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Gao F, Liu S, Sun Y, Yu C, Zheng L, Sun L, Wang G, Sun Y, Bao Y, Song Z, Yang X, Ke C. Testes-specific protease 50 heightens stem-like properties and improves mitochondrial function in colorectal cancer. Life Sci 2025; 370:123560. [PMID: 40086746 DOI: 10.1016/j.lfs.2025.123560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2024] [Revised: 02/26/2025] [Accepted: 03/09/2025] [Indexed: 03/16/2025]
Abstract
AIMS The progression of colorectal cancer (CRC) is driven by a small subset of cancer stem-like cells (CSCs), and mitochondrial function is essential for maintaining their stemness. TSP50, a novel identified oncogene, has been found to promote cell proliferation in multiple cancer types. In this study, we detected the regulatory role of TSP50 in regulating CSC-like properties and mitochondrial mass in CRC. MATERIALS AND METHODS First, TSP50 expression and clinical relevance were analyzed via clinical databases and immunohistochemical (IHC). Subsequently, bioinformatic analyses, CRC cell lines, tumorsphere cultures, and mouse xenograft models were utilized to evaluate the relationship between TSP50 and CSC-like properties as well as mitochondrial mass. Finally, immunofluorescence, immunoprecipitation, and Western blotting were performed to dissect the regulatory mechanisms of TSP50, followed by rescue experiments conducted both in vitro and in vivo. KEY FINDINGS TSP50 was overexpressed in CRC tissues, correlating with poor drug response and shorter overall survival (OS). Meanwhile, TSP50 was shown to enhance CSC-like properties in both CRC cells and mouse xenograft models, while concurrently increasing mitochondrial mass and reducing ROS levels, these effects were partially reversed by inhibition of the PI3K/AKT pathway. Mechanistic investigations revealed that TSP50-induced activation of PI3K/AKT signaling is primarily mediated by the enhanced catalytic activity of PI3K p110α subunit. SIGNIFICANCE Collectively, TSP50 drives CRC malignancy by promoting CSC-like properties and enhancing mitochondrial function through PI3K/AKT signaling. These findings identify TSP50 as a potential therapeutic target for eliminating CSC-like cells and improving clinical outcomes in CRC treatment.
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Affiliation(s)
- Feng Gao
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China; China International Joint Research Center for Human Stem Cell Bank, Northeast Normal University, Changchun, Jilin 130024, China
| | - Sichen Liu
- Division of Thyroid Surgery, China-Japan Union Hospital of Jilin University, Jilin Provincial Key Laboratory of Surgical Translational Medicine, Jilin Provincial Engineering Laboratory for Thyroid Disease Control, Jilin, Changchun 130033, China; Department of Neurosurgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, China
| | - Yue Sun
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China
| | - Chunlei Yu
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China
| | - Lihua Zheng
- China International Joint Research Center for Human Stem Cell Bank, Northeast Normal University, Changchun, Jilin 130024, China
| | - Luguo Sun
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China
| | - Guannan Wang
- China International Joint Research Center for Human Stem Cell Bank, Northeast Normal University, Changchun, Jilin 130024, China
| | - Ying Sun
- China International Joint Research Center for Human Stem Cell Bank, Northeast Normal University, Changchun, Jilin 130024, China
| | - Yongli Bao
- China International Joint Research Center for Human Stem Cell Bank, Northeast Normal University, Changchun, Jilin 130024, China
| | - Zhenbo Song
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China
| | - Xiaoguang Yang
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China.
| | - Chao Ke
- Department of Neurosurgery, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, China.
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Rice CPJ, Chelakkot VS, Conohan NT, Hirasawa K. Cancer stem cell populations are resistant to 5-aminolevulinic acid-photodynamic therapy (5-ALA-PDT). Sci Rep 2025; 15:4367. [PMID: 39910203 PMCID: PMC11799205 DOI: 10.1038/s41598-025-88173-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 01/24/2025] [Indexed: 02/07/2025] Open
Abstract
Photodynamic therapy (PDT) is a minimally invasive treatment approved for many types of cancers. PDT involves the administration of photoactive substances called photosensitizers (PS) that selectively accumulate in cancer cells and are subsequently excited/activated by irradiation with light at wavelengths of optimal absorbance. Activated PS leads to the generation of singlet oxygen and other reactive oxygen species (ROS), promoting cancer cell death. 5-aminolevulinic acid (5-ALA) is a naturally occurring PS precursor, which is metabolically converted to the PS, protoporphyrin IX (PPIX). Although 5-ALA-PDT is effective at killing cancer cells, in prior studies conducted by our group we normally observed in in vitro experiments that approximately 5-10% of cells survive 5-ALA-PDT, which served as an impetus for further investigation. Identifying the mechanisms of resistance to 5-ALA-PDT-mediated cell death is important to prevent tumor recurrence following 5-ALA-PDT. Previously, we reported that oncogenic activation of Ras/MEK promotes PPIX efflux and reduces cellular sensitivity to 5-ALA-PDT through increased expression of ABCB1 transporter. As cancer stem cells (CSCs) are known to drive resistance to other cancer treatments and have high efflux of chemotherapeutic agents via ABC-family transporters, we hypothesize that CSCs underlie 5-ALA-PDT resistance. In this study, we determined (1) if CSCs are resistant to 5-ALA-PDT and (2) if CSCs play roles in establishing resistant populations of 5-ALA-PDT. When we compared CSC populations before and after 5-ALA-PDT, we found that CSCs were less susceptible to 5-ALA-PDT. Moreover, we found that the CSC population was enriched in 5-ALA-PDT-resistant cell lines compared to the parental cell line. Our results indicate that CSCs are not sensitive to 5-ALA-PDT, which may contribute to establishment of 5-ALA-PDT resistance.
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Affiliation(s)
- Chantel P J Rice
- Division of BioMedical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Vipin Shankar Chelakkot
- Division of BioMedical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Noah T Conohan
- Division of BioMedical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
| | - Kensuke Hirasawa
- Division of BioMedical Sciences, Memorial University of Newfoundland, St. John's, Newfoundland, Canada.
