCs), can lead to drug resistance. Through extensive research on the mechanisms of drug resistance, more effective anti-resistance drugs and therapeutic approaches are being developed. This review explores drug resistance mechanisms and summarizes relevant anti-resistance drugs. In addition, due to the therapeutic limitations of the aforementioned treatments, new advances in nanocarrier-based combination immunotherapy to address the challenge of drug resistance have been described. Nanocarriers combined with immunotherapy can not only target tumor sites for targeted drug release but also modulate the autoimmune system and enhance immune efficacy, thereby overcoming tumor drug resistance. This review suggests new strategies for overcoming tumor drug resistance and is expected to inform tumor treatment and prognosis.
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Affiliation(s)
- Yun Liu
- School of Stomatology, Shandong Second Medical University, Weifang, 261053, China
| | - Xinyu Sun
- School of Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Chen Wei
- School of Medical Sciences, Shandong Second Medical University, Weifang, 261053, China
| | - Shoudong Guo
- School of Pharmacy, Shandong Second Medical University, Weifang, 261053, China
| | - Chunxiao Song
- Anorectal Department, Weifang people's Hospital, Weifang, 261000, China
| | - Jiangyu Zhang
- school of Chemistry and Chemical Engineering, Xingtai University, Xingtai, 054001, China
| | - Jingkun Bai
- School of Bioscience and Technology, Shandong Second Medical University, Weifang, 261053, China
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4
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Panda SK, Robinson N, Desiderio V. Decoding secret role of mesenchymal stem cells in regulating cancer stem cells and drug resistance. Biochim Biophys Acta Rev Cancer 2024; 1879:189205. [PMID: 39481663 DOI: 10.1016/j.bbcan.2024.189205] [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: 06/25/2024] [Revised: 09/23/2024] [Accepted: 10/22/2024] [Indexed: 11/02/2024]
Abstract
Drug resistance caused by the efflux of chemotherapeutic drugs is one of the most challenging obstacles to successful cancer therapy. Several efflux transporters have been identified since the discovery of the P-gp/ABCB1 transporter in 1976. Over the last four decades, researchers have focused on developing efflux transporter inhibitors to overcome drug resistance. However, even with the third-generation inhibitors available, we are still far from effectively inhibiting the efflux transporters. Additionally, Cancer stem cells (CSCs) pose another significant challenge, contributing to cancer recurrence even after successful treatment. The ability of CSCs to enter dormancy and evade detection makes them almost invulnerable to chemotherapeutic drug treatment. In this review, we discuss how Mesenchymal stem cells (MSCs), one of the key components of the Tumor Microenvironment (TME), regulate both the CSCs and efflux transporters. We propose a new approach focusing on MSCs, which can be crucial to successfully address CSCs and efflux transporters.
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Affiliation(s)
- Sameer Kumar Panda
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy; Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia
| | - Nirmal Robinson
- Center for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA 5001, Australia
| | - Vincenzo Desiderio
- Department of Experimental Medicine, University of Campania "Luigi Vanvitelli", Naples 80138, Italy.
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5
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Sindeeva OA, Demina PA, Kozyreva ZV, Terentyeva DA, Gusliakova OI, Muslimov AR, Sukhorukov GB. Single Mesenchymal Stromal Cell Migration Tracking into Glioblastoma Using Photoconvertible Vesicles. NANOMATERIALS (BASEL, SWITZERLAND) 2024; 14:1215. [PMID: 39057891 PMCID: PMC11279842 DOI: 10.3390/nano14141215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Revised: 07/13/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024]
Abstract
Reliable cell labeling and tracking techniques are imperative for elucidating the intricate and ambiguous interactions between mesenchymal stromal cells (MSCs) and tumors. Here, we explore fluorescent photoconvertible nanoengineered vesicles to study mMSC migration in brain tumors. These 3 μm sized vesicles made of carbon nanoparticles, Rhodamine B (RhB), and polyelectrolytes are readily internalized by cells. The dye undergoes photoconversion under 561 nm laser exposure with a fluorescence blue shift upon demand. The optimal laser irradiation duration for photoconversion was 0.4 ms, which provided a maximal blue shift of the fluorescent signal label without excessive laser exposure on cells. Vesicles modified with an extra polymer layer demonstrated enhanced intracellular uptake without remarkable effects on cell viability, motility, or proliferation. The optimal ratio of 20 vesicles per mMSC was determined. Moreover, the migration of individual mMSCs within 2D and 3D glioblastoma cell (EPNT-5) colonies over 2 days and in vivo tumor settings over 7 days were traced. Our study provides a robust nanocomposite platform for investigating MSC-tumor dynamics and offers insights into envisaged therapeutic strategies. Photoconvertible vesicles also present an indispensable tool for studying complex fundamental processes of cell-cell interactions for a wide range of problems in biomedicine.
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Affiliation(s)
- Olga A. Sindeeva
- Vladimir Zelman Center for Neurobiology and Brain Rehabilitation, Skoltech, 3 Nobel Str., 121205 Moscow, Russia; (Z.V.K.); (D.A.T.); (O.I.G.)
| | - Polina A. Demina
- Science Medical Center, Saratov State University, 83 Astrakhanskaya Str., 410012 Saratov, Russia;
| | - Zhanna V. Kozyreva
- Vladimir Zelman Center for Neurobiology and Brain Rehabilitation, Skoltech, 3 Nobel Str., 121205 Moscow, Russia; (Z.V.K.); (D.A.T.); (O.I.G.)
| | - Daria A. Terentyeva
- Vladimir Zelman Center for Neurobiology and Brain Rehabilitation, Skoltech, 3 Nobel Str., 121205 Moscow, Russia; (Z.V.K.); (D.A.T.); (O.I.G.)
| | - Olga I. Gusliakova
- Vladimir Zelman Center for Neurobiology and Brain Rehabilitation, Skoltech, 3 Nobel Str., 121205 Moscow, Russia; (Z.V.K.); (D.A.T.); (O.I.G.)
- Science Medical Center, Saratov State University, 83 Astrakhanskaya Str., 410012 Saratov, Russia;
| | - Albert R. Muslimov
- Center for Molecular and Cell Technologies, Saint Petersburg State Chemical and Pharmaceutical University, 14 Professora Popova Str., lit. A, 197022 St. Petersburg, Russia;
| | - Gleb B. Sukhorukov
- Vladimir Zelman Center for Neurobiology and Brain Rehabilitation, Skoltech, 3 Nobel Str., 121205 Moscow, Russia; (Z.V.K.); (D.A.T.); (O.I.G.)
- Life Improvement by Future Technology (LIFT) Center, 121205 Moscow, Russia
- School of Engineering and Materials Science, Queen Mary University of London, Mile End Road, London E1 4NS, UK
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6
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Oliveira-Lopes AF, Götze MM, Lopes-Neto BE, Guerreiro DD, Bustamante-Filho IC, Moura AA. Molecular and Pathobiology of Canine Mammary Tumour: Defining a Translational Model for Human Breast Cancer. Vet Comp Oncol 2024. [PMID: 39011576 DOI: 10.1111/vco.12996] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 06/26/2024] [Accepted: 07/02/2024] [Indexed: 07/17/2024]
Abstract
Canine mammary tumours (CMT) have histological, clinicopathological and molecular resemblances to human breast cancer (HBC), positioning them as viable models for studying the human disease. CMT initiation and progression occur spontaneously in immune-competent animals, which challenge the suggested limitations of genetically modified mice, also enabling the evaluation of immunotherapies in canine patients. Dogs have shorter life expectancy compared to humans, and cancer advances more rapidly in this species. This makes it possible to perform studies about the clinical efficacy of new therapeutic modalities in a much shorter time than in human patients. The identification of biomarkers for tumour subtypes, progression and treatment response paves the way for the development of novel therapeutic and diagnostic approaches. This review addresses the similarities between CMT and HBC and the molecular signatures identified in CMT samples that have been explored to date. We proposed a detailed molecular exploration of the CMT stroma using state-of-the-art methods in transcriptomics and proteomics. Using CMT as an analog for HBC not only helps to understand the complexities of the disease, but also to advance comparative oncology to the next level to prove the claim of dogs as a valid translational model.
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Affiliation(s)
| | - Marcelo M Götze
- Graduate Studies Program in Biotechnology, University of Vale do Taquari-Univates, Lajeado, Brazil
| | | | - Denise D Guerreiro
- Department of Animal Science, Federal University of Ceará, Fortaleza, Brazil
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7
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Chu X, Tian W, Ning J, Xiao G, Zhou Y, Wang Z, Zhai Z, Tanzhu G, Yang J, Zhou R. Cancer stem cells: advances in knowledge and implications for cancer therapy. Signal Transduct Target Ther 2024; 9:170. [PMID: 38965243 PMCID: PMC11224386 DOI: 10.1038/s41392-024-01851-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 03/27/2024] [Accepted: 04/28/2024] [Indexed: 07/06/2024] Open
Abstract
Cancer stem cells (CSCs), a small subset of cells in tumors that are characterized by self-renewal and continuous proliferation, lead to tumorigenesis, metastasis, and maintain tumor heterogeneity. Cancer continues to be a significant global disease burden. In the past, surgery, radiotherapy, and chemotherapy were the main cancer treatments. The technology of cancer treatments continues to develop and advance, and the emergence of targeted therapy, and immunotherapy provides more options for patients to a certain extent. However, the limitations of efficacy and treatment resistance are still inevitable. Our review begins with a brief introduction of the historical discoveries, original hypotheses, and pathways that regulate CSCs, such as WNT/β-Catenin, hedgehog, Notch, NF-κB, JAK/STAT, TGF-β, PI3K/AKT, PPAR pathway, and their crosstalk. We focus on the role of CSCs in various therapeutic outcomes and resistance, including how the treatments affect the content of CSCs and the alteration of related molecules, CSCs-mediated therapeutic resistance, and the clinical value of targeting CSCs in patients with refractory, progressed or advanced tumors. In summary, CSCs affect therapeutic efficacy, and the treatment method of targeting CSCs is still difficult to determine. Clarifying regulatory mechanisms and targeting biomarkers of CSCs is currently the mainstream idea.
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Affiliation(s)
- Xianjing Chu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wentao Tian
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jiaoyang Ning
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Gang Xiao
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yunqi Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Ziqi Wang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Zhuofan Zhai
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guilong Tanzhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Jie Yang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Department of Dermatology, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Rongrong Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, 410008, China.
- Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, 410008, China.
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8
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Gil-Chinchilla JI, Zapata AG, Moraleda JM, García-Bernal D. Bioengineered Mesenchymal Stem/Stromal Cells in Anti-Cancer Therapy: Current Trends and Future Prospects. Biomolecules 2024; 14:734. [PMID: 39062449 PMCID: PMC11275142 DOI: 10.3390/biom14070734] [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: 05/08/2024] [Revised: 06/11/2024] [Accepted: 06/19/2024] [Indexed: 07/28/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are one of the most widely used cell types in advanced therapies due to their therapeutic potential in the regulation of tissue repair and homeostasis, and immune modulation. However, their use in cancer therapy is controversial: they can inhibit cancer cell proliferation, but also potentially promote tumour growth by supporting angiogenesis, modulation of the immune milieu and increasing cancer stem cell invasiveness. This opposite behaviour highlights the need for careful and nuanced use of MSCs in cancer treatment. To optimize their anti-cancer effects, diverse strategies have bioengineered MSCs to enhance their tumour targeting and therapeutic properties or to deliver anti-cancer drugs. In this review, we highlight the advanced uses of MSCs in cancer therapy, particularly as carriers of targeted treatments due to their natural tumour-homing capabilities. We also discuss the potential of MSC-derived extracellular vesicles to improve the efficiency of drug or molecule delivery to cancer cells. Ongoing clinical trials are evaluating the therapeutic potential of these cells and setting the stage for future advances in MSC-based cancer treatment. It is critical to identify the broad and potent applications of bioengineered MSCs in solid tumour targeting and anti-cancer agent delivery to position them as effective therapeutics in the evolving field of cancer therapy.
