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1
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Qi X, Zhou J, Wang P, Li Y, Li H, Miao Y, Ma X, Luo X, Zhang Z, He Y, Shen W, Zhao W, Cui R, Li C, Zhu H, Lyu J. KLF7-regulated ITGA2 as a therapeutic target for inhibiting oral cancer stem cells. Cell Death Dis 2025; 16:354. [PMID: 40316546 PMCID: PMC12048542 DOI: 10.1038/s41419-025-07689-8] [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: 10/30/2024] [Revised: 04/16/2025] [Accepted: 04/23/2025] [Indexed: 05/04/2025]
Abstract
Cancer stem cells (CSCs) play crucial roles in tumor metastasis, therapy resistance, and immune evasion. Identifying and understanding the factors that regulate the stemness of tumor cells presents promising opportunities for developing effective therapeutic strategies. In this study on oral squamous cell carcinoma (OSCC), we confirmed the key role of KLF7 in maintaining the stemness of OSCC. Using chromatin immunoprecipitation sequencing and dual-luciferase assays, we identified ITGA2, a membrane receptor, as a key downstream gene regulated by KLF7 in the maintenance of stemness. Tumor sphere formation assays, flow cytometry analyses, and in vivo limiting dilution tumorigenicity evaluations demonstrated that knocking down ITGA2 significantly impaired stemness. Upon binding to its extracellular matrix (ECM) ligand, type I collagen, ITGA2 activates stemness-associated signaling pathways, including PI3K-AKT, MAPK, and Hippo. TC-I 15, a small-molecule inhibitor of the ITGA2-collagen interaction, significantly sensitizes oral squamous cell carcinoma (OSCC) to cisplatin in xenograft models. In summary, we reveal that the KLF7/ITGA2 axis is a crucial modulator of stemness in OSCC. Our findings suggest that ITGA2 is a promising therapeutic target, offering a novel anti-CSC strategy.
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Affiliation(s)
- Xin Qi
- Zhejiang University, School of Medicine, First Affiliated Hospital, Hangzhou, Zhejiang, P. R. China
| | - Jiang Zhou
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for CANCER; Cancer Center of Zhejiang University, Hangzhou, China
| | - Pan Wang
- Department of Stomatology, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China
| | - Yunyan Li
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for CANCER; Cancer Center of Zhejiang University, Hangzhou, China
| | - Haoran Li
- Zhejiang University, School of Medicine, First Affiliated Hospital, Hangzhou, Zhejiang, P. R. China
| | - Yuwen Miao
- Zhejiang University, School of Medicine, Affiliated Stomatology Hospital, Hangzhou, Zhejiang, P. R. China
| | - XiaoQing Ma
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for CANCER; Cancer Center of Zhejiang University, Hangzhou, China
| | - Xiayan Luo
- Zhejiang University, School of Medicine, First Affiliated Hospital, Hangzhou, Zhejiang, P. R. China
| | - Zhiling Zhang
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for CANCER; Cancer Center of Zhejiang University, Hangzhou, China
| | - Yanling He
- Zhejiang University, School of Medicine, First Affiliated Hospital, Hangzhou, Zhejiang, P. R. China
| | - Wenyi Shen
- Zhejiang University, School of Medicine, First Affiliated Hospital, Hangzhou, Zhejiang, P. R. China
| | - Wenquan Zhao
- Zhejiang University, School of Medicine, First Affiliated Hospital, Hangzhou, Zhejiang, P. R. China
| | - Rutao Cui
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for CANCER; Cancer Center of Zhejiang University, Hangzhou, China
| | - Cang Li
- Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China.
- Zhejiang Provincial Clinical Research Center for CANCER; Cancer Center of Zhejiang University, Hangzhou, China.
| | - Huiyong Zhu
- Zhejiang University, School of Medicine, First Affiliated Hospital, Hangzhou, Zhejiang, P. R. China.
| | - Jiong Lyu
- Zhejiang University, School of Medicine, First Affiliated Hospital, Hangzhou, Zhejiang, P. R. China.
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Azar BKY, Vakhshiteh F. The Pre-metastatic Niche: How Cancer Stem Cell-Derived Exosomal MicroRNA Fit into the Puzzle. Stem Cell Rev Rep 2025; 21:1062-1074. [PMID: 40095238 DOI: 10.1007/s12015-025-10866-z] [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] [Accepted: 03/12/2025] [Indexed: 03/19/2025]
Abstract
Cancer metastasis is a complicated biological process that critically affects cancer progression, patient outcomes, and treatment plans. A significant step in metastasis is the formation of a pre-metastatic niche (PMN). A small subset of cells within tumors, known as cancer stem cells (CSCs), possess unique characteristics including, differentiation into different cell types within the tumor, self-renewal, and resistance to conventional therapies, that enable them to initiate tumors and drive metastasis. PMN plays an important role in preparing secondary organs for the arrival and proliferation of CSCs, thereby facilitating metastasis. CSC-derived exosomes are crucial components in the complex interplay between CSCs and the tumor microenvironment. These exosomes function as transporters of various substances that can promote cancer progression, metastasis, and modulation of pre-metastatic environments by delivering microRNA (miRNA, miR) cargo. This review aims to illustrate how exosomal miRNAs (exo-miRs) secreted by CSCs can predispose PMN and promote angiogenesis and metastasis.
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Affiliation(s)
- Behjat Kheiri Yeghaneh Azar
- Department of Molecular Medicine, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Faezeh Vakhshiteh
- Oncopathology Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iran.
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3
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Kim H, Jung SH, Jo S, Han JW, Yoon M, Lee JH. Anti‑angiogenic effect of Bryopsis plumosa‑derived peptide via aquaporin 3 in non‑small cell lung cancer. Int J Oncol 2025; 66:5. [PMID: 39611488 PMCID: PMC11637497 DOI: 10.3892/ijo.2024.5711] [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: 06/10/2024] [Accepted: 10/30/2024] [Indexed: 11/30/2024] Open
Abstract
Developing novel anti‑angiogenic agents with minimal toxicity is notably challenging for cancer therapeutics. The discovery and development of peptides, whether derived from natural sources or synthesized, has potential for developing anti‑angiogenic agents characterized by their ability to penetrate cancer cells, high specificity and low toxicity. The present study identified a Bryopsis plumose‑derived anticancer and anti‑angiogenesis marine‑derived peptide 06 (MP06). A 22‑amino acid peptide was synthesized and conjugated with fluorescein isothiocyanate (FITC‑MP06) for intracellular localization in H1299 non‑small cell lung cancer cells. Regulatory effects of this peptide on the viability, migration and self‑renewal of lung cancer cells was assessed. Furthermore, anti‑angiogenic effect of MP06 was investigated by monitoring vascular tube formation in human umbilical vein endothelial cells and a zebrafish model. Aquaporin (AQP)3, a membrane channel in various tissues, is involved in regulating stemness, epithelial‑mesenchymal transition (EMT) and angiogenesis. MP06 downregulated AQP3 expression. Consistently, AQP3 knockdown by RNA silencing downregulated its gene expression, leading to a decrease in stemness, EMT and angiogenesis properties in H1299 cells. MP06 could thus serve as a novel therapeutic target with anticancer and angiogenesis properties for non‑small cell lung cancer.
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Affiliation(s)
- Heabin Kim
- Department of Bio-material Research, National Marine Biodiversity Institute of Korea, Seocheon 33662, Republic of Korea
| | - Seung-Hyun Jung
- Department of Bio-material Research, National Marine Biodiversity Institute of Korea, Seocheon 33662, Republic of Korea
| | - Seonmi Jo
- Department of Biological Application & Technology, National Marine Biodiversity Institute of Korea, Seocheon 33662, Republic of Korea
| | - Jong Won Han
- Department of Ecology & Conservation, National Marine Biodiversity Institute of Korea, Seocheon 33662, Republic of Korea
| | - Moongeun Yoon
- Department of Bio-material Research, National Marine Biodiversity Institute of Korea, Seocheon 33662, Republic of Korea
| | - Jei Ha Lee
- Department of Bio-material Research, National Marine Biodiversity Institute of Korea, Seocheon 33662, Republic of Korea
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Kinoshita J, Doden K, Sakimura Y, Hayashi S, Saito H, Tsuji T, Yamamoto D, Moriyama H, Minamoto T, Inaki N. Crosstalk Between Omental Adipose-Derived Stem Cells and Gastric Cancer Cells Regulates Cancer Stemness and Chemotherapy Resistance. Cancers (Basel) 2024; 16:4275. [PMID: 39766174 PMCID: PMC11674675 DOI: 10.3390/cancers16244275] [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: 09/08/2024] [Revised: 10/08/2024] [Accepted: 10/10/2024] [Indexed: 01/11/2025] Open
Abstract
Background: Peritoneal metastasis (PM) remains a major challenge in patients with gastric cancer (GC) and occurs preferentially in adipose-rich organs, such as the omentum. Adipose-derived stem cells (ASCs) may influence cancer behavior. This study aimed to investigate whether ASCs isolated from the omentum can act as progenitors of cancer-associated fibroblasts (CAFs) and analyze their effects on the cancer stem cell (CSC) niche and the treatment resistance of GC cells. Methods: ASCs were isolated from the human omentum and their cellular characteristics were analyzed during co-culturing with GC cells. Results: ASCs express CAF markers and promote desmoplasia in cancer stroma in a mouse xenograft model. When co-cultured with GC cells, ASCs enhanced the sphere-forming efficiency of MKN45 and MKN74 cells. ASCs increased IL-6 secretion and enhanced the expression of Nanog and CD44v6 in GC cells; however, these changes were suppressed by the inhibition of IL-6. Xenograft mouse models co-inoculated with MKN45 cells and ASCs showed enhanced CD44v6 and Nanog expression and markedly reduced apoptosis induced by 5-FU treatment. Conclusion: This study improves our understanding of ASCs' role in PM treatment resistance and has demonstrated the potential for new treatment strategies targeting ASCs.
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Affiliation(s)
- Jun Kinoshita
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Kenta Doden
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Yusuke Sakimura
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Saki Hayashi
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Hiroto Saito
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Toshikatsu Tsuji
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Daisuke Yamamoto
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Hideki Moriyama
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
| | - Toshinari Minamoto
- Japan Community Health Care Organization Kanazawa Hospital, Kanazawa 920-8610, Japan;
- Department of Molecular and Cellular Pathology, Kanazawa University, Kanazawa 920-8640, Japan
| | - Noriyuki Inaki
- Department of Gastrointestinal Surgery, Kanazawa University, Kanazawa 920-8641, Japan; (K.D.); (Y.S.); (S.H.); (H.S.); (T.T.); (D.Y.); (H.M.); (N.I.)
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Hou W, Huang L, Wang J, Luyten W, Lai J, Zhou Z, Kang S, Dai P, Wang Y, Huang H, Lan J. Cajaninstilbene Acid and Its Derivative as Multi-Therapeutic Agents: A Comprehensive Review. Molecules 2024; 29:5440. [PMID: 39598829 PMCID: PMC11597117 DOI: 10.3390/molecules29225440] [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: 10/27/2024] [Revised: 11/12/2024] [Accepted: 11/14/2024] [Indexed: 11/29/2024] Open
Abstract
Pigeon pea (Cajanus cajan (L.) Millsp.) is a traditional Chinese medicinal plant widely utilized in folk medicine due to its significant pharmacological and nutritional properties. Cajaninstilbene acid (CSA), a stilbene compound derived from pigeon pea leaves, has been extensively investigated since the 1980s. A thorough understanding of CSA's mechanisms of action and its therapeutic effects on various diseases is crucial for developing novel therapeutic approaches. This paper presents an overview of recent research advancements concerning the biological activities and mechanisms of CSA and its derivatives up to February 2024. The review encompasses discussions on the in vivo metabolism of CSA and its derivatives, including antipathogenic micro-organisms activity, anti-tumor activity, systematic and organ protection activity (such as bone protection, cardiovascular protection, neuroprotection), anti-inflammatory activity, antioxidant activity, immune regulation as well as action mechanism of CSA and its derivatives. The most studied activities are antipathogenic micro-organisms activities. Additionally, the structure-activity relationships of CSA and its derivatives as well as the total synthesis of CSA are explored, highlighting the potential for developing new pharmaceutical agents. This review aims to provide a foundation for future clinical applications of CSA and its derivatives.