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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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4
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Wang X, Zhong F, Chen T, Wang H, Wang W, Jin H, Li C, Guo X, Liu Y, Zhang Y, Li B. Cholesterol neutralized vemurafenib treatment by promoting melanoma stem-like cells via its metabolite 27-hydroxycholesterol. Cell Mol Life Sci 2024; 81:226. [PMID: 38775844 PMCID: PMC11111659 DOI: 10.1007/s00018-024-05267-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2023] [Revised: 04/14/2024] [Accepted: 05/05/2024] [Indexed: 05/25/2024]
Abstract
Vemurafenib has been used as first-line therapy for unresectable or metastatic melanoma with BRAFV600E mutation. However, overall survival is still limited due to treatment resistance after about one year. Therefore, identifying new therapeutic targets for melanoma is crucial for improving clinical outcomes. In the present study, we found that lowering intracellular cholesterol by knocking down DHCR24, the limiting synthetase, impaired tumor cell proliferation and migration and abrogated the ability to xenotransplant tumors. More importantly, administration of DHCR24 or cholesterol mediated resistance to vemurafenib and promoted the growth of melanoma spheroids. Mechanistically, we identified that 27-hydroxycholesterol (27HC), a primary metabolite of cholesterol synthesized by the enzyme cytochrome P450 27A1 (CYP27A1), reproduces the phenotypes induced by DHCR24 or cholesterol administration and activates Rap1-PI3K/AKT signaling. Accordingly, CYP27A1 is highly expressed in melanoma patients and upregulated by DHCR24 induction. Dafadine-A, a CYP27A1 inhibitor, attenuates cholesterol-induced growth of melanoma spheroids and abrogates the resistance property of vemurafenib-resistant melanoma cells. Finally, we confirmed that the effects of cholesterol on melanoma resistance require its metabolite 27HC through CYP27A1 catalysis, and that 27HC further upregulates Rap1A/Rap1B expression and increases AKT phosphorylation. Thus, our results suggest that targeting 27HC may be a useful strategy to overcome treatment resistance in metastatic melanoma.
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Affiliation(s)
- Xiaohong Wang
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Feiliang Zhong
- Key Laboratory of Industrial Fermentation Microbiology of the Ministry of Education, College of Biotechnology, Tianjin University of Science and Technology, Tianjin, 300457, People's Republic of China
| | - Tingting Chen
- School of Basic Medicine, Guangdong Medical University, Dongguan, 523808, Guangdong, China
| | - Hongbo Wang
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Weifang Wang
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Hongkai Jin
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Chouyang Li
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Xuan Guo
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Ying Liu
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China
| | - Yu Zhang
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
| | - Bo Li
- Liaoning Technology and Engineering Center for Tumor Immunology and Molecular Theranotics, Collaborative Innovation Center for Age-Related Disease, Life Science Institute of Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
- College of Basic Medical Science, Jinzhou Medical University, Jinzhou, 121001, Liaoning, China.
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Cao J, Zhang Z, Zhou L, Luo M, Li L, Li B, Nice EC, He W, Zheng S, Huang C. Oncofetal reprogramming in tumor development and progression: novel insights into cancer therapy. MedComm (Beijing) 2023; 4:e427. [PMID: 38045829 PMCID: PMC10693315 DOI: 10.1002/mco2.427] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Revised: 10/20/2023] [Accepted: 10/23/2023] [Indexed: 12/05/2023] Open
Abstract
Emerging evidence indicates that cancer cells can mimic characteristics of embryonic development, promoting their development and progression. Cancer cells share features with embryonic development, characterized by robust proliferation and differentiation regulated by signaling pathways such as Wnt, Notch, hedgehog, and Hippo signaling. In certain phase, these cells also mimic embryonic diapause and fertilized egg implantation to evade treatments or immune elimination and promote metastasis. Additionally, the upregulation of ATP-binding cassette (ABC) transporters, including multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 1 (MRP1), and breast cancer-resistant protein (BCRP), in drug-resistant cancer cells, analogous to their role in placental development, may facilitate chemotherapy efflux, further resulting in treatment resistance. In this review, we concentrate on the underlying mechanisms that contribute to tumor development and progression from the perspective of embryonic development, encompassing the dysregulation of developmental signaling pathways, the emergence of dormant cancer cells, immune microenvironment remodeling, and the hyperactivation of ABC transporters. Furthermore, we synthesize and emphasize the connections between cancer hallmarks and embryonic development, offering novel insights for the development of innovative cancer treatment strategies.
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Affiliation(s)
- Jiangjun Cao
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Zhe Zhang
- Zhejiang Provincial Key Laboratory of Pancreatic Diseasethe First Affiliated HospitalSchool of MedicineZhejiang UniversityZhejiangChina
| | - Li Zhou
- Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education)Department of Infectious Diseasesthe Second Affiliated HospitalInstitute for Viral Hepatitis, Chongqing Medical UniversityChongqingChina
| | - Maochao Luo
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Lei Li
- Department of anorectal surgeryHospital of Chengdu University of Traditional Chinese Medicine and Chengdu University of Traditional Chinese MedicineChengduChina
| | - Bowen Li
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
| | - Edouard C. Nice
- Department of Biochemistry and Molecular BiologyMonash UniversityClaytonVICAustralia
| | - Weifeng He
- State Key Laboratory of TraumaBurn and Combined InjuryInstitute of Burn Research, Southwest Hospital, Third Military Medical University (Army Medical University)ChongqingChina
| | - Shaojiang Zheng
- Hainan Cancer Medical Center of The First Affiliated Hospital, the Hainan Branch of National Clinical Research Center for Cancer, Hainan Engineering Research Center for Biological Sample Resources of Major DiseasesHainan Medical UniversityHaikouChina
- Key Laboratory of Tropical Cardiovascular Diseases Research of Hainan Province, Hainan Women and Children's Medical Center, Key Laboratory of Emergency and Trauma of Ministry of EducationHainan Medical UniversityHaikouChina
| | - Canhua Huang
- West China School of Basic Medical Sciences and Forensic Medicine, and Department of Biotherapy Cancer Center and State Key Laboratory of Biotherapy, West China HospitalSichuan UniversityChengduChina
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6
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Jiang L, Li L, Liu Y, Zhan M, Lu L, Yuan S, Liu Y. Drug resistance mechanism of kinase inhibitors in the treatment of hepatocellular carcinoma. Front Pharmacol 2023; 14:1097277. [PMID: 36891274 PMCID: PMC9987615 DOI: 10.3389/fphar.2023.1097277] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Accepted: 02/01/2023] [Indexed: 02/16/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer, and it usually occurs following chronic liver disease. Although some progress has been made in the treatment of HCC, the prognosis of patients with advanced HCC is not optimistic, mainly because of the inevitable development of drug resistance. Therefore, multi-target kinase inhibitors for the treatment of HCC, such as sorafenib, lenvatinib, cabozantinib, and regorafenib, produce small clinical benefits for patients with HCC. It is necessary to study the mechanism of kinase inhibitor resistance and explore possible solutions to overcome this resistance to improve clinical benefits. In this study, we reviewed the mechanisms of resistance to multi-target kinase inhibitors in HCC and discussed strategies that can be used to improve treatment outcomes.