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Affiliation(s)
- Jesús I. Gil-Chinchilla
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
| | - Agustín G. Zapata
- Department of Cell Biology, Complutense University, 28040 Madrid, Spain;
| | - Jose M. Moraleda
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
- Department of Medicine, University of Murcia, 30120 Murcia, Spain
| | - David García-Bernal
- Hematopoietic Transplant and Cellular Therapy Unit, Instituto Murciano de Investigación Biosanitaria (IMIB) Pascual Parrilla, Virgen de la Arrixaca University Hospital, University of Murcia, 30120 Murcia, Spain;
- Department of Biochemistry, Molecular Biology and Immunology, University of Murcia, 30120 Murcia, Spain
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Guo Q, Zhou Y, Xie T, Yuan Y, Li H, Shi W, Zheng L, Li X, Zhang W. Tumor microenvironment of cancer stem cells: Perspectives on cancer stem cell targeting. Genes Dis 2024; 11:101043. [PMID: 38292177 PMCID: PMC10825311 DOI: 10.1016/j.gendis.2023.05.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2022] [Accepted: 05/25/2023] [Indexed: 02/01/2024] Open
Abstract
There are few tumor cell subpopulations with stem cell characteristics in tumor tissue, defined as cancer stem cells (CSCs) or cancer stem-like cells (CSLCs), which can reconstruct neoplasms with malignant biological behaviors such as invasiveness via self-renewal and unlimited generation. The microenvironment that CSCs depend on consists of various cellular components and corresponding medium components. Among these factors existing at a variety of levels and forms, cytokine networks and numerous signal pathways play an important role in signaling transduction. These factors promote or maintain cancer cell stemness, and participate in cancer recurrence, metastasis, and resistance. This review aims to summarize the recent molecular data concerning the multilayered relationship between CSCs and CSC-favorable microenvironments. We also discuss the therapeutic implications of targeting this synergistic interplay, hoping to give an insight into targeting cancer cell stemness for tumor therapy and prognosis.
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Affiliation(s)
- Qianqian Guo
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450003, China
| | - Yi Zhou
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Tianyuan Xie
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Yin Yuan
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Huilong Li
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Wanjin Shi
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Lufeng Zheng
- School of Life Science and Technology, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Nanjing, Jiangsu 211198, China
| | - Xiaoman Li
- Jiangsu Key Laboratory for Pharmacology and Safety Evaluation of Chinese Materia Medica, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
| | - Wenzhou Zhang
- Department of Pharmacy, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, Henan 450003, China
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10
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Saadh MJ, Alhuthali HM, Gonzales Aníbal O, Asenjo-Alarcón JA, Younus DG, Alhili A, Adhab ZH, Alsalmi O, Gharib AF, Pecho RDC, Akhavan-Sigari R. Mesenchymal stem cells and their extracellular vesicles in urological cancers: Prostate, bladder, and kidney. Cell Biol Int 2024; 48:3-19. [PMID: 37947445 DOI: 10.1002/cbin.12098] [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: 07/19/2023] [Revised: 08/31/2023] [Accepted: 10/12/2023] [Indexed: 11/12/2023]
Abstract
Mesenchymal stem cells (MSCs) are recognized for their remarkable ability to differentiate into multiple cell types. They are also known to possess properties that can fight cancer, leading to attempts to modify MSCs for use in anticancer treatments. However, MSCs have also been found to participate in pathways that promote tumor growth. Many studies have been conducted to explore the potential of MSCs for clinical applications, but the results have been inconclusive, possibly due to the diverse nature of MSC populations. Furthermore, the conflicting roles of MSCs in inhibiting tumors and promoting tumor growth hinder their adaptation to anticancer therapies. Antitumorigenic and protumorigenic properties of MSCs in urological cancers such as bladder, prostate, and renal are not as well established, and data comparing them are still limited. MSCs hold significant promise as a vehicle for delivering anticancer agents and suicide genes to tumors. Presently, numerous studies have concentrated on the products derived from MSCs, such as extracellular vesicles (EVs), as a form of cell-free therapy. This work aimed to review and discuss the current knowledge of MSCs and their EVs in urological cancer therapy.
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Affiliation(s)
| | - Hayaa M Alhuthali
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | | | | | | | - Ahmed Alhili
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | | | - Ohud Alsalmi
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | - Amal F Gharib
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, Taif University, Taif, Saudi Arabia
| | | | - Reza Akhavan-Sigari
- Department of Neurosurgery, University Medical Center Tuebingen, Tuebingen, Germany
- Department of Health Care Management and Clinical Research, Collegium Humanum Warsaw Management University, Warsaw, Poland
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11
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Rismanbaf A. Improving targeted small molecule drugs to overcome chemotherapy resistance. Cancer Rep (Hoboken) 2024; 7:e1945. [PMID: 37994401 PMCID: PMC10809209 DOI: 10.1002/cnr2.1945] [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: 07/15/2023] [Revised: 10/25/2023] [Accepted: 11/12/2023] [Indexed: 11/24/2023] Open
Abstract
BACKGROUND Conventional cancer treatments face the challenge of therapeutic resistance, which causes poor treatment outcomes. The use of combination therapies can improve treatment results in patients and is one of the solutions to overcome this challenge. Chemotherapy is one of the conventional treatments that, due to the non-targeted and lack of specificity in targeting cancer cells, can cause serious complications in the short and long-term for patients by damaging healthy cells. Also, the employment of a wide range of strategies for chemotherapy resistance by cancer cells, metastasis, and cancer recurrence create serious problems to achieve the desired results of chemotherapy. Accordingly, targeted therapies can be used as a combination treatment with chemotherapy to both cause less damage to healthy cells, which as a result, they reduce the side effects of chemotherapy, and by targeting the factors that cause therapeutic challenges, can improve the results of chemotherapy in patients. RECENT FINDINGS Small molecules are one of the main targeted therapies that can be used for diverse targets in cancer treatment due to their penetration ability and characteristics. However, small molecules in cancer treatment are facing obstacles that a better understanding of cancer biology, as well as the mechanisms and factors involved in chemotherapy resistance, can lead to the improvement of this type of major targeted therapy. CONCLUSION In this review article, at first, the challenges that lead to not achieving the desired results in chemotherapy and how cancer cells can be resistant to chemotherapy are examined, and at the end, research areas are suggested that more focusing on them, can lead to the improvement of the results of using targeted small molecules as an adjunctive treatment for chemotherapy in the conditions of chemotherapy resistance and metastasis of cancer cells.
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Affiliation(s)
- Amirhossein Rismanbaf
- Department of Cellular and Molecular Biology, Faculty of Advanced Science and Technology, Tehran Medical SciencesIslamic Azad UniversityTehranIran
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12
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Hazrati A, Malekpour K, Mirsanei Z, Khosrojerdi A, Rahmani-Kukia N, Heidari N, Abbasi A, Soudi S. Cancer-associated mesenchymal stem/stromal cells: role in progression and potential targets for therapeutic approaches. Front Immunol 2023; 14:1280601. [PMID: 38022534 PMCID: PMC10655012 DOI: 10.3389/fimmu.2023.1280601] [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: 08/20/2023] [Accepted: 10/11/2023] [Indexed: 12/01/2023] Open
Abstract
Malignancies contain a relatively small number of Mesenchymal stem/stromal cells (MSCs), constituting a crucial tumor microenvironment (TME) component. These cells comprise approximately 0.01-5% of the total TME cell population. MSC differentiation potential and their interaction with the tumor environment enable these cells to affect tumor cells' growth, immune evasion, metastasis, drug resistance, and angiogenesis. This type of MSC, known as cancer-associated mesenchymal stem/stromal cells (CA-MSCs (interacts with tumor/non-tumor cells in the TME and affects their function by producing cytokines, chemokines, and various growth factors to facilitate tumor cell migration, survival, proliferation, and tumor progression. Considering that the effect of different cells on each other in the TME is a multi-faceted relationship, it is essential to discover the role of these relationships for targeting in tumor therapy. Due to the immunomodulatory role and the tissue repair characteristic of MSCs, these cells can help tumor growth from different aspects. CA-MSCs indirectly suppress antitumor immune response through several mechanisms, including decreasing dendritic cells (DCs) antigen presentation potential, disrupting natural killer (NK) cell differentiation, inducing immunoinhibitory subsets like tumor-associated macrophages (TAMs) and Treg cells, and immune checkpoint expression to reduce effector T cell antitumor responses. Therefore, if these cells can be targeted for treatment so that their population decreases, we can hope for the treatment and improvement of the tumor conditions. Also, various studies show that CA-MSCs in the TME can affect other vital aspects of a tumor, including cell proliferation, drug resistance, angiogenesis, and tumor cell invasion and metastasis. In this review article, we will discuss in detail some of the mechanisms by which CA-MSCs suppress the innate and adaptive immune systems and other mechanisms related to tumor progression.
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Affiliation(s)
- Ali Hazrati
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Kosar Malekpour
- Department of Immunology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Zahra Mirsanei
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arezou Khosrojerdi
- Infectious Diseases Research Center, Birjand University of Medical Sciences, Birjand, Iran
| | - Nasim Rahmani-Kukia
- Department of Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Neda Heidari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ardeshir Abbasi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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13
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Smeriglio P, Zalc A. Cranial Neural Crest Cells Contribution to Craniofacial Bone Development and Regeneration. Curr Osteoporos Rep 2023; 21:624-631. [PMID: 37421571 DOI: 10.1007/s11914-023-00804-8] [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] [Accepted: 06/14/2023] [Indexed: 07/10/2023]
Abstract
PURPOSE OF REVIEW This review aims to summarize (i) the latest evidence on cranial neural crest cells (CNCC) contribution to craniofacial development and ossification; (ii) the recent discoveries on the mechanisms responsible for their plasticity; and (iii) the newest procedures to ameliorate maxillofacial tissue repair. RECENT FINDINGS CNCC display a remarkable differentiation potential that exceeds the capacity of their germ layer of origin. The mechanisms by which they expand their plasticity was recently described. Their ability to participate to craniofacial bone development and regeneration open new perspectives for treatments of traumatic craniofacial injuries or congenital syndromes. These conditions can be life-threatening, require invasive maxillofacial surgery and can leave deep sequels on our health or quality of life. With accumulating evidence showing how CNCC-derived stem cells potential can ameliorate craniofacial reconstruction and tissue repair, we believe a deeper understanding of the mechanisms regulating CNCC plasticity is essential to ameliorate endogenous regeneration and improve tissue repair therapies.