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Affiliation(s)
- Wen Hou
- Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, School of Pharmacy, Gannan Medical University, Ganzhou 341000, China; (W.H.)
| | - Lejun Huang
- School of Rehabilitation, Gannan Medical University, Ganzhou 341000, China;
| | - Jinyang Wang
- Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, School of Pharmacy, Gannan Medical University, Ganzhou 341000, China; (W.H.)
| | - Walter Luyten
- Department of Biology, Animal Physiology and Neurobiology Section, KU Leuven, 3000 Leuven, Belgium
| | - Jia Lai
- Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, School of Pharmacy, Gannan Medical University, Ganzhou 341000, China; (W.H.)
| | - Zhinuo Zhou
- Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, School of Pharmacy, Gannan Medical University, Ganzhou 341000, China; (W.H.)
| | - Sishuang Kang
- Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, School of Pharmacy, Gannan Medical University, Ganzhou 341000, China; (W.H.)
| | - Ping Dai
- Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, School of Pharmacy, Gannan Medical University, Ganzhou 341000, China; (W.H.)
| | - Yanzhu Wang
- Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, School of Pharmacy, Gannan Medical University, Ganzhou 341000, China; (W.H.)
| | - Hao Huang
- Jiangxi Province Key Laboratory of Pharmacology of Traditional Chinese Medicine, School of Pharmacy, Gannan Medical University, Ganzhou 341000, China; (W.H.)
| | - Jinxia Lan
- School of Public Health and Health Management, Gannan Medical University, Ganzhou 341000, China
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6
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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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Lavudi K, Nuguri SM, Pandey P, Kokkanti RR, Wang QE. ALDH and cancer stem cells: Pathways, challenges, and future directions in targeted therapy. Life Sci 2024; 356:123033. [PMID: 39222837 DOI: 10.1016/j.lfs.2024.123033] [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: 06/11/2024] [Revised: 08/16/2024] [Accepted: 08/30/2024] [Indexed: 09/04/2024]
Abstract
Human ALDH comprise 19 subfamilies in which ALDH1A1, ALDH1A3, ALDH3A1, ALDH5A1, ALDH7A1, and ALDH18A1 are implicated in CSC. Studies have shown that ALDH can also be involved in drug resistance and standard chemotherapy regimens are ineffective in treating patients at the stage of disease recurrence. Existing chemotherapeutic drugs eliminate the bulk of tumors but are usually not effective against CSC which express ALDH+ population. Henceforth, targeting ALDH is convincing to treat the patient's post-relapse. Combination therapies that interlink signaling mechanisms seem promising to increase the overall disease-free survival rate. Therefore, targeting ALDH through ALDH inhibitors along with immunotherapies may create a novel platform for translational research. This review aims to fill in the gap between ALDH1 family members in relation to its cell signaling mechanisms, highlighting their potential as molecular targets to sensitize recurrent tumors and bring forward the future development concerning the current progress and draw backs. This review summarizes the role of cancer stem cells and their upregulation by maintaining the tumor microenvironment in which ALDH is specifically highlighted. It discusses the regulation of ALDH family proteins and the crosstalk between ALDH and CSC in relation to cancer metabolism. Furthermore, it establishes the correlation between ALDH involved signaling mechanisms and their specific targeted inhibitors, as well as their functional modularity, bioavailability, and mechanistic role in various cancers.
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Affiliation(s)
- Kousalya Lavudi
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, United States; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States
| | - Shreya Madhav Nuguri
- Department of Food science and Technology, The Ohio State University, Columbus, OH, United States
| | - Prashant Pandey
- Department of Pharmaceutical Sciences, Babasaheb Bhimrao Ambedkar University, Lucknow 226025, U.P., India; Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta T6G 2E1, Canada
| | | | - Qi-En Wang
- Department of Radiation Oncology, College of Medicine, The Ohio State University, Columbus, OH 43210, United States; Comprehensive Cancer Center, The Ohio State University, Columbus, OH 43210, United States.
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Dakal TC, Bhushan R, Xu C, Gadi BR, Cameotra SS, Yadav V, Maciaczyk J, Schmidt‐Wolf IGH, Kumar A, Sharma A. Intricate relationship between cancer stemness, metastasis, and drug resistance. MedComm (Beijing) 2024; 5:e710. [PMID: 39309691 PMCID: PMC11416093 DOI: 10.1002/mco2.710] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 08/02/2024] [Accepted: 08/05/2024] [Indexed: 09/25/2024] Open
Abstract
Cancer stem cells (CSCs) are widely acknowledged as the drivers of tumor initiation, epithelial-mesenchymal transition (EMT) progression, and metastasis. Originating from both hematologic and solid malignancies, CSCs exhibit quiescence, pluripotency, and self-renewal akin to normal stem cells, thus orchestrating tumor heterogeneity and growth. Through a dynamic interplay with the tumor microenvironment (TME) and intricate signaling cascades, CSCs undergo transitions from differentiated cancer cells, culminating in therapy resistance and disease recurrence. This review undertakes an in-depth analysis of the multifaceted mechanisms underlying cancer stemness and CSC-mediated resistance to therapy. Intrinsic factors encompassing the TME, hypoxic conditions, and oxidative stress, alongside extrinsic processes such as drug efflux mechanisms, collectively contribute to therapeutic resistance. An exploration into key signaling pathways, including JAK/STAT, WNT, NOTCH, and HEDGEHOG, sheds light on their pivotal roles in sustaining CSCs phenotypes. Insights gleaned from preclinical and clinical studies hold promise in refining drug discovery efforts and optimizing therapeutic interventions, especially chimeric antigen receptor (CAR)-T cell therapy, cytokine-induced killer (CIK) cell therapy, natural killer (NK) cell-mediated CSC-targeting and others. Ultimately use of cell sorting and single cell sequencing approaches for elucidating the fundamental characteristics and resistance mechanisms inherent in CSCs will enhance our comprehension of CSC and intratumor heterogeneity, which ultimately would inform about tailored and personalized interventions.
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Affiliation(s)
- Tikam Chand Dakal
- Genome and Computational Biology LabDepartment of BiotechnologyMohanlal Sukhadia UniversityUdaipurRajasthanIndia
| | - Ravi Bhushan
- Department of ZoologyM.S. CollegeMotihariBiharIndia
| | - Caiming Xu
- Department of General SurgeryThe First Affiliated Hospital of Dalian Medical UniversityDalianChina
- Department of Molecular Diagnostics and Experimental Therapeutics, Beckman Research InstituteCity of HopeMonroviaCaliforniaUSA
| | - Bhana Ram Gadi
- Stress Physiology and Molecular Biology LaboratoryDepartment of BotanyJai Narain Vyas UniversityJodhpurRajasthanIndia
| | | | - Vikas Yadav
- School of Life SciencesJawaharlal Nehru UniversityNew DelhiIndia
| | - Jarek Maciaczyk
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
| | - Ingo G. H. Schmidt‐Wolf
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
| | - Abhishek Kumar
- Manipal Academy of Higher EducationManipalKarnatakaIndia
- Institute of BioinformaticsInternational Technology ParkBangaloreIndia
| | - Amit Sharma
- Department of Stereotactic and Functional NeurosurgeryUniversity Hospital of BonnBonnGermany
- Center for Integrated Oncology (CIO)Department of Integrated OncologyUniversity Hospital BonnBonnGermany
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Sezginer O, Unver N. Dissection of pro-tumoral macrophage subtypes and immunosuppressive cells participating in M2 polarization. Inflamm Res 2024; 73:1411-1423. [PMID: 38935134 PMCID: PMC11349836 DOI: 10.1007/s00011-024-01907-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2024] [Revised: 06/06/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024] Open
Abstract
Alternatively activated macrophage (M2) polarization can result in one of four subtypes based on cytokines and signaling pathways associated with macrophage activation: M2a, M2b, M2c, and M2d macrophages. The majority of M2 subtypes are anti-inflammatory and pro-angiogenic, secreting growth factors (VEGF, PDGF) and matrix metalloproteinases (MMP2, MMP9) which boost tumor growth, metastasis, and invasion. M2-polarized macrophages are associated with immune suppressor cells harboring Myeloid derived suppressor cells, Regulatory T cells (Tregs), Regulatory B cells as well as alternatively activated (N2) neutrophils. Treg cells selectively support the metabolic stability, mitochondrial integrity, and survival rate of M2-like TAMs in an indirect environment. Also, the contribution of Breg cells influences macrophage polarization towards the M2 direction. TAM is activated when TAN levels in the tumor microenvironment are insufficient or vice versa, suggesting that macrophage and its polarization are fine-tuned. Understanding the functions of immune suppressive cells, mediators, and signaling pathways involved with M2 polarization will allow us to identify potential strategies for targeting the TAM repolarization phenotype for innovative immunotherapy approaches. In this review, we have highlighted the critical factors for M2 macrophage polarization, differential cytokine/chemokine profiles of M1 and M2 macrophage subtypes, and other immune cells' impact on the polarization within the immunosuppressive niche.
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Affiliation(s)
- Onurcan Sezginer
- Department of Basic Oncology, Cancer Institute, Hacettepe University, Sihhiye, Ankara, 06100, Türkiye
| | - Nese Unver
- Department of Basic Oncology, Cancer Institute, Hacettepe University, Sihhiye, Ankara, 06100, Türkiye.
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10
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Chen H, Fang S, Zhu X, Liu H. Cancer-associated fibroblasts and prostate cancer stem cells: crosstalk mechanisms and implications for disease progression. Front Cell Dev Biol 2024; 12:1412337. [PMID: 39092186 PMCID: PMC11291335 DOI: 10.3389/fcell.2024.1412337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 07/05/2024] [Indexed: 08/04/2024] Open
Abstract
The functional heterogeneity and ecological niche of prostate cancer stem cells (PCSCs), which are major drivers of prostate cancer development and treatment resistance, have attracted considerable research attention. Cancer-associated fibroblasts (CAFs), which are crucial components of the tumor microenvironment (TME), substantially affect PCSC stemness. Additionally, CAFs promote PCSC growth and survival by releasing signaling molecules and modifying the surrounding environment. Conversely, PCSCs may affect the characteristics and behavior of CAFs by producing various molecules. This crosstalk mechanism is potentially crucial for prostate cancer progression and the development of treatment resistance. Using organoids to model the TME enables an in-depth study of CAF-PCSC interactions, providing a valuable preclinical tool to accurately evaluate potential target genes and design novel treatment strategies for prostate cancer. The objective of this review is to discuss the current research on the multilevel and multitarget regulatory mechanisms underlying CAF-PCSC interactions and crosstalk, aiming to inform therapeutic approaches that address challenges in prostate cancer treatment.
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Affiliation(s)
| | | | | | - Hao Liu
- Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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11
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Zhao X, Luo T, Qiu Y, Yang Z, Wang D, Wang Z, Zeng J, Bi Z. Mechanisms of traditional Chinese medicine overcoming of radiotherapy resistance in breast cancer. Front Oncol 2024; 14:1388750. [PMID: 38993643 PMCID: PMC11237312 DOI: 10.3389/fonc.2024.1388750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2024] [Accepted: 05/30/2024] [Indexed: 07/13/2024] Open
Abstract
Breast cancer stands as the most prevalent malignancy among women, with radiotherapy serving as a primary treatment modality. Despite radiotherapy, a subset of breast cancer patients experiences local recurrence, attributed to the intrinsic resistance of tumors to radiation. Therefore, there is a compelling need to explore novel approaches that can enhance cytotoxic effects through alternative mechanisms. Traditional Chinese Medicine (TCM) and its active constituents exhibit diverse pharmacological actions, including anti-tumor effects, offering extensive possibilities to identify effective components capable of overcoming radiotherapy resistance. This review delineates the mechanisms underlying radiotherapy resistance in breast cancer, along with potential candidate Chinese herbal medicines that may sensitize breast cancer cells to radiotherapy. The exploration of such herbal interventions holds promise for improving therapeutic outcomes in the context of breast cancer radiotherapy resistance.
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Affiliation(s)
- Xiaohui Zhao
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Department of Oncology, Shenshan Medical Centre, Memorial Hospital of Sun Yat-Sen University, Shanwei, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Ting Luo
- Department of Oncology, Shenshan Medical Centre, Memorial Hospital of Sun Yat-Sen University, Shanwei, China
| | - Yuting Qiu
- Department of Oncology, Shenshan Medical Centre, Memorial Hospital of Sun Yat-Sen University, Shanwei, China
| | - Zhiwei Yang
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Danni Wang
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zairui Wang
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
| | - Jiale Zeng
- Department of Radiology, Sun Yat-Sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhuofei Bi
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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12
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Ghiandai V, Grassi ES, Gazzano G, Fugazzola L, Persani L. Characterization of EpCAM in thyroid cancer biology by three-dimensional spheroids in vitro model. Cancer Cell Int 2024; 24:196. [PMID: 38835027 DOI: 10.1186/s12935-024-03378-2] [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: 02/09/2024] [Accepted: 05/19/2024] [Indexed: 06/06/2024] Open
Abstract
BACKGROUND Thyroid cancer (TC) is the most common endocrine malignancy. Nowadays, undifferentiated thyroid cancers (UTCs) are still lethal, mostly due to the insurgence of therapy resistance and disease relapse. These events are believed to be caused by a subpopulation of cancer cells with stem-like phenotype and specific tumor-initiating abilities, known as tumor-initiating cells (TICs). A comprehensive understanding of how to isolate and target these cells is necessary. Here we provide insights into the role that the protein Epithelial Cell Adhesion Molecule (EpCAM), a known TICs marker for other solid tumors, may have in TC biology, thus considering EpCAM a potential marker of thyroid TICs in UTCs. METHODS The characterization of EpCAM was accomplished through Western Blot and Immunofluorescence on patient-derived tissue samples, adherent cell cultures, and 3D sphere cultures of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) cell lines. The frequency of tumor cells with putative tumor-initiating ability within the 3D cultures was assessed through extreme limiting dilution analysis (ELDA). EpCAM proteolytic cleavages were studied through treatments with different cleavages' inhibitors. To evaluate the involvement of EpCAM in inducing drug resistance, Vemurafenib (PLX-4032) treatments were assessed through MTT assay. RESULTS Variable EpCAM expression pattern was observed in TC tissue samples, with increased cleavage in the more UTC. We demonstrated that EpCAM is subjected to an intense cleavage process in ATC-derived 3D tumor spheres and that the 3D model faithfully mimics what was observed in patient's samples. We also proved that the integrity of the protein appears to be crucial for the generation of 3D spheres, and its expression and cleavage in a 3D system could contribute to drug resistance in thyroid TICs. CONCLUSIONS Our data provide novel information on the role of EpCAM expression and cleavage in the biology of thyroid TICs, and our 3D model reflects the variability of EpCAM cleavage observed in tissue samples. EpCAM evaluation could play a role in clinical decisions regarding patient therapy since its expression and cleavage may have a fundamental role in the switch to a drug-resistant phenotype of UTC cells.