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Affiliation(s)
- Lei Jiang
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital AffiliatedWith Jinan University), Zhuhai, Guangdong, China
| | - Luan Li
- Jiangsu Cancer Hospital, Jiangsu Institute of Cancer Research, The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
| | - Yongzhuang Liu
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Liaoning Province, China
| | - Meixiao Zhan
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital AffiliatedWith Jinan University), Zhuhai, Guangdong, China
| | - Ligong Lu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital AffiliatedWith Jinan University), Zhuhai, Guangdong, China
| | - Shengtao Yuan
- Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing, Liaoning Province, China
| | - Yanyan Liu
- Guangdong Provincial Key Laboratory of Tumor Interventional Diagnosis and Treatment, Zhuhai People’s Hospital (Zhuhai Hospital AffiliatedWith Jinan University), Zhuhai, Guangdong, China
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7
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Sabu A, Liu TI, Ng SS, Doong RA, Huang YF, Chiu HC. Nanomedicines Targeting Glioma Stem Cells. ACS APPLIED MATERIALS & INTERFACES 2023; 15:158-181. [PMID: 35544684 DOI: 10.1021/acsami.2c03538] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/15/2023]
Abstract
Glioblastoma (GBM), classified as a grade IV glioma, is a rapidly growing, aggressive, and most commonly occurring tumor of the central nervous system. Despite the therapeutic advances, it carries an ominous prognosis, with a median survival of 14.6 months after diagnosis. Accumulating evidence suggests that cancer stem cells in GBM, termed glioma stem cells (GSCs), play a crucial role in tumor propagation, treatment resistance, and tumor recurrence. GSCs, possessing the capacity for self-renewal and multilineage differentiation, are responsible for tumor growth and heterogeneity, leading to primary obstacles to current cancer therapy. In this respect, increasing efforts have been devoted to the development of anti-GSC strategies based on targeting GSC surface markers, blockage of essential signaling pathways of GSCs, and manipulating the tumor microenvironment (GSC niches). In this review, we will discuss the research knowledge regarding GSC-based therapy and the underlying mechanisms for the treatment of GBM. Given the rapid progression in nanotechnology, innovative nanomedicines developed for GSC targeting will also be highlighted from the perspective of rationale, advantages, and limitations. The goal of this review is to provide broader understanding and key considerations toward the future direction of GSC-based nanotheranostics to fight against GBM.
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Affiliation(s)
- Arjun Sabu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Te-I Liu
- Institute of Atomic and Molecular Sciences, Academia Sinica, Taipei 10617, Taiwan
| | - Siew Suan Ng
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
- Institute of Analytical and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Ruey-An Doong
- Institute of Analytical and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
| | - Yu-Fen Huang
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
- Institute of Analytical and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
| | - Hsin-Cheng Chiu
- Department of Biomedical Engineering and Environmental Sciences, National Tsing Hua University, Hsinchu 30013, Taiwan
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8
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Rajput S, Sharma PK, Malviya R. Biomarkers and Treatment Strategies for Breast Cancer Recurrence. Curr Drug Targets 2023; 24:1209-1220. [PMID: 38164731 DOI: 10.2174/0113894501258059231103072025] [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: 04/15/2023] [Revised: 07/14/2023] [Accepted: 10/03/2023] [Indexed: 01/03/2024]
Abstract
Despite recent treatment advancements, breast cancer remains a life-threatening disease. Although treatment is successful in the early stages, a significant proportion of individuals with breast cancer eventually experience a recurrence of the disease. Breast tumour recurrence poses a significant medical issue. Despite tumours being a primary cause of mortality, there remains a limited understanding of the fundamental mechanisms underlying tumour recurrence. The majority of the time, after surgery or medical treatment, this metastatic disease manifests itself after the disease is undiagnosed for a considerable amount of time. This phenomenon is commonly referred to as a relapse or recurrence. Metastatic breast cancer has the potential to recur at varying intervals, ranging from a few months to several decades following the initial diagnosis and treatment. This article aimed to summarise the primary causes of breast cancer recurrence and highlight the key issues that need to be addressed in order to effectively decrease the mortality rate among breast cancer patients. This article discusses various therapeutic approaches currently employed and emerging treatment strategies that hold the potential for the complete cure of cancer.
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Affiliation(s)
- Shivam Rajput
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Pramod Kumar Sharma
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
| | - Rishabha Malviya
- Department of Pharmacy, School of Medical and Allied Sciences, Galgotias University, Greater Noida, Uttar Pradesh, India
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Adil M, Kanwal S, Rasheed S, Iqbal M, Abbas G. Cancer Chemoresistance; Recent Challenges and Future Considerations. Cancer Treat Res 2023; 185:237-253. [PMID: 37306912 DOI: 10.1007/978-3-031-27156-4_12] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Cancer remains one of the serious health hazards and major causes of human mortality across the world. Despite the development of many typical antineoplastic drugs and introduction of novel targeted agents, chemoresistance constitutes a major challenge in the effective therapeutic management of cancer. Drug inactivation, efflux of anticancer agents, modification of target sites, enhanced repair of DNA damage, apoptosis failure and induction of epithelial-mesenchymal transition are the principal mechanisms of cancer chemoresistance. Moreover, epigenetics, cell signaling, tumor heterogeneity, stem cells, microRNAs, endoplasmic reticulum, tumor microenvironment and exosomes have also been implicated in the multifaceted phenomenon of anticancer drug resistance. The tendency of resistance is either intrinsically possessed or subsequently acquired by cancerous cells. From clinical oncology standpoint, therapeutic failure and tumor progression are the most probable consequences of cancer chemoresistance. Combination therapy can help to overcome the issue of drug resistance, and therefore, the development of such treatment regimens is recommended for counteracting the emergence and dissemination of cancer chemoresistance. This chapter outlines the current knowledge on underlying mechanisms, contributory biological factors and likely consequences of cancer chemoresistance. Besides, prognostic biomarkers, diagnostic methods and potential approaches to overcome the emergence of antineoplastic drug resistance have also been described.
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Affiliation(s)
- Muhammad Adil
- Pharmacology and Toxicology Section, University of Veterinary and Animal Sciences, Lahore, Jhang Campus, Jhang, 35200, Pakistan.
| | - Shamsa Kanwal
- Microbiology Section, University of Veterinary and Animal Sciences, Lahore, Jhang Campus, Jhang, 35200, Pakistan
| | - Sarmad Rasheed
- Microbiology Section, University of Veterinary and Animal Sciences, Lahore, Jhang Campus, Jhang, 35200, Pakistan
| | - Mavara Iqbal
- Microbiology Section, University of Veterinary and Animal Sciences, Lahore, Jhang Campus, Jhang, 35200, Pakistan
| | - Ghazanfar Abbas
- Microbiology Section, University of Veterinary and Animal Sciences, Lahore, Jhang Campus, Jhang, 35200, Pakistan
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Akbari ME, Ghelichi-Ghojogh M, Nikeghbalian Z, Karami M, Akbari A, Hashemi M, Nooraei S, Ghiasi M, Fararouei M, Moradian F. Neoadjuvant VS adjuvant chemotherapy in patients with locally advanced breast cancer; a retrospective cohort study. Ann Med Surg (Lond) 2022; 84:104921. [PMID: 36536751 PMCID: PMC9758373 DOI: 10.1016/j.amsu.2022.104921] [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: 08/21/2022] [Revised: 11/07/2022] [Accepted: 11/13/2022] [Indexed: 11/17/2022] Open
Abstract
Background Breast cancer is one of the most common challenges for women's health. Until now, neoadjuvant chemotherapy is a standard approach in locally advanced breast cancer (LABC), as it increases the probability of breast-conserving surgery (BCS). This study aimed to compare the survival rate in neoadjuvant and adjuvant groups to suggest a better treatment strategy for locally advanced breast cancer. Methods The study was conducted between 2009 and 2019 on 845 LABC patients at the Cancer Research Center of Shahid Beheshti University of Medical Sciences in Iran. All patients with LABC at stages 3A, 3B, and two were evaluated for treatment with adjuvants (n = 520 female patients) and neoadjuvant (n = 320 female patients) treatment strategies. Patients were followed up for at least 120 months. The Kaplan-Meier method calculated the survival rate using SPSS version 23 software. Result The 5 and 10 years survival rates of neoadjuvant and adjuvant groups were 87 ± 0.04, 80 ± 0.07% and 87 ± 0.02, 83 ± 0.03%, respectively. Statistical analysis results with the mentioned treatment strategies did not show any significant difference in overall survival. Conclusion The result of this study on LABC patients demonstrated that compared to surgery first following adjuvant chemotherapy, the neoadjuvant chemotherapy has several benefits, including downstaging and more BCS, with no statistically significant difference in the overall survival rate of the patients.