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Affiliation(s)
- Piera Smeriglio
- Centre de Recherche en Myologie, Institut de Myologie, INSERM, Sorbonne Université, 75013, Paris, France.
| | - Antoine Zalc
- Institut Cochin, CNRS, INSERM, Université Paris Cité, 75014, Paris, France.
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14
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Gordon JAR, Evans MF, Ghule PN, Lee K, Vacek P, Sprague BL, Weaver DL, Stein GS, Stein JL. Identification of molecularly unique tumor-associated mesenchymal stromal cells in breast cancer patients. PLoS One 2023; 18:e0282473. [PMID: 36940196 PMCID: PMC10027225 DOI: 10.1371/journal.pone.0282473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 02/16/2023] [Indexed: 03/21/2023] Open
Abstract
The tumor microenvironment is a complex mixture of cell types that bi-directionally interact and influence tumor initiation, progression, recurrence, and patient survival. Mesenchymal stromal cells (MSCs) of the tumor microenvironment engage in crosstalk with cancer cells to mediate epigenetic control of gene expression. We identified CD90+ MSCs residing in the tumor microenvironment of patients with invasive breast cancer that exhibit a unique gene expression signature. Single-cell transcriptional analysis of these MSCs in tumor-associated stroma identified a distinct subpopulation characterized by increased expression of genes functionally related to extracellular matrix signaling. Blocking the TGFβ pathway reveals that these cells directly contribute to cancer cell proliferation. Our findings provide novel insight into communication between breast cancer cells and MSCs that are consistent with an epithelial to mesenchymal transition and acquisition of competency for compromised control of proliferation, mobility, motility, and phenotype.
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Affiliation(s)
- Jonathan A. R. Gordon
- Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Mark F. Evans
- Department of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Prachi N. Ghule
- Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Kyra Lee
- Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Pamela Vacek
- Department of Surgery, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Brian L. Sprague
- Department of Surgery, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Donald L. Weaver
- Department of Pathology and Laboratory Medicine, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Gary S. Stein
- Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
| | - Janet L. Stein
- Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT, United States of America
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15
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Dai X, Zhu K. Cold atmospheric plasma: Novel opportunities for tumor microenvironment targeting. Cancer Med 2023; 12:7189-7206. [PMID: 36762766 PMCID: PMC10067048 DOI: 10.1002/cam4.5491] [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: 06/23/2022] [Revised: 07/17/2022] [Accepted: 11/17/2022] [Indexed: 02/11/2023] Open
Abstract
With mounting preclinical and clinical evidences on the prominent roles of the tumor microenvironment (TME) played during carcinogenesis, the TME has been recognized and used as an important onco-therapeutic target during the past decade. Delineating our current knowledge on TME components and their functionalities can help us recognize novel onco-therapeutic opportunities and establish treatment modalities towards desirable anti-cancer outcome. By identifying and focusing on primary cellular components in the TME, that is, tumor-infiltrating lymphocytes, tumor-associated macrophages, cancer-associated fibroblasts and mesenchymal stem cells, we decomposed their primary functionalities during carcinogenesis, categorized current therapeutic approaches utilizing traits of these components, and forecasted possible benefits that cold atmospheric plasma, a redox modulating tool with selectivity against cancer cells, may convey by targeting the TME. Our insights may open a novel therapeutic avenue for cancer control taking advantages of redox homeostasis and immunostasis.
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Affiliation(s)
- Xiaofeng Dai
- Wuxi School of Medicine, Jiangnan University, Wuxi, China
| | - Kaiyuan Zhu
- Affiliated Hospital of Jiangnan University, Wuxi, China
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16
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Johnson CS, Cook LM. Osteoid cell-derived chemokines drive bone-metastatic prostate cancer. Front Oncol 2023; 13:1100585. [PMID: 37025604 PMCID: PMC10070788 DOI: 10.3389/fonc.2023.1100585] [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: 11/16/2022] [Accepted: 03/07/2023] [Indexed: 04/08/2023] Open
Abstract
One of the greatest challenges in improving prostate cancer (PCa) survival is in designing new therapies to effectively target bone metastases. PCa regulation of the bone environment has been well characterized; however, bone-targeted therapies have little impact on patient survival, demonstrating a need for understanding the complexities of the tumor-bone environment. Many factors contribute to creating a favorable microenvironment for prostate tumors in bone, including cell signaling proteins produced by osteoid cells. Specifically, there has been extensive evidence from both past and recent studies that emphasize the importance of chemokine signaling in promoting PCa progression in the bone environment. Chemokine-focused strategies present promising therapeutic options for treating bone metastasis. These signaling pathways are complex, with many being produced by (and exerting effects on) a plethora of different cell types, including stromal and tumor cells of the prostate tumor-bone microenvironment. This review highlights an underappreciated molecular family that should be interrogated for treatment of bone metastatic prostate cancer (BM-PCa).
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Affiliation(s)
- Catherine S. Johnson
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
- Eppley Institute for Research in Cancer and Allied Diseases, Omaha, NE, United States
| | - Leah M. Cook
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, United States
- Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, United States
- *Correspondence: Leah M. Cook,
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17
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Zhao C, Liu S, Gao F, Zou Y, Ren Z, Yu Z. The role of tumor microenvironment reprogramming in primary liver cancer chemotherapy resistance. Front Oncol 2022; 12:1008902. [PMID: 36505831 PMCID: PMC9731808 DOI: 10.3389/fonc.2022.1008902] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/01/2022] [Indexed: 11/25/2022] Open
Abstract
Primary liver cancer (PLC), including hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC), and other rare tumours, is the second leading cause of cancer-related mortality. It has been a major contributor to the cancer burden worldwide. Of all primary liver cancer, HCC is the most common type. Over the past few decades, chemotherapy, immunotherapy and other therapies have been identified as applicable to the treatment of HCC. However, evidence suggests that chemotherapy resistance is associated with higher mortality rates in liver cancer. The tumour microenvironment (TME), which includes molecular, cellular, extracellular matrix(ECM), and vascular signalling pathways, is a complex ecosystem. It is now increasingly recognized that the tumour microenvironment plays a pivotal role in PLC prognosis, progression and treatment response. Cancer cells reprogram the tumour microenvironment to develop resistance to chemotherapy drugs distinct from normal differentiated tissues. Chemotherapy resistance mechanisms are reshaped during TME reprogramming. For this reason, TME reprogramming can provide a powerful tool to understand better both cancer-fate processes and regenerative, with the potential to develop a new treatment. This review discusses the recent progress of tumour drug resistance, particularly tumour microenvironment reprogramming in tumour chemotherapy resistance, and focuses on its potential application prospects.
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Affiliation(s)
- Chunyu Zhao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Shanshuo Liu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Feng Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yawen Zou
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Ren
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, Shandong, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zujiang Yu
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Gene Hospital of Henan Province; Precision Medicine Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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18
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Chen J, Li Z, Zhao Q, Chen L. Roles of apelin/APJ system in cancer: Biomarker, predictor, and emerging therapeutic target. J Cell Physiol 2022; 237:3734-3751. [DOI: 10.1002/jcp.30845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2022] [Revised: 07/15/2022] [Accepted: 07/19/2022] [Indexed: 11/11/2022]
Affiliation(s)
- Jiawei Chen
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology University of South China Hengyang Hunan China
| | - Zhiyue Li
- Health Management Center, The Third Xiangya Hospital Central South University Changsha Hunan Province China
| | - Qun Zhao
- Department of Orthopedics Third Xiangya Hospital of Central South University Changsha Hunan China
| | - Linxi Chen
- Hunan Provincial Key Laboratory of Tumor Microenvironment Responsive Drug Research, Hengyang Medical School, Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Institute of Pharmacy and Pharmacology University of South China Hengyang Hunan China
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19
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Ramuta TŽ, Kreft ME. Mesenchymal Stem/Stromal Cells May Decrease Success of Cancer Treatment by Inducing Resistance to Chemotherapy in Cancer Cells. Cancers (Basel) 2022; 14:cancers14153761. [PMID: 35954425 PMCID: PMC9367361 DOI: 10.3390/cancers14153761] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 12/04/2022] Open
Abstract
Simple Summary Tumours consist of different cell types and an extracellular matrix, all of which together form a complex microenvironment. The tumour microenvironment plays a critical role in various aspects of tumour development and progression. Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells that have a tri-lineage differentiation capacity and are one of the key stromal cells in the tumour microenvironment. Following the interaction with cancer cells, they are transformed from naïve MSCs to tumour-associated MSCs, which substantially affect tumour growth and progression as well as the development of chemoresistance in cancer cells. The aim of this review article is to provide an overview of studies that have investigated how MSCs affect the susceptibility of cancer cells to chemotherapeutics. Their results show that MSCs protect cancer cells from chemotherapeutics by influencing several signalling pathways. This knowledge is crucial for the development of new treatment approaches that will lead to improved treatment outcomes. Abstract The tumour microenvironment, which is comprised of various cell types and the extracellular matrix, substantially impacts tumour initiation, progression, and metastasis. Mesenchymal stem/stromal cells (MSCs) are one of the key stromal cells in the tumour microenvironment, and their interaction with cancer cells results in the transformation of naïve MSCs to tumour-associated MSCs. The latter has an important impact on tumour growth and progression. Recently, it has been shown that they can also contribute to the development of chemoresistance in cancer cells. This review provides an overview of 42 studies published between 1 January 2001 and 1 January 2022 that examined the effect of MSCs on the susceptibility of cancer cells to chemotherapeutics. The studies showed that MSCs affect various signalling pathways in cancer cells, leading to protection against chemotherapy-induced damage. Promising results emerged from the use of inhibitors of various signalling pathways that are affected in cancer cells due to interactions with MSCs in the tumour microenvironment. These studies present a good starting point for the investigation of novel treatment approaches and demonstrate the importance of targeting the stroma in the tumour microenvironment to improve treatment outcomes.
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20
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Parayath NN, Gandham SK, Amiji MM. Tumor-targeted miRNA nanomedicine for overcoming challenges in immunity and therapeutic resistance. Nanomedicine (Lond) 2022; 17:1355-1373. [PMID: 36255330 PMCID: PMC9706370 DOI: 10.2217/nnm-2022-0130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
miRNA are critical messengers in the tumor microenvironment (TME) that influence various processes leading to immune suppression, tumor progression, metastasis and resistance. Strategies to modulate miRNAs in the TME have important implications in overcoming these challenges. However, miR delivery to specific cells in the TME has been challenging. This review discusses nanomedicine strategies to achieve cell-specific delivery of miRNAs. The key goal of delivery is to activate the tumor immune landscape as well as to prevent chemotherapy resistance. Specifically, the use of hyaluronic acid-based nanoparticle miRNA delivery to the TME is discussed. The discussion is focused on miRNA-125b for reprogramming tumor-associated macrophages to overcome immunosuppression and miRNA-let-7b to overcome resistance to anticancer chemotherapeutics because both these miRNAs have been extensively evaluated for delivery with hyaluronic acid-based delivery systems.