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Affiliation(s)
- Viola Ghiandai
- Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
| | - Elisa Stellaria Grassi
- Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy
| | - Giacomo Gazzano
- Pathology Unit, Istituto Auxologico Italiano IRCCS, Milan, Italy
| | - Laura Fugazzola
- Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy
| | - Luca Persani
- Department of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan, Italy.
- Department of Medical Biotechnology and Translational Medicine (BIOMETRA), Università degli Studi di Milano, Milan, Italy.
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13
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Standing D, Dandawate P, Gunewardena S, Covarrubias-Zambrano O, Roby KF, Khabele D, Jewell A, Tawfik O, Bossmann SH, Godwin AK, Weir SJ, Jensen RA, Anant S. Selective targeting of IRAK1 attenuates low molecular weight hyaluronic acid-induced stemness and non-canonical STAT3 activation in epithelial ovarian cancer. Cell Death Dis 2024; 15:362. [PMID: 38796478 PMCID: PMC11127949 DOI: 10.1038/s41419-024-06717-3] [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: 11/29/2023] [Revised: 04/30/2024] [Accepted: 05/02/2024] [Indexed: 05/28/2024]
Abstract
Advanced epithelial ovarian cancer (EOC) survival rates are dishearteningly low, with ~25% surviving beyond 5 years. Evidence suggests that cancer stem cells contribute to acquired chemoresistance and tumor recurrence. Here, we show that IRAK1 is upregulated in EOC tissues, and enhanced expression correlates with poorer overall survival. Moreover, low molecular weight hyaluronic acid, which is abundant in malignant ascites from patients with advanced EOC, induced IRAK1 phosphorylation leading to STAT3 activation and enhanced spheroid formation. Knockdown of IRAK1 impaired tumor growth in peritoneal disease models, and impaired HA-induced spheroid growth and STAT3 phosphorylation. Finally, we determined that TCS2210, a known inducer of neuronal differentiation in mesenchymal stem cells, is a selective inhibitor of IRAK1. TCS2210 significantly inhibited EOC growth in vitro and in vivo both as monotherapy, and in combination with cisplatin. Collectively, these data demonstrate IRAK1 as a druggable target for EOC.
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Affiliation(s)
- David Standing
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Prasad Dandawate
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Sumedha Gunewardena
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA
| | | | - Katherine F Roby
- Department of Cell Biology and Physiology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Dineo Khabele
- Department of Obstetrics and Gynecology, Washington University in St. Louis, St. Louis, MO, USA
| | - Andrea Jewell
- Department of Gynecologic Oncology, University of Kansas Medical Center, Kansas City, KS, USA
| | | | - Stefan H Bossmann
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
| | - Andrew K Godwin
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
- Kansas Institute for Precision Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Scott J Weir
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA
- Department of Pharmacology and Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
- Institute for Advancing Medical Innovation, University of Kansas Medical Center, Kansas City, KS, USA
| | - Roy A Jensen
- Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
| | - Shrikant Anant
- Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
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14
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Jo MY, Jeong YJ, Song KH, Choi YH, Kwon TK, Chang YC. 4-O-Methylascochlorin Synergistically Enhances 5-Fluorouracil-Induced Apoptosis by Inhibiting the Wnt/β-Catenin Signaling Pathway in Colorectal Cancer Cells. Int J Mol Sci 2024; 25:5746. [PMID: 38891932 PMCID: PMC11172374 DOI: 10.3390/ijms25115746] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/20/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
4-O-Methyl-ascochlorin (MAC), a derivative of the prenyl-phenol antibiotic ascochlorin extracted from the fungus Ascochyta viciae, shows anticarcinogenic effects on various cancer cells. 5-Fluorouracil (5-FU) is used to treat colorectal cancer (CRC); however, its efficacy must be enhanced. In this study, we investigated the molecular mechanisms by which MAC acts synergistically with 5-FU to inhibit cell proliferation and induce apoptosis in CRC cells. MAC enhanced the cytotoxic effects of 5-FU by suppressing the Akt/mTOR/p70S6K and Wnt/β-catenin signaling pathways. It also reduced the viability of 5-FU-resistant (5-FU-R) cells. Furthermore, expression of anti-apoptosis-related proteins and cancer stem-like cell (CSC) markers by 5-FU-R cells decreased in response to MAC. Similar to MAC, the knockdown of CTNNB1 induced apoptosis and reduced expression of mRNA encoding CRC markers in 5-FU-R cells. In summary, these results suggest that MAC and other β-catenin modulators may be useful in overcoming the 5-FU resistance of CRC cells.
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Affiliation(s)
- Min-Young Jo
- Research Institute of Biomedical Engineering and Department of Cell Biology, Daegu Catholic University School of Medicine, Daegu 42472, Republic of Korea
| | - Yun-Jeong Jeong
- Research Institute of Biomedical Engineering and Department of Cell Biology, Daegu Catholic University School of Medicine, Daegu 42472, Republic of Korea
| | - Kwon-Ho Song
- Research Institute of Biomedical Engineering and Department of Cell Biology, Daegu Catholic University School of Medicine, Daegu 42472, Republic of Korea
| | - Yung Hyun Choi
- Department of Biochemistry, College of Korean Medicine, Dong-Eui University, Busan 47227, Republic of Korea
| | - Taeg Kyu Kwon
- Department of Immunology, School of Medicine, Keimyung University, Daegu 42601, Republic of Korea
| | - Young-Chae Chang
- Research Institute of Biomedical Engineering and Department of Cell Biology, Daegu Catholic University School of Medicine, Daegu 42472, Republic of Korea
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15
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Sarkar R, Biswas S, Ghosh R, Samanta P, Pakhira S, Mondal M, Dutta Gupta Y, Bhandary S, Saha P, Bhowmik A, Hajra S. Exosome-sheathed porous silica nanoparticle-mediated co-delivery of 3,3'-diindolylmethane and doxorubicin attenuates cancer stem cell-driven EMT in triple negative breast cancer. J Nanobiotechnology 2024; 22:285. [PMID: 38796426 PMCID: PMC11127288 DOI: 10.1186/s12951-024-02518-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Accepted: 05/01/2024] [Indexed: 05/28/2024] Open
Abstract
BACKGROUND Therapeutic management of locally advanced and metastatic triple negative breast cancer (TNBC) is often limited due to resistance to conventional chemotherapy. Metastasis is responsible for more than 90% of breast cancer-associated mortality; therefore, the clinical need to prevent or target metastasis is immense. The epithelial to mesenchymal transition (EMT) of cancer stem cells (CSCs) is a crucial determinant in metastasis. Doxorubicin (DOX) is the frequently used chemotherapeutic drug against TNBC that may increase the risk of metastasis in patients. After cancer treatment, CSCs with the EMT characteristic persist, which contributes to advanced malignancy and cancer recurrence. The latest developments in nanotechnology for medicinal applications have raised the possibility of using nanomedicines to target these CSCs. Hence, we present a novel approach of combinatorial treatment of DOX with dietary indole 3,3'-diindolylmethane (DIM) which is an intriguing field of research that may target CSC mediated EMT induction in TNBC. For efficient delivery of both the compounds to the tumor niche, advance method of drug delivery based on exosomes sheathed with mesoporous silica nanoparticles may provide an attractive strategy. RESULTS DOX, according to our findings, was able to induce EMT in CSCs, making the breast cancer cells more aggressive and metastatic. In CSCs produced from spheres of MDAMB-231 and 4T1, overexpression of N-cadherin, Snail, Slug, and Vimentin as well as downregulation of E-cadherin by DOX treatment not only demonstrated EMT induction but also underscored the pressing need for a novel chemotherapeutic combination to counteract this detrimental effect of DOX. To reach this goal, DIM was combined with DOX and delivered to the CSCs concomitantly by loading them in mesoporous silica nanoparticles encapsulated in exosomes (e-DDMSNP). These exosomes improved the specificity, stability and better homing ability of DIM and DOX in the in vitro and in vivo CSC niche. Furthermore, after treating the CSC-enriched TNBC cell population with e-DDMSNP, a notable decrease in DOX mediated EMT induction was observed. CONCLUSION Our research seeks to propose a new notion for treating TNBC by introducing this unique exosomal nano-preparation against CSC induced EMT.
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Affiliation(s)
- Rupali Sarkar
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700 026, India
| | - Souradeep Biswas
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700 026, India
| | - Rituparna Ghosh
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700 026, India
| | - Priya Samanta
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700 026, India
| | - Shampa Pakhira
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700 026, India
| | - Mrinmoyee Mondal
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700 026, India
| | - Yashaswi Dutta Gupta
- Department of Biological Sciences, School of Life Science and Biotechnology, Adamas University, Kolkata, 700126, West Bengal, India
| | - Suman Bhandary
- Department of Biological Sciences, School of Life Science and Biotechnology, Adamas University, Kolkata, 700126, West Bengal, India
| | - Prosenjit Saha
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700 026, India
| | - Arijit Bhowmik
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700 026, India.
| | - Subhadip Hajra
- Department of Cancer Chemoprevention, Chittaranjan National Cancer Institute (CNCI), 37, S.P. Mukherjee Road, Kolkata, West Bengal, 700 026, India.
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16
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Zhu Y, Liu T, Deng X, Sheng D, Chen J, Kuang Y, Dai Z, Chen H. Ultrasound-mediated intra-/extracellular dual intervening effect combined with all-trans retinoic acid for cancer stemness inhibition. NANO TODAY 2024; 55:102207. [DOI: 10.1016/j.nantod.2024.102207] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Eslami M, Memarsadeghi O, Davarpanah A, Arti A, Nayernia K, Behnam B. Overcoming Chemotherapy Resistance in Metastatic Cancer: A Comprehensive Review. Biomedicines 2024; 12:183. [PMID: 38255288 PMCID: PMC10812960 DOI: 10.3390/biomedicines12010183] [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: 11/26/2023] [Revised: 12/17/2023] [Accepted: 01/05/2024] [Indexed: 01/24/2024] Open
Abstract
The management of metastatic cancer is complicated by chemotherapy resistance. This manuscript provides a comprehensive academic review of strategies to overcome chemotherapy resistance in metastatic cancer. The manuscript presents background information on chemotherapy resistance in metastatic cancer cells, highlighting its clinical significance and the current challenges associated with using chemotherapy to treat metastatic cancer. The manuscript delves into the molecular mechanisms underlying chemotherapy resistance in subsequent sections. It discusses the genetic alterations, mutations, and epigenetic modifications that contribute to the development of resistance. Additionally, the role of altered drug metabolism and efflux mechanisms, as well as the activation of survival pathways and evasion of cell death, are explored in detail. The strategies to overcome chemotherapy resistance are thoroughly examined, covering various approaches that have shown promise. These include combination therapy approaches, targeted therapies, immunotherapeutic strategies, and the repurposing of existing drugs. Each strategy is discussed in terms of its rationale and potential effectiveness. Strategies for early detection and monitoring of chemotherapy drug resistance, rational drug design vis-a-vis personalized medicine approaches, the role of predictive biomarkers in guiding treatment decisions, and the importance of lifestyle modifications and supportive therapies in improving treatment outcomes are discussed. Lastly, the manuscript outlines the clinical implications of the discussed strategies. It provides insights into ongoing clinical trials and emerging therapies that address chemotherapy resistance in metastatic cancer cells. The manuscript also explores the challenges and opportunities in translating laboratory findings into clinical practice and identifies potential future directions and novel therapeutic avenues. This comprehensive review provides a detailed analysis of strategies to overcome chemotherapy resistance in metastatic cancer. It emphasizes the importance of understanding the molecular mechanisms underlying resistance and presents a range of approaches for addressing this critical issue in treating metastatic cancer.
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Affiliation(s)
- Maryam Eslami
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Omid Memarsadeghi
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Ali Davarpanah
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran; (M.E.); (O.M.); (A.D.)