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Affiliation(s)
| | - Mousa Ghelichi-Ghojogh
- Metabolic Disorders Research Center, Golestan University of Medical Science, Gorgan, Iran
| | - Zahra Nikeghbalian
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Karami
- School of Nursing & Midwifery, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Atieh Akbari
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mehrdad Hashemi
- Department of Genetics, Faculty of Advanced Science and Technology, Islamic Azad University, Tehran Medical Sciences, Tehran, Iran
| | - Saghi Nooraei
- National Institute for Genetic Engineering and Biotechnology, Tehran, Iran
| | - Mohsen Ghiasi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Fararouei
- HIV/ADIS Research Center, Shiraz University of Medical Science, Shiraz, Iran
| | - Farid Moradian
- Department of General Surgery, Alborz University of Medical Science, Alborz, Iran
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11
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Cancer stem cell markers interplay with chemoresistance in triple negative breast cancer: A therapeutic perspective. Bull Cancer 2022; 109:960-971. [DOI: 10.1016/j.bulcan.2022.05.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 04/18/2022] [Accepted: 05/03/2022] [Indexed: 11/19/2022]
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12
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Saha T, Lukong KE. Breast Cancer Stem-Like Cells in Drug Resistance: A Review of Mechanisms and Novel Therapeutic Strategies to Overcome Drug Resistance. Front Oncol 2022; 12:856974. [PMID: 35392236 PMCID: PMC8979779 DOI: 10.3389/fonc.2022.856974] [Citation(s) in RCA: 71] [Impact Index Per Article: 23.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 02/21/2022] [Indexed: 12/12/2022] Open
Abstract
Breast cancer is the most frequent type of malignancy in women worldwide, and drug resistance to the available systemic therapies remains a major challenge. At the molecular level, breast cancer is heterogeneous, where the cancer-initiating stem-like cells (bCSCs) comprise a small yet distinct population of cells within the tumor microenvironment (TME) that can differentiate into cells of multiple lineages, displaying varying degrees of cellular differentiation, enhanced metastatic potential, invasiveness, and resistance to radio- and chemotherapy. Based on the expression of estrogen and progesterone hormone receptors, expression of human epidermal growth factor receptor 2 (HER2), and/or BRCA mutations, the breast cancer molecular subtypes are identified as TNBC, HER2 enriched, luminal A, and luminal B. Management of breast cancer primarily involves resection of the tumor, followed by radiotherapy, and systemic therapies including endocrine therapies for hormone-responsive breast cancers; HER2-targeted therapy for HER2-enriched breast cancers; chemotherapy and poly (ADP-ribose) polymerase inhibitors for TNBC, and the recent development of immunotherapy. However, the complex crosstalk between the malignant cells and stromal cells in the breast TME, rewiring of the many different signaling networks, and bCSC-mediated processes, all contribute to overall drug resistance in breast cancer. However, strategically targeting bCSCs to reverse chemoresistance and increase drug sensitivity is an underexplored stream in breast cancer research. The recent identification of dysregulated miRNAs/ncRNAs/mRNAs signatures in bCSCs and their crosstalk with many cellular signaling pathways has uncovered promising molecular leads to be used as potential therapeutic targets in drug-resistant situations. Moreover, therapies that can induce alternate forms of regulated cell death including ferroptosis, pyroptosis, and immunotherapy; drugs targeting bCSC metabolism; and nanoparticle therapy are the upcoming approaches to target the bCSCs overcome drug resistance. Thus, individualizing treatment strategies will eliminate the minimal residual disease, resulting in better pathological and complete response in drug-resistant scenarios. This review summarizes basic understanding of breast cancer subtypes, concept of bCSCs, molecular basis of drug resistance, dysregulated miRNAs/ncRNAs patterns in bCSCs, and future perspective of developing anticancer therapeutics to address breast cancer drug resistance.
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Affiliation(s)
- Taniya Saha
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
| | - Kiven Erique Lukong
- Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada
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13
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Comparison of Colorectal Cancer Stem Cells and Oxaliplatin-Resistant Cells Unveils Functional Similarities. Cells 2022; 11:cells11030511. [PMID: 35159320 PMCID: PMC8833894 DOI: 10.3390/cells11030511] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 01/27/2022] [Accepted: 01/29/2022] [Indexed: 02/01/2023] Open
Abstract
Colorectal cancer is the second most common cancer in women, the third in men, and an important cause of cancer-related mortality. Recurrence and the development of chemotherapy resistance are major hindrances for patients’ treatment. The presence of cancer stem cells with chemotherapy resistance able to generate proliferating tumor cells contributes to tumor recurrence and resistance. In addition, tumor cells can develop chemoresistance through adaptation mechanisms. In this article, cancer stem cells were isolated from HT29 and SW620 colorectal cancer cell lines. Oxaliplatin resistance was induced by a single drug treatment simulating the usual guidelines of patient treatment. A comparison of these two populations showed similarities since cancer stem cells presented increased oxaliplatin resistance, and resistant cells contained an increased number of cancer stem cells. Cancer stem cells isolated from resistant cells showed increased oxaliplatin resistance. Cell invasion capacity and epithelial-mesenchymal transition were increased both in cancer stem cells and oxaliplatin-resistant cells. mRNA expression analysis showed that both cell types shared a significant proportion of commonly regulated genes. In summary, the data presented indicate that colorectal cancer stem cells and oxaliplatin-resistant cells are highly related cell populations that might have interesting implications in the development of tumor recurrence and resistance to chemotherapy.