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Affiliation(s)
- Neha N Parayath
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
| | - Srujan K Gandham
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA
| | - Mansoor M Amiji
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, Northeastern University, Boston, MA 02115, USA,Department of Chemical Engineering, College of Engineering, Northeastern University, Boston, MA 02115, USA,Author for correspondence: Tel.: +1 617 373 3137;
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21
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Zhang Z, Zhou X, Guo J, Zhang F, Qian Y, Wang G, Duan M, Wang Y, Zhao H, Yang Z, Liu Z, Jiang X. TA-MSCs, TA-MSCs-EVs, MIF: their crosstalk in immunosuppressive tumor microenvironment. J Transl Med 2022; 20:320. [PMID: 35842634 PMCID: PMC9287873 DOI: 10.1186/s12967-022-03528-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 07/08/2022] [Indexed: 11/24/2022] Open
Abstract
As an important component of the immunosuppressive tumor microenvironment (TME), it has been established that mesenchymal stem cells (MSCs) promote the progression of tumor cells. MSCs can directly promote the proliferation, migration, and invasion of tumor cells via cytokines and chemokines, as well as promote tumor progression by regulating the functions of anti-tumor immune and immunosuppressive cells. MSCs-derived extracellular vesicles (MSCs-EVs) contain part of the plasma membrane and signaling factors from MSCs; therefore, they display similar effects on tumors in the immunosuppressive TME. The tumor-promoting role of macrophage migration inhibitory factor (MIF) in the immunosuppressive TME has also been revealed. Interestingly, MIF exerts similar effects to those of MSCs in the immunosuppressive TME. In this review, we summarized the main effects and related mechanisms of tumor-associated MSCs (TA-MSCs), TA-MSCs-EVs, and MIF on tumors, and described their relationships. On this basis, we hypothesized that TA-MSCs-EVs, the MIF axis, and TA-MSCs form a positive feedback loop with tumor cells, influencing the occurrence and development of tumors. The functions of these three factors in the TME may undergo dynamic changes with tumor growth and continuously affect tumor development. This provides a new idea for the targeted treatment of tumors with EVs carrying MIF inhibitors.
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Affiliation(s)
- Zhenghou Zhang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiangyu Zhou
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jinshuai Guo
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Fusheng Zhang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yiping Qian
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Guang Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Meiqi Duan
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Yutian Wang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Haiying Zhao
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zhi Yang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China
| | - Zunpeng Liu
- Department of Orthopedics, The Fourth Affiliated Hospital of China Medical University, Shenyang, China.
| | - Xiaofeng Jiang
- Department of General Surgery, The Fourth Affiliated Hospital of China Medical University, Shenyang, Liaoning, China.
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22
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Tang DG. Understanding and targeting prostate cancer cell heterogeneity and plasticity. Semin Cancer Biol 2022; 82:68-93. [PMID: 34844845 PMCID: PMC9106849 DOI: 10.1016/j.semcancer.2021.11.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 11/01/2021] [Accepted: 11/01/2021] [Indexed: 12/12/2022]
Abstract
Prostate cancer (PCa) is a prevalent malignancy that occurs primarily in old males. Prostate tumors in different patients manifest significant inter-patient heterogeneity with respect to histo-morphological presentations and molecular architecture. An individual patient tumor also harbors genetically distinct clones in which PCa cells display intra-tumor heterogeneity in molecular features and phenotypic marker expression. This inherent PCa cell heterogeneity, e.g., in the expression of androgen receptor (AR), constitutes a barrier to the long-term therapeutic efficacy of AR-targeting therapies. Furthermore, tumor progression as well as therapeutic treatments induce PCa cell plasticity such that AR-positive PCa cells may turn into AR-negative cells and prostate tumors may switch lineage identity from adenocarcinomas to neuroendocrine-like tumors. This induced PCa cell plasticity similarly confers resistance to AR-targeting and other therapies. In this review, I first discuss PCa from the perspective of an abnormal organ development and deregulated cellular differentiation, and discuss the luminal progenitor cells as the likely cells of origin for PCa. I then focus on intrinsic PCa cell heterogeneity in treatment-naïve tumors with the presence of prostate cancer stem cells (PCSCs). I further elaborate on PCa cell plasticity induced by genetic alterations and therapeutic interventions, and present potential strategies to therapeutically tackle PCa cell heterogeneity and plasticity. My discussions will make it clear that, to achieve enduring clinical efficacy, both intrinsic PCa cell heterogeneity and induced PCa cell plasticity need to be targeted with novel combinatorial approaches.
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Affiliation(s)
- Dean G Tang
- Department of Pharmacology & Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA; Experimental Therapeutics (ET) Graduate Program, The University at Buffalo & Roswell Park Comprehensive Cancer Center, Buffalo, NY 14263, USA.
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23
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Frisbie L, Buckanovich RJ, Coffman L. Carcinoma Associated Mesenchymal Stem/Stromal Cells - Architects of the Pro-tumorigenic tumor microenvironment. Stem Cells 2022; 40:705-715. [PMID: 35583414 PMCID: PMC9406606 DOI: 10.1093/stmcls/sxac036] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Accepted: 05/12/2022] [Indexed: 11/13/2022]
Abstract
The interaction between tumor cells and non-malignant hosts cells within the tumor microenvironment (TME) is critical to the pathophysiology of cancer. These non-malignant host cells, consisting of a variety of stromal, immune and endothelial cells, engage in a complex bidirectional crosstalk with the malignant tumor cells. Mesenchymal stem/stromal cells (MSCs) are one of these host cells, and they play a critical role in directing the formation and function of the entire TME. These MSCs are epigenetically reprogrammed by cancer cells to assume a strongly pro-tumorigenic phenotype and are referred to as carcinoma-associated mesenchymal stem/stromal cells (CA-MSCs). Studies over the last decade demonstrate that CA-MSCs not only directly interact with cancer cells to promote tumor growth and metastasis, but also orchestrate the formation of the TME. CA-MSCs can differentiate into virtually all stromal sub-lineages present in the TME, including pro-tumorigenic cancer associated fibroblasts (CAF), myofibroblasts, and adipocytes. CA-MSCs and the CAFs they produce, secrete much of the extracellular matrix in the TME. Furthermore, CA-MSC secreted factors promote angiogenesis, and recruit immunosuppressive myeloid cells effectively driving tumor immune exclusion. Thus CA-MSCs impact nearly every aspect of the TME. Despite their influence on cancer biology, as CA-MSCs represent a heterogenous population without a single definitive marker, significant confusion remains regarding the origin and proper identification CA-MSCs. This review will focus on the impact of CA-MSCs on cancer progression and metastasis and the ongoing work on CA-MSC identification, nomenclature and mechanism of action.
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Affiliation(s)
- Len Frisbie
- Department of Integrative Systems Biology, University of Pittsburgh, Pittsburgh, PA
| | - Ronald J Buckanovich
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.,Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, PA
| | - Lan Coffman
- Division of Hematology/Oncology, Department of Medicine, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, PA.,Division of Gynecologic Oncology, Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee Women's Research Institute, University of Pittsburgh, Pittsburgh, PA
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24
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Lee U, Cho EY, Jho EH. Regulation of Hippo signaling by metabolic pathways in cancer. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2022; 1869:119201. [PMID: 35026349 DOI: 10.1016/j.bbamcr.2021.119201] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Revised: 12/12/2021] [Accepted: 12/18/2021] [Indexed: 12/12/2022]
Abstract
Hippo signaling is known to maintain balance between cell proliferation and apoptosis via tight regulation of factors, such as metabolic cues, cell-cell contact, and mechanical cues. Cells directly recognize glucose, lipids, and other metabolic cues and integrate multiple signaling pathways, including Hippo signaling, to adjust their proliferation and apoptosis depending on nutrient conditions. Therefore, the dysregulation of the Hippo signaling pathway can promote tumor initiation and progression. Alteration in metabolic cues is considered a major factor affecting the risk of cancer formation and progression. It has recently been shown that the dysregulation of the Hippo signaling pathway, through diverse routes activated by metabolic cues, can lead to cancer with a poor prognosis. In addition, unique crosstalk between metabolic pathways and Hippo signaling pathways can inhibit the effect of anticancer drugs and promote drug resistance. In this review, we describe an integrated perspective of the relationship between the Hippo signaling pathway and metabolic signals in the context of cancer. We also characterize the mechanisms involved in changes in metabolism that are linked to the Hippo signaling pathway in the cancer microenvironment and propose several novel targets for anticancer drug treatment.
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Affiliation(s)
- Ukjin Lee
- Department of Life Science, University of Seoul, 02504 Seoul, Republic of Korea
| | - Eun-Young Cho
- Department of Life Science, University of Seoul, 02504 Seoul, Republic of Korea
| | - Eek-Hoon Jho
- Department of Life Science, University of Seoul, 02504 Seoul, Republic of Korea.
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25
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Jing Y, Liang W, Zhang L, Tang J, Huang Z. The Role of Mesenchymal Stem Cells in the Induction of Cancer-Stem Cell Phenotype. Front Oncol 2022; 12:817971. [PMID: 35251985 PMCID: PMC8891610 DOI: 10.3389/fonc.2022.817971] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Accepted: 01/19/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer stem cells (CSCs) modify and form their microenvironment by recruiting and activating specific cell types such as mesenchymal stem cells (MSCs). Tumor-infiltrating MSCs help to establish a suitable tumor microenvironment for the restoration of CSCs and tumor progression. In addition, crosstalk between cancer cells and MSCs in the microenvironment induces a CSC phenotype in cancer cells. Many mechanisms are involved in crosstalk between CSCs/cancer cells and MSCs including cell-cell interaction, secretion of exosomes, and paracrine secretion of several molecules including inflammatory mediators, cytokines, and growth factors. Since this crosstalk may contribute to drug resistance, metastasis, and tumor growth, it is suggested that blockade of the crosstalk between MSCs and CSCs/cancer cells can provide a new avenue to improving the cancer therapeutic tools. In this review, we will discuss the role of MSCs in the induction of cancer stem cell phenotype and the restoration of CSCs. We also discuss targeting the crosstalk between MSCs and CSCs/cancer cells as a therapeutic strategy.
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Affiliation(s)
- Yuanming Jing
- Department of Gastrointestinal Surgery, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Wenqing Liang
- Department of Orthopaedics, Zhoushan Hospital of Traditional Chinese Medicine Affiliated to Zhejiang Chinese Medical University, Zhoushan, China
| | - Lin Zhang
- Department of Pharmacy, Shaoxing People’s Hospital, Shaoxing Hospital, Zhejiang University School of Medicine, Shaoxing, China
| | - Junjun Tang
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Zongliang Huang, ; Junjun Tang ,
| | - Zongliang Huang
- Department of Radiology, Tongji Hospital, School of Medicine, Tongji University, Shanghai, China
- *Correspondence: Zongliang Huang, ; Junjun Tang ,
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26
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Vicinanza C, Lombardi E, Da Ros F, Marangon M, Durante C, Mazzucato M, Agostini F. Modified mesenchymal stem cells in cancer therapy: A smart weapon requiring upgrades for wider clinical applications. World J Stem Cells 2022; 14:54-75. [PMID: 35126828 PMCID: PMC8788179 DOI: 10.4252/wjsc.v14.i1.54] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 08/06/2021] [Accepted: 12/23/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem stromal cells (MSC) are characterized by the intriguing capacity to home toward cancer cells after systemic administration. Thus, MSC can be harnessed as targeted delivery vehicles of cytotoxic agents against tumors. In cancer patients, MSC based advanced cellular therapies were shown to be safe but their clinical efficacy was limited. Indeed, the amount of systemically infused MSC actually homing to human cancer masses is insufficient to reduce tumor growth. Moreover, induction of an unequivocal anticancer cytotoxic phenotype in expanded MSC is necessary to achieve significant therapeutic efficacy. Ex vivo cell modifications are, thus, required to improve anti-cancer properties of MSC. MSC based cellular therapy products must be handled in compliance with good manufacturing practice (GMP) guidelines. In the present review we include MSC-improving manipulation approaches that, even though actually tested at preclinical level, could be compatible with GMP guidelines. In particular, we describe possible approaches to improve MSC homing on cancer, including genetic engineering, membrane modification and cytokine priming. Similarly, we discuss appropriate modalities aimed at inducing a marked cytotoxic phenotype in expanded MSC by direct chemotherapeutic drug loading or by genetic methods. In conclusion, we suggest that, to configure MSC as a powerful weapon against cancer, combinations of clinical grade compatible modification protocols that are currently selected, should be introduced in the final product. Highly standardized cancer clinical trials are required to test the efficacy of ameliorated MSC based cell therapies.