- International Faculty, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran 1949635881, Iran
| | - Afshin Arti
- Department of Biomedical Engineering, Central Tehran Branch, Islamic Azad University, Tehran 1469669191, Iran;
| | - Karim Nayernia
- International Center for Personalized Medicine (P7Medicine), 40235 Dusseldorf, Germany
| | - Babak Behnam
- Department of Regulatory Affairs, Amarex Clinical Research, NSF International, Germantown, MD 20874, USA
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18
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Wang WD, Guo YY, Yang ZL, Su GL, Sun ZJ. Sniping Cancer Stem Cells with Nanomaterials. ACS NANO 2023; 17:23262-23298. [PMID: 38010076 DOI: 10.1021/acsnano.3c07828] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
Cancer stem cells (CSCs) drive tumor initiation, progression, and therapeutic resistance due to their self-renewal and differentiation capabilities. Despite encouraging progress in cancer treatment, conventional approaches often fail to eliminate CSCs, necessitating the development of precise targeted strategies. Recent advances in materials science and nanotechnology have enabled promising CSC-targeted approaches, harnessing the power of tailoring nanomaterials in diverse therapeutic applications. This review provides an update on the current landscape of nanobased precision targeting approaches against CSCs. We elucidate the nuanced application of organic, inorganic, and bioinspired nanomaterials across a spectrum of therapeutic paradigms, encompassing targeted therapy, immunotherapy, and multimodal synergistic therapies. By examining the accomplishments and challenges in this potential field, we aim to inform future efforts to advance nanomaterial-based therapies toward more effective "sniping" of CSCs and tumor clearance.
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Affiliation(s)
- Wen-Da Wang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Yan-Yu Guo
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Zhong-Lu Yang
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Guang-Liang Su
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
| | - Zhi-Jun Sun
- State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, Key Laboratory of Oral Biomedicine Ministry of Education, Hubei Key Laboratory of Stomatology, School & Hospital of Stomatology, Wuhan University, Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan 430079, China
- Department of Oral Maxillofacial-Head Neck Oncology, School and Hospital of Stomatology, Wuhan University, Wuhan 430079, China
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Berger K, Persson E, Gregersson P, Ruiz-Martínez S, Jonasson E, Ståhlberg A, Rhost S, Landberg G. Interleukin-6 Induces Stem Cell Propagation through Liaison with the Sortilin-Progranulin Axis in Breast Cancer. Cancers (Basel) 2023; 15:5757. [PMID: 38136303 PMCID: PMC10741783 DOI: 10.3390/cancers15245757] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 10/25/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Unraveling the complex network between cancer cells and their tumor microenvironment is of clinical importance, as it might allow for the identification of new targets for cancer treatment. Cytokines and growth factors secreted by various cell types present in the tumor microenvironment have the potential to affect the challenging subpopulation of cancer stem cells showing treatment-resistant properties as well as aggressive features. By using various model systems, we investigated how the breast cancer stem cell-initiating growth factor progranulin influenced the secretion of cancer-associated proteins. In monolayer cultures, progranulin induced secretion of several inflammatory-related cytokines, such as interleukin (IL)-6 and -8, in a sortilin-dependent manner. Further, IL-6 increased the cancer stem fraction similarly to progranulin in the breast cancer cell lines MCF7 and MDA-MB-231 monitored by the surrogate mammosphere-forming assay. In a cohort of 63 patient-derived scaffold cultures cultured with breast cancer cells, we observed significant correlations between IL-6 and progranulin secretion, clearly validating the association between IL-6 and progranulin also in human-based microenvironments. In conclusion, the interplay between progranulin and IL-6 highlights a dual breast cancer stem cell-promoting function via sortilin, further supporting sortilin as a highly relevant therapeutic target for aggressive breast cancer.
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Affiliation(s)
- Karoline Berger
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Emma Persson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Pernilla Gregersson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Santiago Ruiz-Martínez
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Emma Jonasson
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Anders Ståhlberg
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
- Wallenberg Center for Molecular and Translational Medicine, University of Gothenburg, 41390 Gothenburg, Sweden
- Department of Clinical Genetics and Genomics, Sahlgrenska University Hospital, 41346 Gothenburg, Sweden
| | - Sara Rhost
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
| | - Göran Landberg
- Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, 40530 Gothenburg, Sweden; (K.B.); (E.P.); (P.G.); (S.R.-M.); (E.J.); (A.S.); (S.R.)
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20
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Marcu LG, Dell’Oro M, Bezak E. Opportunities in Cancer Therapies: Deciphering the Role of Cancer Stem Cells in Tumour Repopulation. Int J Mol Sci 2023; 24:17258. [PMID: 38139085 PMCID: PMC10744048 DOI: 10.3390/ijms242417258] [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: 11/18/2023] [Revised: 12/06/2023] [Accepted: 12/06/2023] [Indexed: 12/24/2023] Open
Abstract
Tumour repopulation during treatment is a well acknowledged yet still challenging aspect of cancer management. The latest research results show clear evidence towards the existence of cancer stem cells (CSCs) that are responsible for tumour repopulation, dissemination, and distant metastases in most solid cancers. Cancer stem cell quiescence and the loss of asymmetrical division are two powerful mechanisms behind repopulation. Another important aspect in the context of cancer stem cells is cell plasticity, which was shown to be triggered during fractionated radiotherapy, leading to cell dedifferentiation and thus reactivation of stem-like properties. Repopulation during treatment is not limited to radiotherapy, as there is clinical proof for repopulation mechanisms to be activated through other conventional treatment techniques, such as chemotherapy. The dynamic nature of stem-like cancer cells often elicits resistance to treatment by escaping drug-induced cell death. The aims of this scoping review are (1) to describe the main mechanisms used by cancer stem cells to initiate tumour repopulation during therapy; (2) to present clinical evidence for tumour repopulation during radio- and chemotherapy; (3) to illustrate current trends in the identification of CSCs using specific imaging techniques; and (4) to highlight novel technologies that show potential in the eradication of CSCs.
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Affiliation(s)
- Loredana G. Marcu
- UniSA Allied Health & Human Performance, University of South Australia, Adelaide, SA 5001, Australia;
- Faculty of Informatics and Science, University of Oradea, 410087 Oradea, Romania
| | - Mikaela Dell’Oro
- Australian Centre for Quantitative Imaging, School of Medicine, The University of Western Australia, Perth, WA 6009, Australia;
| | - Eva Bezak
- UniSA Allied Health & Human Performance, University of South Australia, Adelaide, SA 5001, Australia;
- Faculty of Chemistry & Physics, University of Adelaide, Adelaide, SA 5000, Australia
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Wu Y, Liang H, Luo A, Li Y, Liu Z, Li X, Li W, Liang K, Li J, Liu Z, Du Y. Gelatin-based 3D biomimetic scaffolds platform potentiates culture of cancer stem cells in esophageal squamous cell carcinoma. Biomaterials 2023; 302:122323. [PMID: 37717405 DOI: 10.1016/j.biomaterials.2023.122323] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 09/02/2023] [Accepted: 09/09/2023] [Indexed: 09/19/2023]
Abstract
Cancer stem cells (CSCs) are crucial for tumorigenesis, metastasis, and therapy resistance in esophageal squamous cell carcinoma (ESCC). To further elucidate the mechanism underlying characteristics of CSCs and develop CSCs-targeted therapy, an efficient culture system that could expand and maintain CSCs is needed. CSCs reside in a complex tumor microenvironment, and three-dimensional (3D) culture systems of biomimetic scaffolds are expected to better support the growth of CSCs by recapitulating the biophysical properties of the extracellular matrix (ECM). Here, we established gelatin-based 3D biomimetic scaffolds mimicking the stiffness and collagen content of ESCC, which could enrich ESCC CSCs efficiently. Biological changes of ESCC cells laden in scaffolds with three different viscoelasticity emulating physiological stiffness of esophageal tissues were thoroughly investigated in varied aspects such as cell morphology, viability, cell phenotype markers, and transcriptomic profiling. The results demonstrated the priming effects of viscoelasticity on the stemness of ESCC. The highly viscous scaffolds (G': 6-403 Pa; G'': 2-75 Pa) better supported the enrichment of ESCC CSCs, and the TGF-beta signaling pathway might be involved in regulating the stemness of ESCC cells. Compared to two-dimensional (2D) cultures, highly viscous scaffolds significantly promoted the clonal expansion of ESCC cells in vitro and tumor formation ability in vivo. Our findings highlight the crucial role of biomaterials' viscoelasticity for the 3D culture of ESCC CSCs in vitro, and this newly-established culture system represents a valuable platform to support their growth, which could facilitate the CSCs-targeted therapy in the future.
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Affiliation(s)
- Yenan Wu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Haiwei Liang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Aiping Luo
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Yong Li
- Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Zhiqiang Liu
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Xin Li
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Wenxin Li
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China
| | - Kaini Liang
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Junyang Li
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Zhihua Liu
- State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
| | - Yanan Du
- Department of Biomedical Engineering, School of Medicine, Tsinghua-Peking Center for Life Sciences, Tsinghua University, Beijing, 100084, China.
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22
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Behnam B, Fazilaty H, Ghadyani M, Fadavi P, Taghizadeh-Hesary F. Ciliated, Mitochondria-Rich Postmitotic Cells are Immune-privileged, and Mimic Immunosuppressive Microenvironment of Tumor-Initiating Stem Cells: From Molecular Anatomy to Molecular Pathway. FRONT BIOSCI-LANDMRK 2023; 28:261. [PMID: 37919090 DOI: 10.31083/j.fbl2810261] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/15/2023] [Accepted: 10/09/2023] [Indexed: 11/04/2023]
Abstract
Cancer whose major problems are metastasis, treatment resistance, and recurrence is the leading cause of death worldwide. Tumor-initiating stem cells (TiSCs) are a subset of the tumor population responsible for tumor resistance and relapse. Understanding the characteristics and shared features between tumor-initiating stem cells (TiSCs) and long-lived postmitotic cells may hold a key to better understanding the biology of cancer. Postmitotic cells have exited the cell cycle and are transitioned into a non-dividing and terminally differentiated state with a specialized function within a tissue. Conversely, a cancer cell with TiSC feature can divide and produce a variety of progenies, and is responsible for disease progression, tumor resistance to therapy and immune system and disease relapse. Surprisingly, our comprehensive evaluation of TiSCs suggests common features with long-lived post-mitotic cells. They are similar in structure (primary cilia, high mitochondrial content, and being protected by a barrier), metabolism (autophagy and senescence), and function (immunoescape and/or immune-privileged by a blood barrier). In-depth exploration showed how mitochondrial metabolism contributes to these shared features, including high energy demands arising from ciliary and microtubular functionality, increased metabolic activity, and movement. These findings can assist in decoding the remaining properties which offer insights into the biology of TiSCs, with potential implications for enhancing cancer treatment strategies and patient prognosis.
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Affiliation(s)
- Babak Behnam
- Department of Regulatory Affairs, Amarex Clinical Research, NSF International, Germantown, MD 20874, USA
| | - Hassan Fazilaty
- Department of Molecular Life Sciences, University of Zurich, 8057 Zurich, Switzerland
| | - Mobina Ghadyani
- School of Science, Monash University, Melbourne, VIC 3800, Australia
| | - Pedram Fadavi
- Department of Radiation Oncology, Iran University of Medical Sciences, 1445613131 Tehran, Iran
| | - Farzad Taghizadeh-Hesary
- Department of Radiation Oncology, Iran University of Medical Sciences, 1445613131 Tehran, Iran
- ENT and Head and Neck Research Center and Department, The Five Senses Health Institute, School of Medicine, Iran University of Medical Sciences, 1445613131 Tehran, Iran
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Brisset M, Mehlen P, Meurette O, Hollande F. Notch receptor/ligand diversity: contribution to colorectal cancer stem cell heterogeneity. Front Cell Dev Biol 2023; 11:1231416. [PMID: 37860822 PMCID: PMC10582728 DOI: 10.3389/fcell.2023.1231416] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 09/21/2023] [Indexed: 10/21/2023] Open
Abstract
Cancer cell heterogeneity is a key contributor to therapeutic failure and post-treatment recurrence. Targeting cell subpopulations responsible for chemoresistance and recurrence seems to be an attractive approach to improve treatment outcome in cancer patients. However, this remains challenging due to the complexity and incomplete characterization of tumor cell subpopulations. The heterogeneity of cells exhibiting stemness-related features, such as self-renewal and chemoresistance, fuels this complexity. Notch signaling is a known regulator of cancer stem cell (CSC) features in colorectal cancer (CRC), though the effects of its heterogenous signaling on CRC cell stemness are only just emerging. In this review, we discuss how Notch ligand-receptor specificity contributes to regulating stemness, self-renewal, chemoresistance and cancer stem cells heterogeneity in CRC.