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14
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Cortes-Dericks L, Galetta D. Impact of Cancer Stem Cells and Cancer Stem Cell-Driven Drug Resiliency in Lung Tumor: Options in Sight. Cancers (Basel) 2022; 14:267. [PMID: 35053430 PMCID: PMC8773978 DOI: 10.3390/cancers14020267] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 12/20/2021] [Accepted: 01/04/2022] [Indexed: 12/12/2022] Open
Abstract
Causing a high mortality rate worldwide, lung cancer remains an incurable malignancy resistant to conventional therapy. Despite the discovery of specific molecular targets and new treatment strategies, there remains a pressing need to develop more efficient therapy to further improve the management of this disease. Cancer stem cells (CSCs) are considered the root of sustained tumor growth. This consensus corroborates the CSC model asserting that a distinct subpopulation of malignant cells within a tumor drives and maintains tumor progression with high heterogeneity. Besides being highly tumorigenic, CSCs are highly refractory to standard drugs; therefore, cancer treatment should be focused on eliminating these cells. Herein, we present the current knowledge of the existence of CSCs, CSC-associated mechanisms of chemoresistance, the ability of CSCs to evade immune surveillance, and potential CSC inhibitors in lung cancer, to provide a wider insight to drive a more efficient elimination of this pro-oncogenic and treatment-resistant cell fraction.
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Affiliation(s)
| | - Domenico Galetta
- Division of Thoracic Surgery, European Institute of Oncology, IRCCS, 20141 Milan, Italy;
- Department of Oncology and Hematology-Oncology-DIPO, University of Milan, 20122 Milan, Italy
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15
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Singh K, Tarapcsák S, Gyöngy Z, Ritter Z, Batta G, Bosire R, Remenyik J, Goda K. Effects of Polyphenols on P-Glycoprotein (ABCB1) Activity. Pharmaceutics 2021; 13:pharmaceutics13122062. [PMID: 34959345 PMCID: PMC8707248 DOI: 10.3390/pharmaceutics13122062] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Revised: 11/09/2021] [Accepted: 11/26/2021] [Indexed: 11/17/2022] Open
Abstract
P-glycoprotein (Pgp, ABCB1) is a member of one of the largest families of active transporter proteins called ABC transporters. Thanks to its expression in tissues with barrier functions and its broad substrate spectrum, it is an important determinant of the absorption, metabolism and excretion of many drugs. Pgp and/or some other drug transporting ABC proteins (e.g., ABCG2, MRP1) are overexpressed in nearly all cancers and cancer stem cells by which cancer cells become resistant against many drugs. Thus, Pgp inhibition might be a strategy for fighting against drug-resistant cancer cells. Previous studies have shown that certain polyphenols interact with human Pgp. We tested the effect of 15 polyphenols of sour cherry origin on the basal and verapamil-stimulated ATPase activity of Pgp, calcein-AM and daunorubicin transport as well as on the conformation of Pgp using the conformation sensitive UIC2 mAb. We found that quercetin, quercetin-3-glucoside, narcissoside and ellagic acid inhibited the ATPase activity of Pgp and increased the accumulation of calcein and daunorubicin by Pgp-positive cells. Cyanidin-3O-sophoroside, catechin, naringenin, kuromanin and caffeic acid increased the ATPase activity of Pgp, while they had only a weaker effect on the intracellular accumulation of fluorescent Pgp substrates. Several tested polyphenols including epicatechin, trans-ferulic acid, oenin, malvin and chlorogenic acid were ineffective in all assays applied. Interestingly, catechin and epicatechin behave differently, although they are stereoisomers. We also investigated the effect of quercetin, naringenin and ellagic acid added in combination with verapamil on the transport activity of Pgp. In these experiments, we found that the transport inhibitory effect of the tested polyphenols and verapamil was additive or synergistic. Generally, our data demonstrate diverse interactions of the tested polyphenols with Pgp. Our results also call attention to the potential risks of drug–drug interactions (DDIs) associated with the consumption of dietary polyphenols concurrently with chemotherapy treatment involving Pgp substrate/inhibitor drugs.
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Affiliation(s)
- Kuljeet Singh
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Szabolcs Tarapcsák
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Utah Center for Genetic Discovery, Eccles Institute of Human Genetics, University of Utah, Salt Lake City, UT 84112, USA
| | - Zsuzsanna Gyöngy
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Zsuzsanna Ritter
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Gyula Batta
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Department of Genetics and Applied Microbiology, Faculty of Science of Technology, University of Debrecen, 4032 Debrecen, Hungary
| | - Rosevalentine Bosire
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
| | - Judit Remenyik
- Institute of Food Technology, Faculty of Agricultural and Food Sciences and Environmental Management, University of Debrecen, 4032 Debrecen, Hungary;
| | - Katalin Goda
- Department of Biophysics and Cell Biology, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary; (K.S.); (S.T.); (Z.G.); (Z.R.); (G.B.); (R.B.)
- Doctoral School of Molecular Cell and Immune Biology, University of Debrecen, 4032 Debrecen, Hungary
- Correspondence:
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16
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Wang Y, Gong X, Li J, Wang H, Xu X, Wu Y, Wang J, Wang S, Li Y, Zhang Z. M2 macrophage microvesicle-inspired nanovehicles improve accessibility to cancer cells and cancer stem cells in tumors. J Nanobiotechnology 2021; 19:397. [PMID: 34838042 PMCID: PMC8627085 DOI: 10.1186/s12951-021-01143-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 11/14/2021] [Indexed: 12/14/2022] Open
Abstract
Cancer cells and cancer stem cells (CSCs) are the major players of cancer malignancy and metastasis, but they are extremely difficult to access. Inspired by the vital role of macrophages and microvesicle-mediated cell–cell communication in tumors, we herein designed M2 macrophage microvesicle-inspired nanovehicle of cabazitaxel (M-CFN) to promote accessibility to cancer cells and CSCs in tumors. In the 4T1 tumor model, M-CFN flexibly permeated the tumor mass, accessed cancer cells and CD90-positive cells, and significantly promoted their entry into CSC fractions in tumors. Moreover, M-CFN treatment profoundly eliminated aldehyde dehydrogenase (ALDH)-expressing CSCs in 4T1 and MCF-7 tumors, produced notable depression of tumor growth and caused 93.86% suppression of lung metastasis in 4T1 models. Therefore, the M2 macrophage microvesicle-inspired nanovehicle provides an encouraging strategy to penetrate the tumor tissues and access these insult cells in tumors for effective cancer therapy. ![]()
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Affiliation(s)
- Yuqi Wang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.,State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xiang Gong
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jie Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Hong Wang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Xiaoxuan Xu
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yao Wu
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Jiaoying Wang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Siling Wang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, 110016, Liaoning, China.
| | - Yaping Li
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
| | - Zhiwen Zhang
- State Key Laboratory of Drug Research & Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. .,Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong, 264000, China.