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Affiliation(s)
- Carla Vicinanza
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Elisabetta Lombardi
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Da Ros
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Miriam Marangon
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Cristina Durante
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Mario Mazzucato
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
| | - Francesco Agostini
- Stem Cell Unit, Centro di Riferimento Oncologico di Aviano, IRCCS, Aviano 33081, Italy
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27
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Zhang X, Li N, Zhu Y, Wen W. The role of mesenchymal stem cells in the occurrence, development, and therapy of hepatocellular carcinoma. Cancer Med 2022; 11:931-943. [PMID: 34981659 PMCID: PMC8855904 DOI: 10.1002/cam4.4521] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 12/03/2021] [Accepted: 12/11/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver malignant tumor, with high recurrence and mortality rates. Mesenchymal stem cells (MSCs) are multipotent cells that can be recruited into the tumor microenvironment (TME). What is known, TME plays a vital part in tumor progression. In recent years, accumulating studies have found that MSCs have a dual role of promotion and inhibition in the occurrence and development of HCC. In this review, we analyzed the role of MSCs in TME and summarized the relationship between MSCs and liver cancer stem cells, the molecular signaling pathway mechanisms of MSCs promoting and inhibiting HCC, and the latest research progress of MSCs in the treatment of HCC.
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Affiliation(s)
- Xiaoli Zhang
- Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Na Li
- Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Ying Zhu
- Liver Disease Center of Integrated Traditional Chinese and Western Medicine, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Wei Wen
- Department of General Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
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28
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Sadanandan N, Shear A, Brooks B, Saft M, Cabantan DAG, Kingsbury C, Zhang H, Anthony S, Wang ZJ, Salazar FE, Lezama Toledo AR, Rivera Monroy G, Vega Gonzales-Portillo J, Moscatello A, Lee JY, Borlongan CV. Treating Metastatic Brain Cancers With Stem Cells. Front Mol Neurosci 2021; 14:749716. [PMID: 34899179 PMCID: PMC8651876 DOI: 10.3389/fnmol.2021.749716] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/20/2021] [Indexed: 12/12/2022] Open
Abstract
Stem cell therapy may present an effective treatment for metastatic brain cancer and glioblastoma. Here we posit the critical role of a leaky blood-brain barrier (BBB) as a key element for the development of brain metastases, specifically melanoma. By reviewing the immunological and inflammatory responses associated with BBB damage secondary to tumoral activity, we identify the involvement of this pathological process in the growth and formation of metastatic brain cancers. Likewise, we evaluate the hypothesis of regenerating impaired endothelial cells of the BBB and alleviating the damaged neurovascular unit to attenuate brain metastasis, using the endothelial progenitor cell (EPC) phenotype of bone marrow-derived mesenchymal stem cells. Specifically, there is a need to evaluate the efficacy for stem cell therapy to repair disruptions in the BBB and reduce inflammation in the brain, thereby causing attenuation of metastatic brain cancers. To establish the viability of stem cell therapy for the prevention and treatment of metastatic brain tumors, it is crucial to demonstrate BBB repair through augmentation of vasculogenesis and angiogenesis. BBB disruption is strongly linked to metastatic melanoma, worsens neuroinflammation during metastasis, and negatively influences the prognosis of metastatic brain cancer. Using stem cell therapy to interrupt inflammation secondary to this leaky BBB represents a paradigm-shifting approach for brain cancer treatment. In this review article, we critically assess the advantages and disadvantages of using stem cell therapy for brain metastases and glioblastoma.
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Affiliation(s)
| | - Alex Shear
- University of Florida, Gainesville, FL, United States
| | - Beverly Brooks
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, United States
| | - Madeline Saft
- University of Michigan, Ann Arbor, MI, United States
| | | | - Chase Kingsbury
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, United States
| | - Henry Zhang
- University of Florida, Gainesville, FL, United States
| | - Stefan Anthony
- Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States
| | - Zhen-Jie Wang
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, United States
| | - Felipe Esparza Salazar
- Centro de Investigación en Ciencias de la Salud (CICSA), Facultad de Ciencias de la Salud (FCS), Universidad Anáhuac México Campus Norte, Huixquilucan, Mexico
| | - Alma R. Lezama Toledo
- Centro de Investigación en Ciencias de la Salud (CICSA), Facultad de Ciencias de la Salud (FCS), Universidad Anáhuac México Campus Norte, Huixquilucan, Mexico
| | - Germán Rivera Monroy
- Centro de Investigación en Ciencias de la Salud (CICSA), Facultad de Ciencias de la Salud (FCS), Universidad Anáhuac México Campus Norte, Huixquilucan, Mexico
| | | | - Alexa Moscatello
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, United States
| | - Jea-Young Lee
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, United States
| | - Cesario V. Borlongan
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, United States
- Center of Excellence for Aging and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, United States
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29
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Tang Q, Cheng B, Dai R, Wang R. The Role of Androgen Receptor in Cross Talk Between Stromal Cells and Prostate Cancer Epithelial Cells. Front Cell Dev Biol 2021; 9:729498. [PMID: 34692685 PMCID: PMC8526848 DOI: 10.3389/fcell.2021.729498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 09/06/2021] [Indexed: 11/13/2022] Open
Abstract
Prostate cancer (PCa) lists as the second most lethal cancer for men in western countries, and androgen receptor (AR) plays a central role in its initiation and progression, which prompts the development of androgen deprivation therapy (ADT) as the standard treatment. Prostate tumor microenvironment, consisting of stromal cells and extracellular matrix (ECM), has dynamic interactions with PCa epithelial cells and affects their growth and invasiveness. Studies have shown that both genomic and non-genomic AR signaling pathways are involved in the biological regulation of PCa epithelial cells. In addition, AR signaling in prostate stroma is also involved in PCa carcinogenesis and progression. Loss of AR in PCa stroma is clinically observed as PCa progresses to advanced stage. Especially, downregulation of AR in stromal fibroblasts dysregulates the expression levels of ECM proteins, thus creating a suitable environment for PCa cells to metastasize. Importantly, ADT treatment enhances this reciprocal interaction and predisposes stromal cells to promote cell invasion of PCa cells. During this process, AR in PCa epithelium actively responds to various stimuli derived from the surrounding stromal cells and undergoes enhanced degradation while elevating the expression of certain genes such as MMP9 responsible for cell invasion. AR reduction in epithelial cells also accelerates these cells to differentiate into cancer stem-like cells and neuroendocrine cells, which are AR-negative PCa cells and inherently resistant to ADT treatments. Overall, understanding of the cross talk between tumor microenvironment and PCa at the molecular level may assist the development of novel therapeutic strategies against this disease. This review will provide a snapshot of AR's action when the interaction of stromal cells and PCa cells occurs.
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Affiliation(s)
- Qianyao Tang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Bo Cheng
- Department of Urology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Rongyang Dai
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
| | - Ronghao Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, China
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30
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Mohr A, Chu T, Clarkson CT, Brooke GN, Teif VB, Zwacka RM. Fas-threshold signalling in MSCs promotes pancreatic cancer progression and metastasis. Cancer Lett 2021; 519:63-77. [PMID: 34171406 DOI: 10.1016/j.canlet.2021.06.017] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 06/13/2021] [Accepted: 06/16/2021] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) belong to the tumour microenvironment and have been implicated in tumour progression. We found that the number of MSCs significantly increased in tumour-burdened mice driven by Fas-threshold signalling. Consequently, MSCs lacking Fas lost their ability to induce metastasis development in a pancreatic cancer model. Mixing of MSCs with pancreatic cancer cells led to sustained production of the pro-metastatic cytokines CCL2 and IL6 by the stem cells. The levels of these cytokines were dependent on the number of MSCs, linking Fas-mediated MSC-proliferation to their capacity to promote tumour progression. Furthermore, we discovered that CCL2 and IL6 were induced by pancreatic cancer cell-derived IL1. Importantly, analysis of patient transcriptomic data revealed that high FasL expression correlates with high levels of MSC markers as well as increased IL6 and CCL2 levels in pancreatic tumours. Moreover, both FasL and CCL2 are linked to elevated levels of markers specific for monocytes known to possess further pro-metastatic activities. These results confirm our experimental findings of a FasL-MSC-IL1-CCL2/IL6 axis in pancreatic cancer and highlights the role of MSCs in tumour progression.
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Affiliation(s)
- Andrea Mohr
- School of Life Sciences, Protein Structure and Mechanism of Disease Group, Cancer and Stem Cell Biology Laboratory, University of Essex, Colchester, CO4 3SQ, UK.
| | - Tianyuan Chu
- School of Life Sciences, Protein Structure and Mechanism of Disease Group, Cancer and Stem Cell Biology Laboratory, University of Essex, Colchester, CO4 3SQ, UK
| | - Christopher T Clarkson
- School of Life Sciences, Genomics and Computational Biology Group, Gene Regulation Laboratory, University of Essex, Colchester, CO4 3SQ, UK
| | - Greg N Brooke
- School of Life Sciences, Protein Structure and Mechanism of Disease Group, Molecular Oncology Laboratory, University of Essex, Colchester, CO4 3SQ, UK
| | - Vladimir B Teif
- School of Life Sciences, Genomics and Computational Biology Group, Gene Regulation Laboratory, University of Essex, Colchester, CO4 3SQ, UK
| | - Ralf M Zwacka
- School of Life Sciences, Protein Structure and Mechanism of Disease Group, Cancer and Stem Cell Biology Laboratory, University of Essex, Colchester, CO4 3SQ, UK.
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31
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Ni Y, Zhou X, Yang J, Shi H, Li H, Zhao X, Ma X. The Role of Tumor-Stroma Interactions in Drug Resistance Within Tumor Microenvironment. Front Cell Dev Biol 2021; 9:637675. [PMID: 34095111 PMCID: PMC8173135 DOI: 10.3389/fcell.2021.637675] [Citation(s) in RCA: 83] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 04/19/2021] [Indexed: 02/05/2023] Open
Abstract
Cancer cells resistance to various therapies remains to be a key challenge nowadays. For a long time, scientists focused on tumor cells themselves for the mechanisms of acquired drug resistance. However, recent evidence showed that tumor microenvironment (TME) is essential for regulating immune escape, drug resistance, progression and metastasis of malignant cells. Reciprocal interactions between cancer cells and non-malignant cells within this milieu often reshape the TME and promote drug resistance. Therefore, advanced knowledge about these sophisticated interactions is significant for the design of effective therapeutic approaches. In this review, we highlight cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), tumor-associated neutrophils (TANs), myeloid-derived suppressor cells (MDSCs), T-regulatory lymphocytes (Tregs), mesenchymal stem cells (MSCs), cancer-associated adipocytes (CAAs), and tumor endothelial cells (TECs) existing in TME, as well as their multiple cross-talk with tumor cells, which eventually endows tumor cells with therapeutic resistance.