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Affiliation(s)
- Morgan Brisset
- Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, Melbourne, VIC, Australia
- Centre for Cancer Research, The University of Melbourne, Melbourne, VIC, Australia
- Cancer Cell Death Laboratory, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Lyon, France
| | - Patrick Mehlen
- Cancer Cell Death Laboratory, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Lyon, France
| | - Olivier Meurette
- Cancer Cell Death Laboratory, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Centre Léon Bérard, Université de Lyon, Lyon, France
| | - Frédéric Hollande
- Department of Clinical Pathology, Victorian Comprehensive Cancer Centre, The University of Melbourne, Melbourne, VIC, Australia
- Centre for Cancer Research, The University of Melbourne, Melbourne, VIC, Australia
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24
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Yang Y, Zuo S, Li W, Di M, Liu J, Chai J, Wang J, Yuan Y, Li M, Jia Q. TRIM21 promotes tumor progression and cancer stemness in cervical squamous cell carcinoma. Pathol Res Pract 2023; 248:154710. [PMID: 37494805 DOI: 10.1016/j.prp.2023.154710] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 07/20/2023] [Accepted: 07/21/2023] [Indexed: 07/28/2023]
Abstract
BACKGROUND The ubiquitin ligase family member triplex motif protein 21 (TRIM21), which is involved in the proliferation, metastasis, and selective death of tumor cells, is crucial in the ubiquitination of a number of tumor marker proteins. As research progresses, more studies demonstrate that TRIM21 expression levels can be used to predict cancer prognosis. However, it is unclear how exactly TRIM21 contributes to cervical squamous carcinoma. METHODS Immunohistochemistry, Western Blot, and q-PCR were utilized to determine the expression level of TRIM21 in 113 patients with CESC removed by stage I surgery at Xijing Hospital from 2018 to 2023 using paraffin-embedded tumor tissues and 12 pairs of fresh tumor tissues and their paracancerous tissues. Log-rank analysis using SPSS 23.0 was performed for prognosis and survival analysis using univariate/multifactorial analysis. CCK-8, wound-healing and Scratch assay verified that TRIM21 promoted cell proliferation, migration and invasion. The effect of overexpression and knockdown of TRIM21 on tumor stemness was examined using sphere-forming assay and Western Blot. Finally, we constructed a xenograft model to observe the effect of TRIM21 on tumorigenesis in Si Ha cell lines in vivo. RESULTS TRIM21 expression is greater in CESC tissues than in paracancerous tissues, according to immunohistochemical data. Similarly, at the protein and mRNA levels, we verified this conclusion using Western-Blotting and q-PCR. Prognostic and OS analysis showed that TRIM21 expression levels are associated with individual prognostic factors. CCK-8, Wound healing, Transwell, and Sphere-forming tests all demonstrated that TRIM21 overexpression enhances Ca Ski cell proliferation, migration, invasion, and stemness. TRIM21 knockdown in Si Ha inhibited tumor cell proliferation, migration, invasion, and stemness. The experimental results of xenograft models demonstrated that TRIM21 knockdown in Si Ha cells inhibited tumor development. CONCLUSION TRIM21 is a poor predictor of prognosis for cervical squamous cell carcinoma and might open up new avenues for investigation into therapeutic targets.
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Affiliation(s)
- Yanru Yang
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Saijie Zuo
- School of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Wenqing Li
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Man Di
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Fourth Military Medical University, Xi'an, China
| | - Jin Liu
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Jia Chai
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, China
| | - Jingjing Wang
- Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Fourth Military Medical University, Xi'an, China.
| | - Yuan Yuan
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
| | - Mingyang Li
- State Key Laboratory of Cancer Biology, Department of Pathology, Xijing Hospital and School of Basic Medicine, Fourth Military Medical University, Xi'an, China.
| | - Qingge Jia
- Department of Reproductive Medicine, Xi'an International Medical Center Hospital, Northwest University, Xi'an, China.
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Lin S, Li K, Qi L. Cancer stem cells in brain tumors: From origin to clinical implications. MedComm (Beijing) 2023; 4:e341. [PMID: 37576862 PMCID: PMC10412776 DOI: 10.1002/mco2.341] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 06/24/2023] [Accepted: 07/04/2023] [Indexed: 08/15/2023] Open
Abstract
Malignant brain tumors are highly heterogeneous tumors with a poor prognosis and a high morbidity and mortality rate in both children and adults. The cancer stem cell (CSC, also named tumor-initiating cell) model states that tumor growth is driven by a subset of CSCs. This model explains some of the clinical observations of brain tumors, including the almost unavoidable tumor recurrence after initial successful chemotherapy and/or radiotherapy and treatment resistance. Over the past two decades, strategies for the identification and characterization of brain CSCs have improved significantly, supporting the design of new diagnostic and therapeutic strategies for brain tumors. Relevant studies have unveiled novel characteristics of CSCs in the brain, including their heterogeneity and distinctive immunobiology, which have provided opportunities for new research directions and potential therapeutic approaches. In this review, we summarize the current knowledge of CSCs markers and stemness regulators in brain tumors. We also comprehensively describe the influence of the CSCs niche and tumor microenvironment on brain tumor stemness, including interactions between CSCs and the immune system, and discuss the potential application of CSCs in brain-based therapies for the treatment of brain tumors.
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Affiliation(s)
- Shuyun Lin
- Institute of Digestive DiseaseThe Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People's HospitalQingyuanGuangdongChina
| | - Kaishu Li
- Institute of Digestive DiseaseThe Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People's HospitalQingyuanGuangdongChina
| | - Ling Qi
- Institute of Digestive DiseaseThe Sixth Affiliated Hospital of Guangzhou Medical UniversityQingyuan People's HospitalQingyuanGuangdongChina
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26
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Kumar HA, Desai A, Mohiddin G, Mishra P, Bhattacharyya A, Nishat R. Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma. JOURNAL OF PHARMACY AND BIOALLIED SCIENCES 2023; 15:S826-S830. [PMID: 37694019 PMCID: PMC10485429 DOI: 10.4103/jpbs.jpbs_81_23] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 02/20/2023] [Accepted: 02/21/2023] [Indexed: 09/12/2023] Open
Abstract
Cancer stem cells (CSCs) are a small sub-population of cells within a tumor mass proficient of tumor initiation and progression. Distinguishing features possessed by CSCs encompass self-renewal, regeneration and capacity to differentiate. These cells are attributed to the phenomenon of aggression, recurrence and metastasis in neoplasms. Due to their cancer initiating and contributing features, a proper understanding of these CSCs and its microenvironment would aid in better understanding of cancer and designing better targeted therapeutic strategies for improved clinical outcome, thus improving the prognosis. This article dispenses a narrative review of CSCs in the context of head and neck carcinoma under the sub headings of overview of cancer stem cells, methods of isolation of these cells, putative CSC markers of head and neck cancer, signaling pathways used by these cells and their therapeutic implications.
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Affiliation(s)
- Harish A. Kumar
- Department of Oral Pathology and Microbiology, Kalinga Institute of Dental Sciences, KIIT Deemed to be University, Bhubaneshwar, Odhisa, India
| | - Anupama Desai
- Department of Periodontology and Oral Implantology, A.M.E’S Dental College, Raichur, Karnataka, India
| | - Gouse Mohiddin
- Department of Oral Pathology and Microbiology, Kalinga Institute of Dental Sciences, KIIT Deemed to be University, Bhubaneshwar, Odhisa, India
| | - Pallavi Mishra
- Department of Oral Pathology and Microbiology, Kalinga Institute of Dental Sciences, KIIT Deemed to be University, Bhubaneshwar, Odhisa, India
| | - Arnab Bhattacharyya
- Department of Oral Pathology and Microbiology, Kalinga Institute of Dental Sciences, KIIT Deemed to be University, Bhubaneshwar, Odhisa, India
| | - Roquaiya Nishat
- Oral Pathology and Microbiology, Private Practitioner, Shri Balaji Dental Clinic, Patia, Bhubaneswar, Odisha, India
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27
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Ponomarev AS, Gilazieva ZE, Solovyova VV, Rizvanov AA. Molecular Mechanisms of Tumor Cell Stemness Modulation during Formation of Spheroids. BIOCHEMISTRY. BIOKHIMIIA 2023; 88:979-994. [PMID: 37751868 DOI: 10.1134/s0006297923070106] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 05/30/2023] [Accepted: 06/07/2023] [Indexed: 09/28/2023]
Abstract
Cancer stem cells (CSCs), their properties and interaction with microenvironment are of interest in modern medicine and biology. There are many studies on the emergence of CSCs and their involvement in tumor pathogenesis. The most important property inherent to CSCs is their stemness. Stemness combines ability of the cell to maintain its pluripotency, give rise to differentiated cells, and interact with environment to maintain a balance between dormancy, proliferation, and regeneration. While adult stem cells exhibit these properties by participating in tissue homeostasis, CSCs behave as their malignant equivalents. High tumor resistance to therapy, ability to differentiate, activate angiogenesis and metastasis arise precisely due to the stemness of CSCs. These cells can be used as a target for therapy of different types of cancer. Laboratory models are needed to study cancer biology and find new therapeutic strategies. A promising direction is three-dimensional tumor models or spheroids. Such models exhibit properties resembling stemness in a natural tumor. By modifying spheroids, it becomes possible to investigate the effect of therapy on CSCs, thus contributing to the development of anti-tumor drug test systems. The review examines the niche of CSCs, the possibility of their study using three-dimensional spheroids, and existing markers for assessing stemness of CSCs.
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Affiliation(s)
- Aleksei S Ponomarev
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia
| | - Zarema E Gilazieva
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia
| | - Valeriya V Solovyova
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia
| | - Albert A Rizvanov
- Kazan (Volga Region) Federal University, Kazan, Republic of Tatarstan, 420008, Russia.
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28
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Wu Y, Song Y, Wang R, Wang T. Molecular mechanisms of tumor resistance to radiotherapy. Mol Cancer 2023; 22:96. [PMID: 37322433 PMCID: PMC10268375 DOI: 10.1186/s12943-023-01801-2] [Citation(s) in RCA: 173] [Impact Index Per Article: 86.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 06/03/2023] [Indexed: 06/17/2023] Open
Abstract
BACKGROUND Cancer is the most prevalent cause of death globally, and radiotherapy is considered the standard of care for most solid tumors, including lung, breast, esophageal, and colorectal cancers and glioblastoma. Resistance to radiation can lead to local treatment failure and even cancer recurrence. MAIN BODY In this review, we have extensively discussed several crucial aspects that cause resistance of cancer to radiation therapy, including radiation-induced DNA damage repair, cell cycle arrest, apoptosis escape, abundance of cancer stem cells, modification of cancer cells and their microenvironment, presence of exosomal and non-coding RNA, metabolic reprogramming, and ferroptosis. We aim to focus on the molecular mechanisms of cancer radiotherapy resistance in relation to these aspects and to discuss possible targets to improve treatment outcomes. CONCLUSIONS Studying the molecular mechanisms responsible for radiotherapy resistance and its interactions with the tumor environment will help improve cancer responses to radiotherapy. Our review provides a foundation to identify and overcome the obstacles to effective radiotherapy.
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Affiliation(s)
- Yu Wu
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, 110042 Liaoning Province China
- School of Graduate, Dalian Medical University, Dalian, 116044 China
| | - Yingqiu Song
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, 110042 Liaoning Province China
| | - Runze Wang
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, 110042 Liaoning Province China
- School of Graduate, Dalian Medical University, Dalian, 116044 China
| | - Tianlu Wang
- Department of Radiotherapy, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Cancer Hospital of Dalian University of Technology, No.44 Xiaoheyan Road, Dadong District, Shenyang, 110042 Liaoning Province China
- Faculty of Medicine, Dalian University of Technology, Dalian, 116024 China
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29
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Tada H, Gonda K, Kitamura N, Ishida T. Clinical Significance of ABCG2/BCRP Quantified by Fluorescent Nanoparticles in Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy. Cancers (Basel) 2023; 15:cancers15082365. [PMID: 37190293 DOI: 10.3390/cancers15082365] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Revised: 04/15/2023] [Accepted: 04/18/2023] [Indexed: 05/17/2023] Open
Abstract
Breast cancer resistance protein (BCRP), also known as ATP-binding cassette transporter G2 (ABCG2), is associated with chemotherapy resistance. BCRP is also implicated in breast cancer stem cells, and is reported as a poor prognostic factor. However, the relationship of BCRP levels in breast cancer tissues with chemotherapy resistance and prognosis has not been clarified. We aimed to evaluate the correlation between BCRP expression and prognosis in breast cancer using immunohistochemistry with fluorescent phosphor-integrated dots (IHC-PIDs). A total of 37 breast cancer patients with residual cancer in the primary tumor and axillary lymph nodes were evaluated. BCRP levels in breast cancer tissue and metastatic lymph nodes were quantitatively detected after neoadjuvant chemotherapy (NAC). Among these 37 patients, 24 had corresponding core needle biopsies obtained before NAC. Biomarker assay with IHC-PIDs showed high accuracy for the quantitative assessment of BCRP with low expression. High BCRP expression in the primary tumor and metastatic lymph nodes after preoperative chemotherapy was associated with worse overall survival. In conclusion, high BCRP levels may be associated with poor prognosis in patients with breast cancer, having residual tumors within the primary tumor and lymph nodes after preoperative chemotherapy. These findings provide a basis for further appropriate adjuvant therapy in these patients.