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17
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Cui X, Liu R, Duan L, Cao D, Zhang Q, Zhang A. CAR-T therapy: Prospects in targeting cancer stem cells. J Cell Mol Med 2021; 25:9891-9904. [PMID: 34585512 PMCID: PMC8572776 DOI: 10.1111/jcmm.16939] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2021] [Revised: 08/20/2021] [Accepted: 09/01/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer stem cells (CSCs), a group of tumour cells with stem cell characteristics, have the ability of self-renewal, multi-lineage differentiation and tumour formation. Since CSCs are resistant to conventional radiotherapy and chemotherapy, their existence may be one of the root causes of cancer treatment failure and tumour progression. The elimination of CSCs may be effective for eventual tumour eradication. Because of the good therapeutic effects without major histocompatibility complex (MHC) restriction and the unique characteristics of CSCs, chimeric antigen receptor T-cell (CAR-T) therapy is expected to be an important method to eliminate CSCs. In this review, we have discussed the feasibility of CSCs-targeted CAR-T therapy for cancer treatment, summarized current research and clinical trials of targeting CSCs with CAR-T cells and forecasted the challenges and future direction from the perspectives of toxicity, persistence and potency, trafficking, infiltration, immunosuppressive tumour microenvironment, and tumour heterogeneity.
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Affiliation(s)
- Xiaoyue Cui
- Basic Laboratory, Suining Central Hospital, Suining, China
| | - Rui Liu
- Department of Breast and Thyroid Surgery, Suining Central Hospital, Suining, China
| | - Lian Duan
- Basic Laboratory, Suining Central Hospital, Suining, China
| | - Dan Cao
- Basic Laboratory, Suining Central Hospital, Suining, China.,Key Laboratory of Metabolic Diseases, Suining Central Hospital, Suining, China
| | - Qiaoling Zhang
- Basic Laboratory, Suining Central Hospital, Suining, China.,Key Laboratory of Metabolic Diseases, Suining Central Hospital, Suining, China
| | - Aijie Zhang
- Basic Laboratory, Suining Central Hospital, Suining, China
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18
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Wang W, Bai L, Xu D, Li W, Cui J. Immunotherapy: A Potential Approach to Targeting Cancer Stem Cells. Curr Cancer Drug Targets 2021; 21:117-131. [PMID: 32364076 DOI: 10.2174/1568009620666200504111914] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Revised: 03/14/2020] [Accepted: 04/04/2020] [Indexed: 12/24/2022]
Abstract
Tumor recurrence and drug resistance are two of the key factors affecting the prognosis of cancer patients. Cancer stem cells (CSCs) are a group of cells with infinite proliferation potential which are not sensitive to traditional therapies, including radio- and chemotherapy. These CSCs are considered to be central to tumor recurrence and the development of drug resistance. In addition, CSCs are important targets in cancer immunotherapy because of their expression of novel tumorassociated antigens, which result from mutations in cancer cells over the course of treatment. Emerging immunotherapies, including cancer vaccines, checkpoint blockade therapies, and transferred immune cell therapies, have all been shown to be more effective when they selectively target CSCs. Such therapies may also provide novel additions to the current therapeutic milieu and may offer new therapeutic combinations for treatment. This review summarizes the relationships between various immunotherapies and CSCs and provides novel insights into potential therapeutic applications for these approaches in the future.
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Affiliation(s)
- Wenjun Wang
- Cancer Center, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Ling Bai
- Cancer Center, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Dongsheng Xu
- Cancer Center, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Wei Li
- Cancer Center, The First Hospital of Jilin University, Changchun 130021, Jilin, China
| | - Jiuwei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun 130021, Jilin, China
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19
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Zappe K, Cichna-Markl M. Aberrant DNA Methylation of ABC Transporters in Cancer. Cells 2020; 9:cells9102281. [PMID: 33066132 PMCID: PMC7601986 DOI: 10.3390/cells9102281] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/18/2020] [Accepted: 09/21/2020] [Indexed: 12/21/2022] Open
Abstract
ATP-binding cassette (ABC) transporters play a crucial role in multidrug resistance (MDR) of cancers. They function as efflux pumps, resulting in limited effectiveness or even failure of therapy. Increasing evidence suggests that ABC transporters are also involved in tumor initiation, progression, and metastasis. Tumors frequently show multiple genetic and epigenetic abnormalities, including changes in histone modification and DNA methylation. Alterations in the DNA methylation status of ABC transporters have been reported for a variety of cancer types. In this review, we outline the current knowledge of DNA methylation of ABC transporters in cancer. We give a brief introduction to structure, function, and gene regulation of ABC transporters that have already been investigated for their DNA methylation status in cancer. After giving an overview of the applied methodologies and the CpGs analyzed, we summarize and discuss the findings on aberrant DNA methylation of ABC transporters by cancer types. We conclude our review with the discussion of the potential to target aberrant DNA methylation of ABC transporters for cancer therapy.
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20
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Jing W, Zhang X, Chen R, Ye X, Zhou M, Li W, Yan W, Xuyun X, Peng J. KD025, an anti-adipocyte differentiation drug, enhances the efficacy of conventional chemotherapeutic drugs in ABCG2-overexpressing leukemia cells. Oncol Lett 2020; 20:309. [PMID: 33093918 PMCID: PMC7573885 DOI: 10.3892/ol.2020.12172] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2020] [Accepted: 08/20/2020] [Indexed: 01/04/2023] Open
Abstract
Most patients with advanced leukemia eventually die from multidrug resistance (MDR). Chemotherapy-resistant leukemia cells may lead to treatment failure and disease relapse. Overexpression of ATP-binding cassette subfamily G member 2 (ABCG2) leads to MDR, which serves as a potential biomarker and target of therapeutic intervention for leukemia cells. Targeting ABCG2 is a potential strategy for selective therapy and eradicate MDR cells, thus improving malignant leukemia treatment. KD025 (SLx-2119) is a novel Rho-associated protein kinase 2-selective inhibitor, which has been shown to inhibit adipogenesis in human adipose-derived stem cells and restore impaired immune homeostasis in autoimmunity therapy. The present study demonstrated that KD025 improved the efficacy of antineoplastic drugs in ABCG2-overexpressing leukemia cells and primary leukemia blast cells derived from patients with leukemia. Moreover, KD025 significantly inhibited the efflux of [3H]-mitoxantrone and hence accumulated higher levels of [3H]-mitoxantrone in HL60/ABCG2 cells. However, mechanistic research indicated that KD025 did not alter the protein levels and subcellular locations of ABCG2. KD025 may restrain the efflux activity of ABCG2 by obstructing ATPase activity. Taken together, KD025 can sensitize conventional antineoplastic drugs in ABCG2-overexpressing leukemia cells by blocking the pump function of ABCG2 protein. The present findings may provide a novel and useful combinational therapeutic strategy of KD025 and antineoplastic drugs for leukemia patients with ABCG2-mediated MDR.