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Affiliation(s)
- Yanghong Ni
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xiaoting Zhou
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Jia Yang
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Houhui Shi
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Hongyi Li
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China.,Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xia Zhao
- Department of Gynecology and Obstetrics, Development and Related Disease of Women and Children Key Laboratory of Sichuan Province, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second Hospital, Sichuan University, Chengdu, China
| | - Xuelei Ma
- Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Collaborative Innovation Center of Biotherapy, Sichuan University, Chengdu, China
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32
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Slow-cycling (dormant) cancer cells in therapy resistance, cancer relapse and metastasis. Semin Cancer Biol 2021; 78:90-103. [PMID: 33979674 DOI: 10.1016/j.semcancer.2021.04.021] [Citation(s) in RCA: 68] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Revised: 04/26/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023]
Abstract
It is increasingly appreciated that cancer cell heterogeneity and plasticity constitute major barriers to effective clinical treatments and long-term therapeutic efficacy. Research in the past two decades suggest that virtually all treatment-naive human cancers harbor subsets of cancer cells that possess many of the cardinal features of normal stem cells. Such stem-like cancer cells, operationally defined as cancer stem cells (CSCs), are frequently quiescent and dynamically change and evolve during tumor progression and therapeutic interventions. Intrinsic tumor cell heterogeneity is reflected in a different aspect in that tumors also harbor a population of slow-cycling cells (SCCs) that are not in the proliferative cell cycle and thus are intrinsically refractory to anti-mitotic drugs. In this Perspective, we focus our discussions on SCCs in cancer and on various methodologies that can be employed to enrich and purify SCCs, compare the similarities and differences between SCCs, CSCs and cancer cells undergoing EMT, and present evidence for the involvement of SCCs in surviving anti-neoplastic treatments, mediating tumor relapse, maintaining tumor dormancy and mediating metastatic dissemination. Our discussions make it clear that an in-depth understanding of the biological properties of SCCs in cancer will be instrumental to developing new therapeutic strategies to prevent tumor relapse and distant metastasis.
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Ivolgin DA, Kudlay DA. Mesenchymal multipotent stromal cells and cancer safety: two sides of the same coin or a double-edged sword (review of foreign literature). RUSSIAN JOURNAL OF PEDIATRIC HEMATOLOGY AND ONCOLOGY 2021; 8:64-84. [DOI: 10.21682/2311-1267-2021-8-1-64-84] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Knowledge about the mechanisms of action of mesenchymal multipotent stromal cells (MSC) has undergone a significant evolution since their discovery. From the first attempts to use the remarkable properties of MSC in restoring the functions of organs and tissues, the most important question arose – how safe their use would be? One of the aspects of safety of the use of such biomaterial is tumorogenicity and oncogenicity. Numerous studies have shown that the mechanisms by which MSC realize their regenerative potential can, in principle, have a stimulating effect on tumor cells. This review presents specific mechanisms that have a potentially pro-tumor effect, which include the homing of MSC to the tumor site, support for replicative and proliferative signaling of both cancer cells and cancer stem cells, angiogenesis, and effects on the epithelial-mesenchymal transition. Along with pro-tumor mechanisms, the mechanisms of possible antitumor action are also described – direct suppression of tumor growth, loading and transportation of chemotherapeutic agents, oncolytic viruses, genetic modifications for targeting cancer, delivery of “suicide genes” to the tumor. Also, in conclusion, a small review of the current clinical trials of MSC as antitumor agents for malignant neoplasms of various localization (gastrointestinal tract, lungs, ovaries) is given.
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Affiliation(s)
- D. A. Ivolgin
- I.I. Mechnikov North-Western State Medical University, Ministry of Health of Russia
| | - D. A. Kudlay
- JSC “GENERIUM”;
I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia (Sechenov University);
National Research Center – Institute of Immunology Federal Medical-Biological Agency of Russia
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34
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Guo Q, Dong Y, Zhang Y, Fu H, Chen C, Wang L, Yang X, Shen M, Yu J, Chen M, Zhang J, Duan Y. Sequential Release of Pooled siRNAs and Paclitaxel by Aptamer-Functionalized Shell-Core Nanoparticles to Overcome Paclitaxel Resistance of Prostate Cancer. ACS APPLIED MATERIALS & INTERFACES 2021; 13:13990-14003. [PMID: 33739080 DOI: 10.1021/acsami.1c00852] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
Paclitaxel (PTX) is a first-line chemotherapeutic agent to treat prostate cancer (PCa), but a large number of patients acquired drug resistance after short-term treatment. To develop combinational therapeutics to overcome PTX-resistant PCa, we established PTX-resistant LNCaP (LNCaP/PTX) cells and found that the LNCaP/PTX cells exhibited epithelial-mesenchymal transition (EMT) and enhanced metastasis during the selection process. We revealed that β-tubulin III, androgen receptor, and CXCR4 expressions were significantly increased in LNCaP/PTX cells and directly contributed to PTX resistance and EMT. Therefore, we developed prostate-specific membrane antigen aptamer (Apt)-functionalized shell-core nanoparticles (PTX/siRNAs NPs-Apt); the hydrophobic DSPE encapsulating PTX formed the dense inner core and the hydrophilic Apt-PEG2K with calcium phosphate (CaP) absorbing siRNAs formed the outer shell to sequentially release siRNAs and PTX, where CaP could trigger lysosomal escape to ensure that pooled siRNAs efficiently released into the cytoplasm to reverse EMT and resensitize PTX, while the PTX located in the core was subsequently released to exert the killing effect of chemotherapy to achieve the best synergistic effect. PTX/siRNAs NPs-Apt showed an enhanced tumor-targeting ability and achieved superior efficacy in the subcutaneous and orthotopic PCa tumor model with minimal side effects.
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Affiliation(s)
- Qianqian Guo
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yang Dong
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yanhua Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Hao Fu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Chuanrong Chen
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Liting Wang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Xupeng Yang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Ming Shen
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Jian Yu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Meiwan Chen
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau 999078, China
| | - Jiali Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Yourong Duan
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200240, China
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35
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Zhang T, Huang T, Su Y, Gao J. Mesenchymal Stem Cells‐Based Targeting Delivery System: Therapeutic Promises and Immunomodulation against Tumor. ADVANCED THERAPEUTICS 2021. [DOI: 10.1002/adtp.202100030] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
- Tianyuan Zhang
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
| | - Ting Huang
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
| | - Yuanqin Su
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
| | - Jianqing Gao
- Zhejiang Province Key Laboratory of Anti‐Cancer Drug Research College of Pharmaceutical Sciences Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
- Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
- Cancer Center of Zhejiang University 866 Yuhangtang Rd Hangzhou 310058 China
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Mesenchymal stem cells and cancer therapy: insights into targeting the tumour vasculature. Cancer Cell Int 2021; 21:158. [PMID: 33685452 PMCID: PMC7938588 DOI: 10.1186/s12935-021-01836-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 02/15/2021] [Indexed: 12/27/2022] Open
Abstract
A crosstalk established between tumor microenvironment and tumor cells leads to contribution or inhibition of tumor progression. Mesenchymal stem cells (MSCs) are critical cells that fundamentally participate in modulation of the tumor microenvironment, and have been reported to be able to regulate and determine the final destination of tumor cell. Conflicting functions have been attributed to the activity of MSCs in the tumor microenvironment; they can confer a tumorigenic or anti-tumor potential to the tumor cells. Nonetheless, MSCs have been associated with a potential to modulate the tumor microenvironment in favouring the suppression of cancer cells, and promising results have been reported from the preclinical as well as clinical studies. Among the favourable behaviours of MSCs, are releasing mediators (like exosomes) and their natural migrative potential to tumor sites, allowing efficient drug delivering and, thereby, efficient targeting of migrating tumor cells. Additionally, angiogenesis of tumor tissue has been characterized as a key feature of tumors for growth and metastasis. Upon introduction of first anti-angiogenic therapy by a monoclonal antibody, attentions have been drawn toward manipulation of angiogenesis as an attractive strategy for cancer therapy. After that, a wide effort has been put on improving the approaches for cancer therapy through interfering with tumor angiogenesis. In this article, we attempted to have an overview on recent findings with respect to promising potential of MSCs in cancer therapy and had emphasis on the implementing MSCs to improve them against the suppression of angiogenesis in tumor tissue, hence, impeding the tumor progression.
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Huang R, Guo L, Gao M, Li J, Xiang S. Research Trends and Regulation of CCL5 in Prostate Cancer. Onco Targets Ther 2021; 14:1417-1427. [PMID: 33664576 PMCID: PMC7921632 DOI: 10.2147/ott.s279189] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Accepted: 01/20/2021] [Indexed: 12/11/2022] Open
Abstract
Prostate cancer (PCa) is considered as the most common cancer of urologic neoplasms, and its development and prognosis are associated with many factors. Chemokine receptor signaling combine with advances in advanced clinicopathological characteristics have provided new insights into the molecular landscape of prostate cancer. Chemokine (C-C motif) ligand 5 (CCL5) is an important member of the CC subfamily of chemokines. The expression of chemokine CCL5 is positively correlated with poor prognostic features in patients with PCa. Current study suggested that CCL5/CCR5 axis plays a significant role in the proliferation, metastasis, angiogenesis, drug resistance of prostate cancer cells and promotes self-renewal of prostate cancer stem cells (PCSCs). Due to the major domination in CCL5 by prostate cancer and the high cancer-specific mortality with prostate cancer, research on the CCL5/CCR5 axis effective antagonists is widespread application. However, challenges for precision oncology of CCL5/CCR5 axis and effective antagonists in CRPC remain. Herein, we summarized the crucial role of CCL5 in promoting the development of PCa and discussed the antitumor application of the antagonists of CCL5/CCR5 axis.
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Affiliation(s)
- Renlun Huang
- Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China
| | - Lang Guo
- Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China
| | - Menghan Gao
- Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden
| | - Jing Li
- Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China
| | - Songtao Xiang
- Department of Urology, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, People's Republic of China
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McGuire JJ, Frieling JS, Lo CH, Li T, Muhammad A, Lawrence HR, Lawrence NJ, Cook LM, Lynch CC. Mesenchymal stem cell-derived interleukin-28 drives the selection of apoptosis resistant bone metastatic prostate cancer. Nat Commun 2021; 12:723. [PMID: 33526787 PMCID: PMC7851397 DOI: 10.1038/s41467-021-20962-6] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 01/06/2021] [Indexed: 01/12/2023] Open
Abstract
Bone metastatic prostate cancer (PCa) promotes mesenchymal stem cell (MSC) recruitment and their differentiation into osteoblasts. However, the effects of bone-marrow derived MSCs on PCa cells are less explored. Here, we report MSC-derived interleukin-28 (IL-28) triggers prostate cancer cell apoptosis via IL-28 receptor alpha (IL-28Rα)-STAT1 signaling. However, chronic exposure to MSCs drives the selection of prostate cancer cells that are resistant to IL-28-induced apoptosis and therapeutics such as docetaxel. Further, MSC-selected/IL-28-resistant prostate cancer cells grow at accelerated rates in bone. Acquired resistance to apoptosis is PCa cell intrinsic, and is associated with a shift in IL-28Rα signaling via STAT1 to STAT3. Notably, STAT3 ablation or inhibition impairs MSC-selected prostate cancer cell growth and survival. Thus, bone marrow MSCs drive the emergence of therapy-resistant bone metastatic prostate cancer yet this can be disabled by targeting STAT3.