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Affiliation(s)
- Hiroshi Tada
- Division of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Miyagi, Japan
| | - Kohsuke Gonda
- Department of Medical Physics, Tohoku University Graduate School of Medicine, Sendai 980-8575, Miyagi, Japan
| | - Narufumi Kitamura
- Department of Medical Physics, Tohoku University Graduate School of Medicine, Sendai 980-8575, Miyagi, Japan
| | - Takanori Ishida
- Division of Breast and Endocrine Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Miyagi, Japan
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30
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Gogola S, Rejzer M, Bahmad HF, Alloush F, Omarzai Y, Poppiti R. Anti-Cancer Stem-Cell-Targeted Therapies in Prostate Cancer. Cancers (Basel) 2023; 15:cancers15051621. [PMID: 36900412 PMCID: PMC10000420 DOI: 10.3390/cancers15051621] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 02/21/2023] [Accepted: 03/04/2023] [Indexed: 03/09/2023] Open
Abstract
Prostate cancer (PCa) is the second-most commonly diagnosed cancer in men around the world. It is treated using a risk stratification approach in accordance with the National Comprehensive Cancer Network (NCCN) in the United States. The main treatment options for early PCa include external beam radiation therapy (EBRT), brachytherapy, radical prostatectomy, active surveillance, or a combination approach. In those with advanced disease, androgen deprivation therapy (ADT) is considered as a first-line therapy. However, the majority of cases eventually progress while receiving ADT, leading to castration-resistant prostate cancer (CRPC). The near inevitable progression to CRPC has spurred the recent development of many novel medical treatments using targeted therapies. In this review, we outline the current landscape of stem-cell-targeted therapies for PCa, summarize their mechanisms of action, and discuss avenues of future development.
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Affiliation(s)
- Samantha Gogola
- Department of Translational Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Michael Rejzer
- Department of Translational Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
| | - Hisham F. Bahmad
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
- Correspondence: or ; Tel.: +1-305-674-2277
| | - Ferial Alloush
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
| | - Yumna Omarzai
- Department of Translational Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
| | - Robert Poppiti
- Department of Translational Medicine, Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, USA
- The Arkadi M. Rywlin M.D. Department of Pathology and Laboratory Medicine, Mount Sinai Medical Center, Miami Beach, FL 33140, USA
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Burko P, D’Amico G, Miltykh I, Scalia F, Conway de Macario E, Macario AJL, Giglia G, Cappello F, Caruso Bavisotto C. Molecular Pathways Implicated in Radioresistance of Glioblastoma Multiforme: What Is the Role of Extracellular Vesicles? Int J Mol Sci 2023; 24:ijms24054883. [PMID: 36902314 PMCID: PMC10003080 DOI: 10.3390/ijms24054883] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/16/2023] [Accepted: 02/28/2023] [Indexed: 03/06/2023] Open
Abstract
Glioblastoma multiforme (GBM) is a primary brain tumor that is very aggressive, resistant to treatment, and characterized by a high degree of anaplasia and proliferation. Routine treatment includes ablative surgery, chemotherapy, and radiotherapy. However, GMB rapidly relapses and develops radioresistance. Here, we briefly review the mechanisms underpinning radioresistance and discuss research to stop it and install anti-tumor defenses. Factors that participate in radioresistance are varied and include stem cells, tumor heterogeneity, tumor microenvironment, hypoxia, metabolic reprogramming, the chaperone system, non-coding RNAs, DNA repair, and extracellular vesicles (EVs). We direct our attention toward EVs because they are emerging as promising candidates as diagnostic and prognostication tools and as the basis for developing nanodevices for delivering anti-cancer agents directly into the tumor mass. EVs are relatively easy to obtain and manipulate to endow them with the desired anti-cancer properties and to administer them using minimally invasive procedures. Thus, isolating EVs from a GBM patient, supplying them with the necessary anti-cancer agent and the capability of recognizing a specified tissue-cell target, and reinjecting them into the original donor appears, at this time, as a reachable objective of personalized medicine.
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Affiliation(s)
- Pavel Burko
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
| | - Giuseppa D’Amico
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
| | - Ilia Miltykh
- Department of Human Anatomy, Institute of Medicine, Penza State University, 440026 Penza, Russia
| | - Federica Scalia
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA
| | - Everly Conway de Macario
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
| | - Alberto J. L. Macario
- Department of Microbiology and Immunology, School of Medicine, University of Maryland at Baltimore-Institute of Marine and Environmental Technology (IMET), Baltimore, MD 21202, USA
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
| | - Giuseppe Giglia
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
- Section of Human Physiology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
| | - Francesco Cappello
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
| | - Celeste Caruso Bavisotto
- Section of Human Anatomy, Department of Biomedicine, Neuroscience and Advanced Diagnostics (BIND), University of Palermo, 90133 Palermo, Italy
- Euro-Mediterranean Institute of Science and Technology (IEMEST), 90139 Palermo, Italy
- Correspondence: ; Tel.: +39-0916553501
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Endogenous Extracellular Matrix Regulates the Response of Osteosarcoma 3D Spheroids to Doxorubicin. Cancers (Basel) 2023; 15:cancers15041221. [PMID: 36831562 PMCID: PMC9954237 DOI: 10.3390/cancers15041221] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Revised: 02/07/2023] [Accepted: 02/09/2023] [Indexed: 02/17/2023] Open
Abstract
The extracellular matrix (ECM) modulates cell behavior, shape, and viability as well as mechanical properties. In recent years, ECM disregulation and aberrant remodeling has gained considerable attention in cancer targeting and prevention since it may stimulate tumorigenesis and metastasis. Here, we developed an in vitro model that aims at mimicking the in vivo tumor microenvironment by recapitulating the interactions between osteosarcoma (OS) cells and ECM with respect to cancer progression. We long-term cultured 3D OS spheroids made of metastatic or non-metastatic OS cells mixed with mesenchymal stromal cells (MSCs); confirmed the deposition of ECM proteins such as Type I collagen, Type III collagen, and fibronectin by the stromal component at the interface between tumor cells and MSCs; and found that ECM secretion is inhibited by a neutralizing anti-IL-6 antibody, suggesting a new role of this cytokine in OS ECM deposition. Most importantly, we showed that the cytotoxic effect of doxorubicin is reduced by the presence of Type I collagen. We thus conclude that ECM protein deposition is crucial for modelling and studying drug response. Our results also suggest that targeting ECM proteins might improve the outcome of a subset of chemoresistant tumors.
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Re-Sensitizing Cancer Stem Cells to Conventional Chemotherapy Agents. Int J Mol Sci 2023; 24:ijms24032122. [PMID: 36768445 PMCID: PMC9917165 DOI: 10.3390/ijms24032122] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/26/2022] [Accepted: 01/04/2023] [Indexed: 01/25/2023] Open
Abstract
Cancer stem cells are found in many cancer types. They comprise a distinct subpopulation of cells within the tumor that exhibit properties of stem cells. They express a number of cell surface markers, such as CD133, CD44, ALDH, and EpCAM, as well as embryonic transcription factors Oct4, Nanog, and SOX2. CSCs are more resistant to conventional chemotherapy and can potentially drive tumor relapse. Therefore, it is essential to understand the molecular mechanisms that drive chemoresistance and to target them with specific therapy effectively. Highly conserved developmental signaling pathways such as Wnt, Hedgehog, and Notch are commonly reported to play a role in CSCs chemoresistance development. Studies show that particular pathway inhibitors combined with conventional therapy may re-establish sensitivity to the conventional therapy. Another significant contributor of chemoresistance is a specific tumor microenvironment. Surrounding stroma in the form of cancer-associated fibroblasts, macrophages, endothelial cells, and extracellular matrix components produce cytokines and other factors, thus creating a favorable environment and decreasing the cytotoxic effects of chemotherapy. Anti-stromal agents may potentially help to overcome these effects. Epigenetic changes and autophagy were also among the commonly reported mechanisms of chemoresistance. This review provides an overview of signaling pathway components involved in the development of chemoresistance of CSCs and gathers evidence from experimental studies in which CSCs can be re-sensitized to conventional chemotherapy agents across different cancer types.
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Marcu LG, Moghaddasi L, Bezak E. Cannot Target What Cannot Be Seen: Molecular Imaging of Cancer Stem Cells. Int J Mol Sci 2023; 24:ijms24021524. [PMID: 36675033 PMCID: PMC9864237 DOI: 10.3390/ijms24021524] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 12/29/2022] [Accepted: 01/10/2023] [Indexed: 01/15/2023] Open
Abstract
Cancer stem cells are known to play a key role in tumour development, proliferation, and metastases. Their unique properties confer resistance to therapy, often leading to treatment failure. It is believed that research into the identification, targeting, and eradication of these cells can revolutionise oncological treatment. Based on the principle that what cannot be seen, cannot be targeted, a primary step in cancer management is the identification of these cells. The current review aims to encompass the state-of-the-art functional imaging techniques that enable the identification of cancer stem cells via various pathways and mechanisms. The paper presents in vivo molecular techniques that are currently available or await clinical implementation. Challenges and future prospects are highlighted to open new research avenues in cancer stem cell imaging.
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Affiliation(s)
- Loredana G. Marcu
- Faculty of Informatics and Science, University of Oradea, 1 Universitatii Str., 410087 Oradea, Romania
- Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
- Correspondence:
| | - Leyla Moghaddasi
- Northern Sydney Cancer Centre, Royal North Shore Hospital, St. Leonards, NSW 2065, Australia
- School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
| | - Eva Bezak
- Cancer Research Institute, University of South Australia, Adelaide, SA 5001, Australia
- School of Physical Sciences, University of Adelaide, Adelaide, SA 5005, Australia
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Wang C, Wang Q, Wang H, Li Z, Chen J, Zhang Z, Zeng H, Yu X, Yang X, Yang X, Li Z. Hydroxyethyl starch-folic acid conjugates stabilized theranostic nanoparticles for cancer therapy. J Control Release 2023; 353:391-410. [PMID: 36473606 DOI: 10.1016/j.jconrel.2022.11.059] [Citation(s) in RCA: 42] [Impact Index Per Article: 21.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 11/21/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022]
Abstract
Small molecular prodrug-based nanomedicines with high drug-loading efficiency and tumor selectivity have attracted great attention for cancer therapy against solid tumors, including triple negative breast cancers (TNBC). However, abnormal tumor mechanical microenvironment (TMME) severely restricts antitumor efficacy of prodrug nanomedicines by limiting drug delivery and fostering cancer stem cells (CSCs). Herein, we employed carbamate disulfide bridged doxorubicin dimeric prodrug as pharmaceutical ingredient, marketed IR780 iodide as photothermal agent, and biocompatible hydroxyethyl starch-folic acid conjugates as amphiphilic surfactant to prepare a theranostic nanomedicine (FDINs), which could actively target at TNBC 4T1 tumor tissues and achieve reduction-responsive drug release with high glutathione concentration in cancer cells and CSCs. Importantly, in addition to directly causing damage to cancer cells and sensitizing chemotherapy, FDINs-mediated photothermal effect regulates aberrant TMME via reducing cancer associated fibroblasts and depleting extracellular matrix proteins, thereby normalizing intratumor vessel structure and function to facilitate drug and oxygen delivery. Furthermore, FDINs potently eliminate CSCs by disrupting unique CSCs niche and consuming intracellular GSH in CSCs. As a result, FDINs significantly suppress tumor growth in both subcutaneous and orthotopic 4T1 tumors. This study provides novel insights on rational design of prodrug nanomedicines for superior therapeutic effect against stroma- and CSCs-rich solid malignancies.
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Affiliation(s)
- Chong Wang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Qiang Wang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Huimin Wang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Zheng Li
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Jitang Chen
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Zhijie Zhang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Haowen Zeng
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Ximiao Yu
- Key Laboratory of Biomedical Photonics (HUST), Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Xiaoquan Yang
- Key Laboratory of Biomedical Photonics (HUST), Ministry of Education, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Xiangliang Yang
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan 430074, PR China; GBA Research Innovation Institute for Nanotechnology, Guangdong 510530, PR China; Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China
| | - Zifu Li
- National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China; Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China; Hubei Key Laboratory of Bioinorganic Chemistry and Materia Medical, Huazhong University of Science and Technology, Wuhan 430074, PR China; Hubei Engineering Research Center for Biomaterials and Medical Protective Materials, Huazhong University of Science and Technology, Wuhan 430074, PR China; Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, PR China.
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Correnti M, Binatti E, Gammella E, Invernizzi P, Recalcati S. The Emerging Role of Tumor Microenvironmental Stimuli in Regulating Metabolic Rewiring of Liver Cancer Stem Cells. Cancers (Basel) 2022; 15:5. [PMID: 36612000 PMCID: PMC9817521 DOI: 10.3390/cancers15010005] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2022] [Revised: 12/14/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022] Open
Abstract
Primary liver cancer (PLC) is one of the most devastating cancers worldwide. Extensive phenotypical and functional heterogeneity is a cardinal hallmark of cancer, including PLC, and is related to the cancer stem cell (CSC) concept. CSCs are responsible for tumor growth, progression, relapse and resistance to conventional therapies. Metabolic reprogramming represents an emerging hallmark of cancer. Cancer cells, including CSCs, are very plastic and possess the dynamic ability to constantly shift between different metabolic states depending on various intrinsic and extrinsic stimuli, therefore amplifying the complexity of understanding tumor heterogeneity. Besides the well-known Warburg effect, several other metabolic pathways including lipids and iron metabolism are altered in PLC. An increasing number of studies supports the role of the surrounding tumor microenvironment (TME) in the metabolic control of liver CSCs. In this review, we discuss the complex metabolic rewiring affecting liver cancer cells and, in particular, liver CSCs. Moreover, we highlight the role of TME cellular and noncellular components in regulating liver CSC metabolic plasticity. Deciphering the specific mechanisms regulating liver CSC-TME metabolic interplay could be very helpful with respect to the development of more effective and innovative combinatorial therapies for PLC treatment.