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Affiliation(s)
- Wen Jing
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510220, P.R. China
| | - Xuerong Zhang
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510220, P.R. China
| | - Ruixia Chen
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510220, P.R. China
| | - Xijiu Ye
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510220, P.R. China
| | - Mao Zhou
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510220, P.R. China
| | - Weixing Li
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510220, P.R. China
| | - Wenchan Yan
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510220, P.R. China
| | - Xiuxiu Xuyun
- Department of Hepatobiliary Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510220, P.R. China
| | - Jun Peng
- Department of Anesthesiology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, Guangdong 510220, P.R. China
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21
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Dzobo K, Senthebane DA, Ganz C, Thomford NE, Wonkam A, Dandara C. Advances in Therapeutic Targeting of Cancer Stem Cells within the Tumor Microenvironment: An Updated Review. Cells 2020; 9:E1896. [PMID: 32823711 PMCID: PMC7464860 DOI: 10.3390/cells9081896] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/04/2020] [Accepted: 08/11/2020] [Indexed: 12/24/2022] Open
Abstract
Despite great strides being achieved in improving cancer patients' outcomes through better therapies and combinatorial treatment, several hurdles still remain due to therapy resistance, cancer recurrence and metastasis. Drug resistance culminating in relapse continues to be associated with fatal disease. The cancer stem cell theory posits that tumors are driven by specialized cancer cells called cancer stem cells (CSCs). CSCs are a subpopulation of cancer cells known to be resistant to therapy and cause metastasis. Whilst the debate on whether CSCs are the origins of the primary tumor rages on, CSCs have been further characterized in many cancers with data illustrating that CSCs display great abilities to self-renew, resist therapies due to enhanced epithelial to mesenchymal (EMT) properties, enhanced expression of ATP-binding cassette (ABC) membrane transporters, activation of several survival signaling pathways and increased immune evasion as well as DNA repair mechanisms. CSCs also display great heterogeneity with the consequential lack of specific CSC markers presenting a great challenge to their targeting. In this updated review we revisit CSCs within the tumor microenvironment (TME) and present novel treatment strategies targeting CSCs. These promising strategies include targeting CSCs-specific properties using small molecule inhibitors, immunotherapy, microRNA mediated inhibitors, epigenetic methods as well as targeting CSC niche-microenvironmental factors and differentiation. Lastly, we present recent clinical trials undertaken to try to turn the tide against cancer by targeting CSC-associated drug resistance and metastasis.
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Affiliation(s)
- Kevin Dzobo
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory, Cape Town 7925, South Africa; (D.A.S.); (C.G.)
- Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Dimakatso Alice Senthebane
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory, Cape Town 7925, South Africa; (D.A.S.); (C.G.)
- Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Chelene Ganz
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town Component, Wernher and Beit Building (South), UCT Medical Campus, Anzio Road, Observatory, Cape Town 7925, South Africa; (D.A.S.); (C.G.)
- Division of Medical Biochemistry and Institute of Infectious Disease and Molecular Medicine, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Cape Town 7925, South Africa
| | - Nicholas Ekow Thomford
- Division of Human Genetics, Department of Pathology and Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa; (N.E.T.); (A.W.); (C.D.)
- Department of Medical Biochemistry, School of Medical Sciences, College of Health Sciences, University of Cape Coast, PMB, Cape Coast, Ghana
| | - Ambroise Wonkam
- Division of Human Genetics, Department of Pathology and Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa; (N.E.T.); (A.W.); (C.D.)
| | - Collet Dandara
- Division of Human Genetics, Department of Pathology and Institute for Infectious Disease and Molecular Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory, Cape Town 7925, South Africa; (N.E.T.); (A.W.); (C.D.)
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22
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Lou H, Li H, Huehn AR, Tarasova NI, Saleh B, Anderson SK, Dean M. Genetic and Epigenetic Regulation of the Smoothened Gene (SMO) in Cancer Cells. Cancers (Basel) 2020; 12:E2219. [PMID: 32784501 PMCID: PMC7464114 DOI: 10.3390/cancers12082219] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/17/2020] [Accepted: 07/28/2020] [Indexed: 12/18/2022] Open
Abstract
(1) Background: The hedgehog (HH) signaling pathway is a key regulator of embryonic patterning, tissue regeneration, stem cell renewal, and cancer growth. The smoothened (SMO) protein regulates the HH signaling pathway and has demonstrated oncogenic activity. (2) Methods: To clarify the role of the HH signaling pathway in tumorigenesis, the expression profile of key HH signaling molecules, including SMO, PTCH1, GLI1, GLI2, and GLI3, were determined in 33 cancer cell lines and normal prostate cells and tissues. We performed a computational analysis of the upstream region of the SMO gene to identify the regulatory elements. (3) Results: Three potential CpG islands and several putative SMO promoter elements were identified. Luciferase reporter assays mapped key SMO promoter elements, and functional binding sites for SP1, AP1, CREB, and AP-2α transcription factors in the core SMO promoter region were confirmed. A hypermethylated SMO promoter was identified in several cancer cell lines suggesting an important role for epigenetic silencing of SMO expression in certain cancer cells. (4) Discussion: These results have important implications for our understanding of regulatory mechanisms controlling HH pathway activity and the molecular basis of SMO gene function. Moreover, this study may prove valuable for future research aimed at producing therapeutic downregulation of SMO expression in cancer cells.
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Affiliation(s)
- Hong Lou
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., National Laboratory for Cancer Research, Gaithersburg, MD 20892, USA;
| | - Hongchuan Li
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA;
| | - Andrew R. Huehn
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; (A.R.H.); (N.I.T.); (B.S.)
- Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06510, USA
| | - Nadya I. Tarasova
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; (A.R.H.); (N.I.T.); (B.S.)
| | - Bahara Saleh
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; (A.R.H.); (N.I.T.); (B.S.)
| | - Stephen K. Anderson
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA;
- Laboratory of Cancer Immunometabolism, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA; (A.R.H.); (N.I.T.); (B.S.)
| | - Michael Dean
- Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD 20892, USA
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Dalpiaz A, Paganetto G, Botti G, Pavan B. Cancer stem cells and nanomedicine: new opportunities to combat multidrug resistance? Drug Discov Today 2020; 25:1651-1667. [PMID: 32763499 DOI: 10.1016/j.drudis.2020.07.023] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Revised: 06/09/2020] [Accepted: 07/29/2020] [Indexed: 12/20/2022]
Abstract
'Multidrug resistance' (MDR) is a difficult challenge for cancer treatment. The combined role of cytochrome P450 enzymes (CYPs) and active efflux transporters (AETs) in cancer cells appears relevant in inducing MDR. Chemotherapeutic drugs can be substrates of both CYPs and AETs and CYP inducers or inhibitors can produce the same effects on AETs. In addition, a small subpopulation of cancer stem-like cells (CSCs) appears to survive conventional chemotherapy, leading to recurrent disease. Natural products appear efficacious against CSCs; their combinational treatments with standard chemotherapy are promising for cancer eradication, in particular when supported by nanotechnologies.
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Affiliation(s)
- Alessandro Dalpiaz
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy
| | - Guglielmo Paganetto
- Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy
| | - Giada Botti
- Department of Chemical and Pharmaceutical Sciences, University of Ferrara, Ferrara, Italy
| | - Barbara Pavan
- Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Ferrara, Italy.