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Affiliation(s)
- Jeremy J McGuire
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Jeremy S Frieling
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Chen Hao Lo
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, USA
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Tao Li
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Ayaz Muhammad
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Harshani R Lawrence
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Nicholas J Lawrence
- Department of Drug Discovery, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Leah M Cook
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Conor C Lynch
- Tumor Biology Department, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
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López-Gil JC, Martin-Hijano L, Hermann PC, Sainz B. The CXCL12 Crossroads in Cancer Stem Cells and Their Niche. Cancers (Basel) 2021; 13:cancers13030469. [PMID: 33530455 PMCID: PMC7866198 DOI: 10.3390/cancers13030469] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/17/2021] [Accepted: 01/19/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary CXCL12 and its receptors have been extensively studied in cancer, including their influence on cancer stem cells (CSCs) and their niche. This intensive research has led to a better understanding of the crosstalk between CXCL12 and CSCs, which has aided in designing several drugs that are currently being tested in clinical trials. However, a comprehensive review has not been published to date. The aim of this review is to provide an overview on how CXCL12 axes are involved in the regulation and maintenance of CSCs, their presence and influence at different cellular levels within the CSC niche, and the current state-of-the-art of therapeutic approaches aimed to target the CXCL12 crossroads. Abstract Cancer stem cells (CSCs) are defined as a subpopulation of “stem”-like cells within the tumor with unique characteristics that allow them to maintain tumor growth, escape standard anti-tumor therapies and drive subsequent repopulation of the tumor. This is the result of their intrinsic “stem”-like features and the strong driving influence of the CSC niche, a subcompartment within the tumor microenvironment that includes a diverse group of cells focused on maintaining and supporting the CSC. CXCL12 is a chemokine that plays a crucial role in hematopoietic stem cell support and has been extensively reported to be involved in several cancer-related processes. In this review, we will provide the latest evidence about the interactions between CSC niche-derived CXCL12 and its receptors—CXCR4 and CXCR7—present on CSC populations across different tumor entities. The interactions facilitated by CXCL12/CXCR4/CXCR7 axes seem to be strongly linked to CSC “stem”-like features, tumor progression, and metastasis promotion. Altogether, this suggests a role for CXCL12 and its receptors in the maintenance of CSCs and the components of their niche. Moreover, we will also provide an update of the therapeutic options being currently tested to disrupt the CXCL12 axes in order to target, directly or indirectly, the CSC subpopulation.
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Affiliation(s)
- Juan Carlos López-Gil
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM, 28029 Madrid, Spain; (J.C.L.-G.); (L.M.-H.)
- Department of Biochemistry, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
- Chronic Diseases and Cancer, Area 3-Instituto Ramon y Cajal de Investigación Sanitaria (IRYCIS), 28029 Madrid, Spain
| | - Laura Martin-Hijano
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM, 28029 Madrid, Spain; (J.C.L.-G.); (L.M.-H.)
- Department of Biochemistry, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
- Chronic Diseases and Cancer, Area 3-Instituto Ramon y Cajal de Investigación Sanitaria (IRYCIS), 28029 Madrid, Spain
| | - Patrick C. Hermann
- Department of Internal Medicine I, Ulm University, 89081 Ulm, Germany
- Correspondence: (P.C.H.); (B.S.J.)
| | - Bruno Sainz
- Department of Cancer Biology, Instituto de Investigaciones Biomédicas “Alberto Sols” (IIBM), CSIC-UAM, 28029 Madrid, Spain; (J.C.L.-G.); (L.M.-H.)
- Department of Biochemistry, Universidad Autónoma de Madrid (UAM), 28029 Madrid, Spain
- Chronic Diseases and Cancer, Area 3-Instituto Ramon y Cajal de Investigación Sanitaria (IRYCIS), 28029 Madrid, Spain
- Correspondence: (P.C.H.); (B.S.J.)
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Yu Y, Yang FH, Zhang WT, Guo YD, Ye L, Yao XD. Mesenchymal stem cells desensitize castration-resistant prostate cancer to docetaxel chemotherapy via inducing TGF-β1-mediated cell autophagy. Cell Biosci 2021; 11:7. [PMID: 33413648 PMCID: PMC7792182 DOI: 10.1186/s13578-020-00494-0] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Accepted: 11/09/2020] [Indexed: 11/10/2022] Open
Abstract
Background Mesenchymal stem cells (MSCs) have been proved to drive castration resistant prostate cancer (CRPC). In this study, we aim to investigate the contribution of MSCs to the development of docetaxel resistance in CRPC cells and its potential mechanisms. Methods The effect of MSCs on CRPC cells resistance to docetaxel was determined using in vivo and in vitro approaches. CCK8 and PI/Annexin V-FITC assay were used to examined the cell viability and apoptosis. The concentration of transforming growth factor-β1 was measured by enzyme-linked immunosorbent assay and small interfering RNA was used for functional analyses. Results MSCs significantly reduced the sensitivity of CRPC cells to docetaxel-induced proliferation inhibition and apoptosis promotion in vivo and in vitro. CRPC cells cocultured with MSCs under docetaxel administration have an increased autophagy activation, while autophagy inhibitor could effectively reversed MSCs-induced resistance to docetaxel. Additionally, MSCs-induced CRPC cell autophagy increase under docetaxel administration depends on MSCs secreting TGF-β1 and inhibition of TGF-β1 secretion in MSCs could consequently increase the sensitivity of CRPC cells to docetaxel. Conclusions These results suggest that docetaxel administrated CRPC cells may elicit MSCs secreting TGF-β1 increase, which desensitizes CRPC to docetaxel chemotherapy accelerating chemoresistance occurrence via inducing cell autophagy.
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Affiliation(s)
- Yang Yu
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Fu-Han Yang
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Wen-Tao Zhang
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Ya-Dong Guo
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Lin Ye
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
| | - Xu-Dong Yao
- Department of Urology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China.
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Exosomes: Their Role in Pathogenesis, Diagnosis and Treatment of Diseases. Cancers (Basel) 2020; 13:cancers13010084. [PMID: 33396739 PMCID: PMC7795854 DOI: 10.3390/cancers13010084] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/18/2020] [Accepted: 12/24/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary The aim of this review is to provide an overview of the current scientific evidence concerning the role played by exosomes in the pathogenesis, diagnosis and treatment of diseases. The potential use of exosomes as delivery vectors for small-molecule therapeutic agents will be discussed. In addition, a special emphasis will be placed on the involvement of exosomes in oncological diseases, as well as to their potential therapeutic application as liquid biopsy tools mainly in cancer diagnosis. A better understanding of exosome biology could improve the results of clinical interventions using exosomes as therapeutic agents. Abstract Exosomes are lipid bilayer particles released from cells into their surrounding environment. These vesicles are mediators of near and long-distance intercellular communication and affect various aspects of cell biology. In addition to their biological function, they play an increasingly important role both in diagnosis and as therapeutic agents. In this paper, we review recent literature related to the molecular composition of exosomes, paying special attention to their role in pathogenesis, along with their application as biomarkers and as therapeutic tools. In this context, we analyze the potential use of exosomes in biomedicine, as well as the limitations that preclude their wider application.
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Mesenchymal stem/stromal cells: Developmental origin, tumorigenesis and translational cancer therapeutics. Transl Oncol 2020; 14:100948. [PMID: 33190044 PMCID: PMC7672320 DOI: 10.1016/j.tranon.2020.100948] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/27/2020] [Accepted: 11/05/2020] [Indexed: 12/20/2022] Open
Abstract
While a large and growing body of research has demonstrated that mesenchymal stem/stromal cells (MSCs) play a dual role in tumor growth and inhibition, studies exploring the capability of MSCs to contribute to tumorigenesis are rare. MSCs are key players during tumorigenesis and cancer development, evident in their faculty to increase cancer stem cells (CSCs) population, to generate the precursors of certain forms of cancer (e.g. sarcoma), and to induce epithelial-mesenchymal transition to create the CSC-like state. Indeed, the origin and localization of the native MSCs in their original tissues are not known. MSCs are identified in the primary tumor sites and the fetal and extraembryonic tissues. Acknowledging the developmental origin of MSCs and tissue-resident native MSCs is essential for better understanding of MSC contributions to the cellular origin of cancer. This review stresses that the plasticity of MSCs can therefore instigate further risk in select therapeutic strategies for some patients with certain forms of cancer. Towards this end, to explore the safe and effective MSC-based anti-cancer therapies requires a strong understanding of the cellular and molecular mechanisms of MSC action, ultimately guiding new strategies for delivering treatment. While clinical trial efforts using MSC products are currently underway, this review also provides new insights on the underlying mechanisms of MSCs to tumorigenesis and focuses on the approaches to develop MSC-based anti-cancer therapeutic applications.
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43
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Lee SH, Reed-Newman T, Anant S, Ramasamy TS. Regulatory Role of Quiescence in the Biological Function of Cancer Stem Cells. Stem Cell Rev Rep 2020; 16:1185-1207. [DOI: 10.1007/s12015-020-10031-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Valcz G, Buzás EI, Sebestyén A, Krenács T, Szállási Z, Igaz P, Molnár B. Extracellular Vesicle-Based Communication May Contribute to the Co-Evolution of Cancer Stem Cells and Cancer-Associated Fibroblasts in Anti-Cancer Therapy. Cancers (Basel) 2020; 12:cancers12082324. [PMID: 32824649 PMCID: PMC7465064 DOI: 10.3390/cancers12082324] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 08/12/2020] [Accepted: 08/16/2020] [Indexed: 02/07/2023] Open
Abstract
Analogously to the natural selective forces in ecosystems, therapies impose selective pressure on cancer cells within tumors. Some tumor cells can adapt to this stress and are able to form resistant subpopulations, parallel with enrichment of cancer stem cell properties in the residual tumor masses. However, these therapy-resistant cells are unlikely to be sufficient for the fast tumor repopulation and regrowth by themselves. The dynamic and coordinated plasticity of residual tumor cells is essential both for the conversion of their regulatory network and for the stromal microenvironment to produce cancer supporting signals. In this nursing tissue "niche", cancer-associated fibroblasts are known to play crucial roles in developing therapy resistance and survival of residual stem-like cells. As paracrine messengers, extracellular vesicles carrying a wide range of signaling molecules with oncogenic potential, can support the escape of some tumor cells from their deadly fate. Here, we briefly overview how extracellular vesicle signaling between fibroblasts and cancer cells including cancer progenitor/stem cells may contribute to the progression, therapy resistance and recurrence of malignant tumors.
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Affiliation(s)
- Gábor Valcz
- 2nd Department of Internal Medicine and MTA-SE Molecular Medicine Research Group, 1051 Budapest, Hungary; (P.I.); (B.M.)