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Affiliation(s)
- Margherita Correnti
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milano, Italy
| | - Eleonora Binatti
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Elena Gammella
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milano, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology, Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milano Bicocca, 20900 Monza, Italy
- European Reference Network on Hepatological Diseases (ERN RARE-LIVER), San Gerardo Hospital, 20900 Monza, Italy
| | - Stefania Recalcati
- Department of Biomedical Sciences for Health, University of Milan, 20133 Milano, Italy
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Raina K, Kandhari K, Jain AK, Ravichandran K, Maroni P, Agarwal C, Agarwal R. Stage-Specific Effect of Inositol Hexaphosphate on Cancer Stem Cell Pool during Growth and Progression of Prostate Tumorigenesis in TRAMP Model. Cancers (Basel) 2022; 14:4204. [PMID: 36077751 PMCID: PMC9455012 DOI: 10.3390/cancers14174204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Revised: 08/23/2022] [Accepted: 08/27/2022] [Indexed: 11/16/2022] Open
Abstract
Herein, we assessed the stage-specific efficacy of inositol hexaphosphate (IP6, phytic acid), a bioactive food component, on prostate cancer (PCa) growth and progression in a transgenic mouse model of prostate cancer (TRAMP). Starting at 4, 12, 20, and 30 weeks of age, male TRAMP mice were fed either regular drinking water or 2% IP6 in water for ~8-15 weeks. Pathological assessments at study endpoint indicated that tumor grade is arrested at earlier stages by IP6 treatment; IP6 also prevented progression to more advanced forms of the disease (~55-70% decrease in moderately and poorly differentiated adenocarcinoma incidence was observed in advanced stage TRAMP cohorts). Next, we determined whether the protective effects of IP6 are mediated via its effect on the expansion of the cancer stem cells (CSCs) pool; results indicated that the anti-PCa effects of IP6 are associated with its potential to eradicate the PCa CSC pool in TRAMP prostate tumors. Furthermore, in vitro assays corroborated the above findings as IP6 decreased the % of floating PC-3 prostaspheres (self-renewal of CSCs) by ~90%. Together, these findings suggest the multifaceted chemopreventive-translational potential of IP6 intervention in suppressing the growth and progression of PCa and controlling this malignancy at an early stage.
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Affiliation(s)
- Komal Raina
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- Department of Pharmaceutical Sciences, South Dakota State University, Brookings, SD 57007, USA
| | - Kushal Kandhari
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Anil K. Jain
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kameswaran Ravichandran
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Paul Maroni
- Department of Surgery, Division of Urology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Chapla Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Rajesh Agarwal
- Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
- University of Colorado Cancer Center, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA
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Peng Z, Hao M, Tong H, Yang H, Huang B, Zhang Z, Luo KQ. The interactions between integrin α 5β 1 of liver cancer cells and fibronectin of fibroblasts promote tumor growth and angiogenesis. Int J Biol Sci 2022; 18:5019-5037. [PMID: 35982891 PMCID: PMC9379399 DOI: 10.7150/ijbs.72367] [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: 02/24/2022] [Accepted: 06/10/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) progression is closely related to pathological fibrosis, which involves heterotypic intercellular interactions (HIIs) between liver cancer cells and fibroblasts. Here, we studied them in a direct coculture model, and identified fibronectin from fibroblasts and integrin-α5β1 from liver cancer cells as the primary responsible molecules utilizing CRISPR/Cas9 gene-editing technology. Coculture led to the formation of 3D multilayer microstructures, and obvious fibronectin remodeling was caused by upregulated integrin-α5β1, which greatly promoted cell growth in 3D microstructures. Integrin-α5 was more sensitive and specific than integrin-β1 in this process. Subsequent mechanistic exploration revealed the activation of integrin-Src-FAK, AKT and ERK signaling pathways. Importantly, the growth-promoting effect of HIIs was verified in a xenograft tumor model, in which more blood vessels were observed in bigger tumors derived from the coculture group than that derived from monocultured groups. Hence, we conducted triculture by introducing human umbilical vein endothelial cells, which aligned to and differentiated along multilayer microstructures in an integrin-α5β1 dependent manner. Furthermore, fibronectin, integrin-α5, and integrin-β1 were upregulated in 52 HCC tumors, and fibronectin was related to microvascular invasion. Our findings identify fibronectin, integrin-α5, and integrin-β1 as tumor microenvironment-related targets and provide a basis for combination targeted therapeutic strategies for future HCC treatment.
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Affiliation(s)
- Zheng Peng
- Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China
| | - Meng Hao
- Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China
| | - Haibo Tong
- Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China
| | - Hongmei Yang
- Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China
| | - Bin Huang
- Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China
| | - Zhigang Zhang
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Kathy Qian Luo
- Faculty of Health Sciences, University of Macau, Taipa, Macao SAR, China.,Ministry of Education-Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macao SAR, China
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Sohn EJ. Differentially expression and function of circular RNAs in ovarian cancer stem cells. J Ovarian Res 2022; 15:97. [PMID: 35978436 PMCID: PMC9382745 DOI: 10.1186/s13048-022-01014-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 06/27/2022] [Indexed: 11/16/2022] Open
Abstract
Background Circular RNAs (circRNAs) are noncoding RNAs that regulate miRNA expression; however, their functions in cancer stem cells (CSCs) are not well known. Methods To determine the function of differentially expression of circRNAs associated with ovarian CSCs, circRNA profiling was conducted using a circRNA-based microarray on sphere-forming cells derived from A2780 and SKOV3 epithelial ovarian cancer cells termed A2780-SP and SKOV3-SP compared to monolayer cells such as A2780 and SKOV3 cells, respectively. Gene Ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed to predict the biological functions of the circRNAs expressed in CSCs. Results The circRNA-based microarray data showed that 159 circRNAs were significantly upregulated (fold change > 1.5) and 55 circRNAs were downregulated in ovarian CSCs compared to monolayer cells. GO and KEGG enrichment analysis of differentially expressed circRNAs in ovarian CSCs showed that they were mainly involved in cell cycle, histone modification, cellular protein metabolic process, cell cycle, apoptotic signaling pathway, and ubiquitin-mediated proteolysis in ovarian cancer. In addition, the hsa-circRNA000963-miRNA-mRNA regulatory network was constructed based on potential target of miRNAs. These analyses involved that the biological function of the hsa-circRNA00096/miRNA/mRNA network was involved in signaling pathways regulating pluripotency of stem cells, PI3K-Akt signaling pathway, cell cycle, p53 signaling pathway, Wnt signaling pathway, calcium modulating pathway, and production of miRNAs involved in gene silencing by miRNA. Conclusions Our data demonstrate the expression profiles of circRNAs in ovarian CSCs and suggest that circRNAs may be potential diagnostic and predictive biomarkers of ovarian cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s13048-022-01014-z.
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Affiliation(s)
- Eun Jung Sohn
- Pusan National University, Yangsan, 50612, Republic of Korea.
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40
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Stem Cells as Target for Prostate cancer Therapy: Opportunities and Challenges. Stem Cell Rev Rep 2022; 18:2833-2851. [PMID: 35951166 DOI: 10.1007/s12015-022-10437-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/24/2022] [Indexed: 10/15/2022]
Abstract
Cancer stem cells (CSCs) and cells in a cancer stem cell-like (CSCL) state have proven to be responsible for tumor initiation, growth, and relapse in Prostate Cancer (PCa) and other cancers; therefore, new strategies are being developed to target such cellular populations. TLR3 activation-based immunotherapy using Polyinosinic:Polycytidylic acid (PIC) has been proposed to be used as a concomitant strategy to first-line treatment. This strategy is based on the induction of apoptosis and an inflammatory response in tumor cells. In combination with retinoids like 9cRA, this treatment can induce CSCs differentiation and apoptosis. A limitation in the use of this combination is the common decreased expression of TLR3 and its main positive regulator p53. observed in many patients suffering of different cancer types such as PCa. Importantly, human exposure to certain toxicants, such as iAs, not only has proven to enrich CSCs population in an in vitro model of human epithelial prostate cells, but additionally, it can also lead to a decreased p53, TLR3 and RA receptor (RARβ), expression/activation and thus hinder this treatment efficacy. Therefore, here we point out the relevance of evaluating the TLR3 and P53 status in PCa patients before starting an immunotherapy based on the use of PIC +9cRA to determine whether they will be responsive to treatment. Additionally, the use of strategies to overcome the lower TLR3, RARβ or p53 expression in PCa patients, like the inclusion of drugs that increase p53 expression, is encouraged, to potentiate the use of PIC+RA based immunotherapy in these patients.
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Park CG, Choi SH, Lee SY, Eun K, Park MG, Jang J, Jeong HJ, Kim SJ, Jeong S, Lee K, Kim H. Cytoplasmic LMO2-LDB1 Complex Activates STAT3 Signaling through Interaction with gp130-JAK in Glioma Stem Cells. Cells 2022; 11:cells11132031. [PMID: 35805116 PMCID: PMC9265747 DOI: 10.3390/cells11132031] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2022] [Revised: 06/19/2022] [Accepted: 06/24/2022] [Indexed: 12/10/2022] Open
Abstract
The oncogenic role of nuclear LIM domain only 2 (LMO2) as a transcriptional regulator is well established, but its function in the cytoplasm is largely unknown. Here, we identified LMO2 as a cytoplasmic activator for signal transducer and activator of transcription 3 (STAT3) signaling in glioma stem cells (GSCs) through biochemical and bioinformatics analyses. LMO2 increases STAT3 phosphorylation by interacting with glycoprotein 130 (gp130) and Janus kinases (JAKs). LMO2-driven activation of STAT3 signaling requires the LDB1 protein and leads to increased expression of an inhibitor of differentiation 1 (ID1), a master regulator of cancer stemness. Our findings indicate that the cytoplasmic LMO2-LDB1 complex plays a crucial role in the activation of the GSC signaling cascade via interaction with gp130 and JAK1/2. Thus, LMO2-LDB1 is a bona fide oncogenic protein complex that activates either the JAK-STAT signaling cascade in the cytoplasm or direct transcriptional regulation in the nucleus.
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Affiliation(s)
- Cheol Gyu Park
- Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea; (C.G.P.); (S.-H.C.); (S.Y.L.); (K.E.); (M.G.P.); (J.J.); (H.J.J.); (S.J.K.); (S.J.); (K.L.)
| | - Sang-Hun Choi
- Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea; (C.G.P.); (S.-H.C.); (S.Y.L.); (K.E.); (M.G.P.); (J.J.); (H.J.J.); (S.J.K.); (S.J.); (K.L.)
| | - Seon Yong Lee
- Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea; (C.G.P.); (S.-H.C.); (S.Y.L.); (K.E.); (M.G.P.); (J.J.); (H.J.J.); (S.J.K.); (S.J.); (K.L.)
| | - Kiyoung Eun
- Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea; (C.G.P.); (S.-H.C.); (S.Y.L.); (K.E.); (M.G.P.); (J.J.); (H.J.J.); (S.J.K.); (S.J.); (K.L.)
- Institute of Animal Molecular Biotechnology, Korea University, Seoul 02841, Korea
| | - Min Gi Park
- Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea; (C.G.P.); (S.-H.C.); (S.Y.L.); (K.E.); (M.G.P.); (J.J.); (H.J.J.); (S.J.K.); (S.J.); (K.L.)
| | - Junseok Jang
- Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea; (C.G.P.); (S.-H.C.); (S.Y.L.); (K.E.); (M.G.P.); (J.J.); (H.J.J.); (S.J.K.); (S.J.); (K.L.)
| | - Hyeon Ju Jeong
- Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea; (C.G.P.); (S.-H.C.); (S.Y.L.); (K.E.); (M.G.P.); (J.J.); (H.J.J.); (S.J.K.); (S.J.); (K.L.)
| | - Seong Jin Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea; (C.G.P.); (S.-H.C.); (S.Y.L.); (K.E.); (M.G.P.); (J.J.); (H.J.J.); (S.J.K.); (S.J.); (K.L.)
| | - Sohee Jeong
- Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea; (C.G.P.); (S.-H.C.); (S.Y.L.); (K.E.); (M.G.P.); (J.J.); (H.J.J.); (S.J.K.); (S.J.); (K.L.)
| | - Kanghun Lee
- Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea; (C.G.P.); (S.-H.C.); (S.Y.L.); (K.E.); (M.G.P.); (J.J.); (H.J.J.); (S.J.K.); (S.J.); (K.L.)
| | - Hyunggee Kim
- Department of Biotechnology, College of Life Science and Biotechnology, Korea University, Seoul 02841, Korea; (C.G.P.); (S.-H.C.); (S.Y.L.); (K.E.); (M.G.P.); (J.J.); (H.J.J.); (S.J.K.); (S.J.); (K.L.)
- Institute of Animal Molecular Biotechnology, Korea University, Seoul 02841, Korea
- Correspondence: ; Tel.: +82-2-3290-3059; Fax: +82-2-3290-3040
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Vasefifar P, Motafakkerazad R, Maleki LA, Najafi S, Ghrobaninezhad F, Najafzadeh B, Alemohammad H, Amini M, Baghbanzadeh A, Baradaran B. Nanog, as a key cancer stem cell marker in tumor progression. Gene X 2022; 827:146448. [PMID: 35337852 DOI: 10.1016/j.gene.2022.146448] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 02/16/2022] [Accepted: 03/18/2022] [Indexed: 12/20/2022] Open
Abstract
Cancer stem cells (CSCs) are a small population of malignant cells that induce tumor onset and development. CSCs share similar features with normal stem cells in the case of self-renewal and differentiation. They also contribute to chemoresistance and metastasis of cancer cells, leading to therapeutic failure. To identify CSCs, multiple cell surface markers have been characterized, including Nanog, which is found at high levels in different cancers. Recent studies have revealed that Nanog upregulation has a substantial association with the advanced stages and poor prognosis of malignancies, playing a pivotal role through tumorigenesis of multiple human cancers, including leukemia, liver, colorectal, prostate, ovarian, lung, head and neck, brain, pancreatic, gastric and breast cancers. Nanog through different signaling pathways, like JAK/STAT and Wnt/β-catenin pathways, induces stemness, self-renewal, metastasis, invasiveness, and chemoresistance of cancer cells. Some of these signaling pathways are common in various types of cancers, but some have been found in one or two cancers. Therefore, this review aimed to focus on the function of Nanog in multiple cancers based on recent studies surveying the suitable approaches to target Nanog and inhibit CSCs residing in tumors to gain favorable results from cancer treatments.
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Affiliation(s)
- Parisa Vasefifar
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | | | - Souzan Najafi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Basira Najafzadeh
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Hajar Alemohammad
- Department of Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
| | - Mohammad Amini
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Baghbanzadeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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43
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Baranovsky A, Ivanov T, Granovskaya M, Papatsenko D, Pervouchine DD. Transcriptome analysis reveals high tumor heterogeneity with respect to re-activation of stemness and proliferation programs. PLoS One 2022; 17:e0268626. [PMID: 35587924 PMCID: PMC9119523 DOI: 10.1371/journal.pone.0268626] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 05/03/2022] [Indexed: 12/01/2022] Open
Abstract
Significant alterations in signaling pathways and transcriptional regulatory programs together represent major hallmarks of many cancers. These, among all, include the reactivation of stemness, which is registered by the expression of pathways that are active in the embryonic stem cells (ESCs). Here, we assembled gene sets that reflect the stemness and proliferation signatures and used them to analyze a large panel of RNA-seq data from The Cancer Genome Atlas (TCGA) Consortium in order to specifically assess the expression of stemness-related and proliferation-related genes across a collection of different tumor types. We introduced a metric that captures the collective similarity of the expression profile of a tumor to that of ESCs, which showed that stemness and proliferation signatures vary greatly between different tumor types. We also observed a high degree of intertumoral heterogeneity in the expression of stemness- and proliferation-related genes, which was associated with increased hazard ratios in a fraction of tumors and mirrored by high intratumoral heterogeneity and a remarkable stemness capacity in metastatic lesions across cancer cells in single cell RNA-seq datasets. Taken together, these results indicate that the expression of stemness signatures is highly heterogeneous and cannot be used as a universal determinant of cancer. This calls into question the universal validity of diagnostic tests that are based on stem cell markers.
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Affiliation(s)
- Artem Baranovsky
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia
- Berlin Institute for Medical Systems Biology, Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Berlin, Germany
| | - Timofei Ivanov
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia
| | | | - Dmitri Papatsenko
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia
| | - Dmitri D. Pervouchine
- Center of Life Sciences, Skolkovo Institute of Science and Technology, Moscow, Russia
- * E-mail:
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44
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Liu Q, Sun W, Zhang H. Roles and new Insights of Macrophages in the Tumor Microenvironment of Thyroid Cancer. Front Pharmacol 2022; 13:875384. [PMID: 35479325 PMCID: PMC9035491 DOI: 10.3389/fphar.2022.875384] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 03/21/2022] [Indexed: 12/17/2022] Open
Abstract
Although most thyroid cancers have a good and predictable prognosis, the anaplastic, medullary, and refractory thyroid cancers still prone to recurrence and metastasis, resulting in poor prognosis. Although a number of newly developed targeted therapies have begun to be indicated for the above types of thyroid cancer in recent years, their ability to improve overall survival remain hindered by low efficacy. As the largest component of immune cells in tumor microenvironment, tumor-associated macrophages play a key role in the invasion and metastasis of thyroid cancer. There is much evidence that the immune system, tumor microenvironment and cancer stem cell interactions may revolutionize traditional therapeutic directions. Tumor-associated macrophages have been extensively studied in a variety of tumors, however, research on the relationship between thyroid cancer and macrophages is still insufficient. In this review, we summarize the functions of tumor-associated macrophages in different types of thyroid cancer, their cytokines or chemokines effect on thyroid cancer and the mechanisms that promote tumor proliferation and migration. In addition, we discuss the mechanisms by which tumor-associated macrophages maintain the stemness of thyroid cancer and potential strategies for targeting tumor-associated macrophages to treat thyroid cancer.
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Affiliation(s)
| | | | - Hao Zhang
- Department of Thyroid Surgery, The First Hospital of China Medical University, Shenyang, China
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45
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Liu K, Gao X, Kang B, Liu Y, Wang D, Wang Y. The Role of Tumor Stem Cell Exosomes in Cancer Invasion and Metastasis. Front Oncol 2022; 12:836548. [PMID: 35350566 PMCID: PMC8958025 DOI: 10.3389/fonc.2022.836548] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 02/07/2022] [Indexed: 12/12/2022] Open
Abstract
Exosomes are lipid membrane bilayer-encapsulated vesicles secreted by cells into the extracellular space. They carry abundant inclusions (such as nucleic acids, proteins, and lipids) that play pivotal roles in intercellular communication. Tumor stem cells are capable of self-renewal and are crucial for survival, proliferation, drug resistance, metastasis, and recurrence of tumors. The miRNAs (microRNAs) in exosomes have various functions, such as participating in inflammatory response, cell migration, proliferation, apoptosis, autophagy, and epithelial-mesenchymal transition. Tumor stem cells secrete exosomes that act as important messengers involved in various tumor processes and several studies provide increasing evidence supporting the importance of these exosomes in tumor recurrence and metastasis. This review primarily focuses on the production and secretion of exosomes from tumors and tumor stem cells and their effects on cancer progression. Cancer stem cancer derived exosome play an important massager in the tumor microenvironment. It also emphasizes on the study of tumor stem cell exosomes in the light of cancer metastasis and recurrence aiming to provide valuable insights and novel perspectives, which could be beneficial for developing effective diagnostic and treatment strategies.
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Affiliation(s)
- Kun Liu
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, ChangChun, China
| | - Xin Gao
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, ChangChun, China
| | - Baoqiang Kang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, ChangChun, China
| | - Yunpeng Liu
- Department of Thoracic Surgery, The First Hospital of Jilin University, Changchun, China
| | - Dingding Wang
- School of Biosciences and Biopharmaceutics, Guangdong Pharmaceutical University, Guangzhou, China
| | - Yi Wang
- Department of Regenerative Medicine, School of Pharmaceutical Sciences, Jilin University, ChangChun, China
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46
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Chen CN, Wang JC, Chen YT, Yang TL. Exploration of the niche effect on tumor satellite budding of head and neck cancer with biomimicking modeling. Biomaterials 2022; 285:121471. [PMID: 35490561 DOI: 10.1016/j.biomaterials.2022.121471] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 03/09/2022] [Accepted: 03/12/2022] [Indexed: 11/24/2022]
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47
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Ponomarev A, Gilazieva Z, Solovyeva V, Allegrucci C, Rizvanov A. Intrinsic and Extrinsic Factors Impacting Cancer Stemness and Tumor Progression. Cancers (Basel) 2022; 14:970. [PMID: 35205716 PMCID: PMC8869813 DOI: 10.3390/cancers14040970] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2021] [Revised: 02/03/2022] [Accepted: 02/08/2022] [Indexed: 02/06/2023] Open
Abstract
Tumor heterogeneity represents an important limitation to the development of effective cancer therapies. The presence of cancer stem cells (CSCs) and their differentiation hierarchies contribute to cancer complexity and confer tumors the ability to grow, resist treatment, survive unfavorable conditions, and invade neighboring and distant tissues. A large body of research is currently focusing on understanding the properties of CSCs, including their cellular and molecular origin, as well as their biological behavior in different tumor types. In turn, this knowledge informs strategies for targeting these tumor initiating cells and related cancer stemness. Cancer stemness is modulated by the tumor microenvironment, which influences CSC function and survival. Several advanced in vitro models are currently being developed to study cancer stemness in order to advance new knowledge of the key molecular pathways involved in CSC self-renewal and dormancy, as well as to mimic the complexity of patients' tumors in pre-clinical drug testing. In this review, we discuss CSCs and the modulation of cancer stemness by the tumor microenvironment, stemness factors and signaling pathways. In addition, we introduce current models that allow the study of CSCs for the development of new targeted therapies.
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Affiliation(s)
- Alexey Ponomarev
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Zarema Gilazieva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Valeriya Solovyeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
| | - Cinzia Allegrucci
- School of Veterinary Medicine and Science (SVMS) and Biodiscovery Institute, University of Nottingham, Nottingham NG7 2RD, UK;
| | - Albert Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, 420008 Kazan, Russia; (A.P.); (Z.G.); (V.S.)
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48
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Heft Neal ME, Brenner JC, Prince MEP, Chinn SB. Advancement in Cancer Stem Cell Biology and Precision Medicine-Review Article Head and Neck Cancer Stem Cell Plasticity and the Tumor Microenvironment. Front Cell Dev Biol 2022; 9:660210. [PMID: 35047489 PMCID: PMC8762309 DOI: 10.3389/fcell.2021.660210] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 12/01/2021] [Indexed: 12/16/2022] Open
Abstract
Head and Neck cancer survival has continued to remain around 50% despite treatment advances. It is thought that cancer stem cells play a key role in promoting tumor heterogeneity, treatment resistance, metastasis, and recurrence in solid malignancies including head and neck cancer. Initial studies identified cancer stem cell markers including CD44 and ALDH in head and neck malignancies and found that these cells show aggressive features in both in vitro and in vivo studies. Recent evidence has now revealed a key role of the tumor microenvironment in maintaining a cancer stem cell niche and promoting cancer stem cell plasticity. There is an increasing focus on identifying and targeting the crosstalk between cancer stem cells and surrounding cells within the tumor microenvironment (TME) as new therapeutic potential, however understanding how CSC maintain a stem-like state is critical to understanding how to therapeutically alter their function. Here we review the current evidence for cancer stem cell plasticity and discuss how interactions with the TME promote the cancer stem cell niche, increase tumor heterogeneity, and play a role in treatment resistance.
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Affiliation(s)
- Molly E Heft Neal
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States
| | - J Chad Brenner
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
| | - Mark E P Prince
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States
| | - Steven B Chinn
- Department of Otolaryngology-Head and Neck Surgery, University of Michigan, Ann Arbor, MI, United States.,Rogel Cancer Center, University of Michigan, Ann Arbor, MI, United States
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49
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Yang Y, Meng WJ, Wang ZQ. Cancer Stem Cells and the Tumor Microenvironment in Gastric Cancer. Front Oncol 2022; 11:803974. [PMID: 35047411 PMCID: PMC8761735 DOI: 10.3389/fonc.2021.803974] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/08/2021] [Indexed: 02/05/2023] Open
Abstract
Gastric cancer (GC) remains one of the leading causes of cancer-related death worldwide. Cancer stem cells (CSCs) might be responsible for tumor initiation, relapse, metastasis and treatment resistance of GC. The tumor microenvironment (TME) comprises tumor cells, immune cells, stromal cells and other extracellular components, which plays a pivotal role in tumor progression and therapy resistance. The properties of CSCs are regulated by cells and extracellular matrix components of the TME in some unique manners. This review will summarize current literature regarding the effects of CSCs and TME on the progression and therapy resistance of GC, while emphasizing the potential for developing successful anti-tumor therapy based on targeting the TME and CSCs.
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Affiliation(s)
| | - Wen-Jian Meng
- Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China
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50
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Danila DC. Liquid biopsy as a cancer biomarker-potential, and challenges. Cancer Biomark 2022. [DOI: 10.1016/b978-0-12-824302-2.00013-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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