- Correspondence:
| | - Edit I. Buzás
- Department of Genetics, Cell- and Immunobiology, Semmelweis University, 1089 Budapest, Hungary;
- MTA-SE Immune-Proteogenomics Extracellular Vesicle Research Group, Hungarian Academy of Sciences, 1089 Budapest, Hungary
- Hungarian Center of Excellence Molecular Medicine-Semmelweis University Extracellular Vesicle Research Group, 1085 Budapest, Hungary
| | - Anna Sebestyén
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary; (A.S.); (T.K.)
| | - Tibor Krenács
- 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, 1085 Budapest, Hungary; (A.S.); (T.K.)
| | - Zoltán Szállási
- Computational Health Informatics Program (CHIP), Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA;
| | - Péter Igaz
- 2nd Department of Internal Medicine and MTA-SE Molecular Medicine Research Group, 1051 Budapest, Hungary; (P.I.); (B.M.)
| | - Béla Molnár
- 2nd Department of Internal Medicine and MTA-SE Molecular Medicine Research Group, 1051 Budapest, Hungary; (P.I.); (B.M.)
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The CCL5/CCR5 Axis in Cancer Progression. Cancers (Basel) 2020; 12:cancers12071765. [PMID: 32630699 PMCID: PMC7407580 DOI: 10.3390/cancers12071765] [Citation(s) in RCA: 250] [Impact Index Per Article: 50.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 06/25/2020] [Accepted: 06/30/2020] [Indexed: 02/07/2023] Open
Abstract
Tumor cells can “hijack” chemokine networks to support tumor progression. In this context, the C-C chemokine ligand 5/C-C chemokine receptor type 5 (CCL5/CCR5) axis is gaining increasing attention, since abnormal expression and activity of CCL5 and its receptor CCR5 have been found in hematological malignancies and solid tumors. Numerous preclinical in vitro and in vivo studies have shown a key role of the CCL5/CCR5 axis in cancer, and thus provided the rationale for clinical trials using the repurposed drug maraviroc, a CCR5 antagonist used to treat HIV/AIDS. This review summarizes current knowledge on the role of the CCL5/CCR5 axis in cancer. First, it describes the involvement of the CCL5/CCR5 axis in cancer progression, including autocrine and paracrine tumor growth, ECM (extracellular matrix) remodeling and migration, cancer stem cell expansion, DNA damage repair, metabolic reprogramming, and angiogenesis. Then, it focuses on individual hematological and solid tumors in which CCL5 and CCR5 have been studied preclinically. Finally, it discusses clinical trials of strategies to counteract the CCL5/CCR5 axis in different cancers using maraviroc or therapeutic monoclonal antibodies.
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Wang Q, Li T, Wu W, Ding G. Interplay between mesenchymal stem cell and tumor and potential application. Hum Cell 2020; 33:444-458. [PMID: 32378164 DOI: 10.1007/s13577-020-00369-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2020] [Accepted: 04/24/2020] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem cells (MSCs) possess the capabilities of self-renewal and multipotent differentiation. Firstly isolated from bone marrow, MSCs are subsequently identified from various post-natal tissue types. Based the differentiation into tissue-specific cells, MSCs were capable of replacing damaged and diseased tissues. In addition, MSCs have been demonstrated to possess important immunomodulatory properties. Increasing data showed that MSCs exhibited tropism for sites of the tumor microenvironment and interacted with tumor cells closely through paracrine signaling. Therefore, better understanding of crosstalk between MSCs and tumor cells will be able to develop potential strategies in the treatment of tumors in the future. Herein, we summarize the research progress of the influence of MSCs on tumor cells and the prospect of their application in tumor therapy in this review.
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Affiliation(s)
- Qing Wang
- Department of Dentistry, Weifang People's Hospital, Weifang, 261000, Shandong, People's Republic of China
| | - Ti Li
- Department of Dentistry, Weifang People's Hospital, Weifang, 261000, Shandong, People's Republic of China
| | - Wei Wu
- Department of Dentistry, Weifang People's Hospital, Weifang, 261000, Shandong, People's Republic of China
| | - Gang Ding
- Department of Stomatology, Yidu Central Hospital, Weifang Medical University, Linglongshan South Road No. 4138, Qingzhou, 262500, Shandong, People's Republic of China.
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Madden EC, Gorman AM, Logue SE, Samali A. Tumour Cell Secretome in Chemoresistance and Tumour Recurrence. Trends Cancer 2020; 6:489-505. [PMID: 32460003 DOI: 10.1016/j.trecan.2020.02.020] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Revised: 02/20/2020] [Accepted: 02/26/2020] [Indexed: 12/22/2022]
Abstract
Chemoresistance is a major factor driving tumour relapse and the high rates of cancer-related deaths. Understanding how cancer cells overcome chemotherapy-induced cell death is critical in promoting patient survival. One emerging mechanism of chemoresistance is the tumour cell secretome (TCS), an array of protumorigenic factors released by tumour cells. Chemotherapy exposure can also alter the composition of the TCS, known as therapy-induced TCS, and can promote tumour relapse and the formation of an immunosuppressive tumour microenvironment (TME). Here, we outline how the TCS can protect cancer cells from chemotherapy-induced cell death. We also highlight recent evidence describing how therapy-induced TCS can impact cancer stem cell (CSC) expansion and tumour-associated immune cells to enable tumour regrowth and antitumour immunity.
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Affiliation(s)
- Emma C Madden
- Apoptosis Research Centre, NUI Galway, Galway, Ireland; School of Natural Sciences, NUI Galway, Galway, Ireland
| | - Adrienne M Gorman
- Apoptosis Research Centre, NUI Galway, Galway, Ireland; School of Natural Sciences, NUI Galway, Galway, Ireland
| | - Susan E Logue
- Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB, Canada.
| | - Afshin Samali
- Apoptosis Research Centre, NUI Galway, Galway, Ireland; School of Natural Sciences, NUI Galway, Galway, Ireland.
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Masoumi J, Jafarzadeh A, Khorramdelazad H, Abbasloui M, Abdolalizadeh J, Jamali N. Role of Apelin/APJ axis in cancer development and progression. Adv Med Sci 2020; 65:202-213. [PMID: 32087570 DOI: 10.1016/j.advms.2020.02.002] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 05/26/2019] [Accepted: 02/11/2020] [Indexed: 02/07/2023]
Abstract
Apelin is an endogenous peptide, which is expressed in a vast board of organs such as the brain, placenta, heart, lungs, kidneys, pancreas, testis, prostate and adipose tissues. The apelin receptor, called angiotensin-like-receptor 1 (APJ), is also expressed in the brain, spleen, placenta, heart, liver, intestine, prostate, thymus, testis, ovary, lungs, kidneys, stomach, and adipose tissue. The apelin/APJ axis is involved in a number of physiological and pathological processes. The apelin expression is increased in various kinds of cancer and the apelin/APJ axis plays a key role in the development of tumors through enhancing angiogenesis, metastasis, cell proliferation and also through the development of cancer stem cells and drug resistance. The apelin also stops the apoptosis of cancer cells. The apelin/APJ axis was considered in this review as an attractive therapeutic target for cancer treatment.
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Zhao J, Zhang Z, Cui Q, Zhao L, Hu Y, Zhao S. Human adipose-derived mesenchymal stem cells inhibit proliferation and induce apoptosis of human gastric cancer HGC-27 cells. 3 Biotech 2020; 10:129. [PMID: 32154042 DOI: 10.1007/s13205-020-2090-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Accepted: 01/21/2020] [Indexed: 02/02/2023] Open
Abstract
The aim of this study was to explore the effects of human adipose-derived mesenchymal stem cells (ASCs) on the growth of gastric cancer cells in vivo and vitro and its mechanism. ASCs were isolated from abandoned adipose tissues, and the surface markers were identified by flow cytometry. In vitro experiments, HGC-27 cells cultured in ASCs-conditioned medium (CM) were assigned as the experimental group, while HGC-27 cells cultured in normal medium were as the control group. MTT and colony formation assays were performed to detect cell viability and colony formatting ability, respectively. Annexin-V/PI assay, Western blot, and caspase-3 enzyme activity assay were performed to detect cells apoptosis. The isolated ASCs could be differentiated into adipocytes and osteoblasts in vitro. Flow cytometry showed that CD73 and CD105 were positively expressed in HGC-27 cells. Compared with the mice injected HGC-27 cells only, the tumor formation in mice injected both ASCs and HGC-27 cells was significantly smaller (P < 0.05). The colony formation ability in experimental group was 40.09% smaller than control group (P < 0.05) and the cell apoptosis rate in experimental group was higher than the control group (P < 0.05). Furthermore, the expressions of cleaved PARP, cleaved caspase-3 proteins, and caspase-3 enzyme viability in experimental group were significantly higher than those of control group (P < 0.05). In conclusion, ASCs can effectively inhibit the growth of HGC-27 cells by inducing apoptosis.
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Affiliation(s)
- Jianhong Zhao
- 1Department of General Surgery, Affiliated Hospital of Hebei University of Engineering, No. 81, Congtai Road, Handan, 056002 Hebei Province China
| | - Zilong Zhang
- 1Department of General Surgery, Affiliated Hospital of Hebei University of Engineering, No. 81, Congtai Road, Handan, 056002 Hebei Province China
| | - Qingfeng Cui
- 1Department of General Surgery, Affiliated Hospital of Hebei University of Engineering, No. 81, Congtai Road, Handan, 056002 Hebei Province China
| | - Lina Zhao
- 2Department of Pediatrics, Affiliated Hospital of Hebei University of Engineering, Handan, 056002 China
| | - Yongjun Hu
- 1Department of General Surgery, Affiliated Hospital of Hebei University of Engineering, No. 81, Congtai Road, Handan, 056002 Hebei Province China
| | - Subin Zhao
- 1Department of General Surgery, Affiliated Hospital of Hebei University of Engineering, No. 81, Congtai Road, Handan, 056002 Hebei Province China
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Advances of Zinc Signaling Studies in Prostate Cancer. Int J Mol Sci 2020; 21:ijms21020667. [PMID: 31963946 PMCID: PMC7014440 DOI: 10.3390/ijms21020667] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 01/16/2020] [Accepted: 01/17/2020] [Indexed: 12/16/2022] Open
Abstract
Prostate cancer (PCa) is one of the most common cancers and the second leading cause of cancer-related death among men worldwide. Despite progresses in early diagnosis and therapeutic strategies, prognosis for patients with advanced PCa remains poor. Noteworthily, a unique feature of healthy prostate is its highest level of zinc content among all soft tissues in the human body, which dramatically decreases during prostate tumorigenesis. To date, several reviews have suggested antitumor activities of zinc and its potential as a therapeutic strategy of PCa. However, an overview about the role of zinc and its signaling in PCa is needed. Here, we review literature related to the content, biological function, compounds and clinical application of zinc in PCa. We first summarize zinc content in prostate tissue and sera of PCa patients with their clinical relevance. We then elaborate biological functions of zinc signaling in PCa on three main aspects, including cell proliferation, death and tumor metastasis. Finally, we discuss clinical applications of zinc-containing compounds and proteins involved in PCa signaling pathways. Based on currently available studies, we conclude that zinc plays a tumor suppressive role and can serve as a biomarker in PCa diagnosis and therapies.
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