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DOCK6 promotes chemo- and radioresistance of gastric cancer by modulating WNT/β-catenin signaling and cancer stem cell traits. Oncogene 2020; 39:5933-5949. [PMID: 32753649 DOI: 10.1038/s41388-020-01390-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Accepted: 07/07/2020] [Indexed: 01/01/2023]
Abstract
Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide and prognosis after potentially curative gastrectomy remains poor. Administration of GC-targeting molecules in combination with adjuvant chemo- or radiotherapy following surgical resection has been proposed as a potentially effective treatment option. Here, we have identified DOCK6, a guanine nucleotide exchange factor (GEF) for Rac1 and CDC42, as an independent biomarker for GC prognosis. Clinical findings indicate the positive correlation of higher DOCK6 expression with tumor size, depth of invasion, lymph node metastasis, vascular invasion, and pathological stage. Furthermore, elevated DOCK6 expression was significantly associated with shorter cumulative survival in both univariate and multivariate analyses. Gene ontology analysis of three independent clinical GC cohorts revealed significant involvement of DOCK6-correlated genes in the WNT/β-catenin signaling pathway. Ectopic expression of DOCK6 promoted GC cancer stem cell (CSC) characteristics and chemo- or radioresistance concomitantly through Rac1 activation. Conversely, depletion of DOCK6 suppressed CSC phenotypes and progression of GC, further demonstrating the pivotal role of DOCK6 in GC progression. Our results demonstrate a novel mechanistic link between DOCK6, Rac1, and β-catenin in GCCSC for the first time, supporting the utility of DOCK6 as an independent marker of GC.
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25
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Kim DS. Cancer stem cell plasticity in glioblastoma multiforme: a perspective on future directions in oncolytic virotherapy. Future Oncol 2020; 16:2251-2264. [PMID: 32744059 DOI: 10.2217/fon-2019-0606] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
The cancer stem cell (CSC) hypothesis suggests that a rare population of stem-like cells underpin tumorigenesis. Oncolytic viruses (OVs) demonstrate novel mechanisms of targeting the elusive CSCs with greater selectivity - promising therapeutic potential against solid tumors such as glioblastoma (GBM) that are resistant to conventional treatment. In general, OVs have failed to translate the efficacy from bench to bedside. The success of OVs rely on the hypothesis that eliminating CSCs is key to preventing recurrence. However, newly emerging evidence of CSC plasticity challenge this hypothesis by proposing that the CSC pool can be regenerated from non-CSCs post-treatment. We review this evidence surrounding the CSC hypothesis to propose an original perspective on why several advanced OVs may be failing to reflect their true potential in clinical trials. We argue that preventing non-CSC to CSC dedifferentiation may be critical to achieving long-term treatment efficacy in future OV clinical trials.
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Affiliation(s)
- David S Kim
- Medical Sciences Division, John Radcliffe Hospital, University of Oxford, Oxford OX1 1DP, United Kingdom
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26
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Shenouda S, Kulkarni K, Abuetabh Y, Sergi C. Cancer Stem Cells and their Management in Cancer Therapy. Recent Pat Anticancer Drug Discov 2020; 15:212-227. [PMID: 32660407 DOI: 10.2174/1574892815666200713145931] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 06/16/2020] [Accepted: 06/20/2020] [Indexed: 11/22/2022]
Abstract
BACKGROUND In the last decade, the proposed Cancer Stem Cell (CSC) hypothesis has steadily changed the way cancer treatment is approached. CSCs may be the source of the heterogeneous non-tumorigenic cell population included in a neoplasm. Intratumor and intertumoral heterogeneity is a well-known phenomenon that massively entangles the diagnosis and treatment of cancer. The literature seems to suggest that heterogeneity develops progressively within tumor-initiating stem cells. CSCs harbor genetic and/or epigenetic alterations that allow them to differentiate into multiple tumor cell types sequentially. OBJECTIVE The CSC hypothesis, cellular therapy, and the most recent patents on CSCs were reviewed. METHODS PubMed, Scopus, and Google Scholar were screened for this information. Also, an analysis of the most recent data targeting CSCs in pediatric cancer developed at two Canadian institutions is provided. The genes involved with the activation of CSCs and the drugs used to antagonize them are also highlighted. RESULTS It is underlined that (1) CSCs possess stem cell-like properties, including the ability for self-renewal; (2) CSCs can start carcinogenesis and are responsible for tumor recurrence after treatment; (3) Although some limitations have been raised, which may oppose the CSC hypothesis, cancer progression and metastasis have been recognized to be caused by CSCs. CONCLUSION The significant roles of cell therapy may include an auto-transplant with high-dose treatment, an improvement of the immune function, creation of chimeric antigen receptor T cells, and the recruitment of NK cell-based immunotherapy.
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Affiliation(s)
- Suzan Shenouda
- Department of Lab. Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Ketan Kulkarni
- Department of Pediatrics, Pediatric Hematology/Oncology, Halifax, NS, Canada
| | - Yasser Abuetabh
- Department of Lab. Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
| | - Consolato Sergi
- Department of Lab. Medicine and Pathology, University of Alberta, Edmonton, AB, Canada
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27
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Elkashty OA, Ashry R, Tran SD. Head and neck cancer management and cancer stem cells implication. Saudi Dent J 2019; 31:395-416. [PMID: 31700218 PMCID: PMC6823822 DOI: 10.1016/j.sdentj.2019.05.010] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 05/27/2019] [Indexed: 12/20/2022] Open
Abstract
Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are heterogeneous in nature. Risk factors for HNSCCs are smoking, excessive alcohol consumption, and the human papilloma virus. Conventional treatments are surgery, radiotherapy, chemotherapy, or a combined modality; however, no international standard mode of therapy exists. In contrast to the conventional model of clonal evolution in tumor development, there is a newly proposed theory based on the activity of cancer stem cells (CSCs) as the model for carcinogenesis. This “CSC hypothesis” may explain the high mortality rate, low response to treatments, and tendency to develop multiple tumors for HNSCC patients. We review current knowledge on HNSCC etiology and treatment, with a focus on CSCs, including their origins, identifications, and effects on therapeutic options.
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Key Words
- ABC, ATP-binding cassette transporters
- ATC, amplifying transitory cell
- Antineoplastic agents
- BMI-1, B cell-specific Moloney murine leukemia virus integration site 1
- Cancer stem cells
- Cancer treatment
- Carcinoma
- EGFR, epidermal growth factor receptor
- HIFs, hypoxia-inducible factors
- Head and neck cancer
- MDR1, Multidrug Resistance Protein 1
- NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells
- PI3K, phosphatidylinositol-4,5-bisphosphate 3-kinase
- Squamous cell
- TKIs, tyrosine kinase inhibitors
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Affiliation(s)
- Osama A Elkashty
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC, Canada.,Oral Pathology Department, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
| | - Ramy Ashry
- Oral Pathology Department, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
| | - Simon D Tran
- McGill Craniofacial Tissue Engineering and Stem Cells Laboratory, Faculty of Dentistry, McGill University, Montreal, QC, Canada
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Gupta R, Bhatt LK, Johnston TP, Prabhavalkar KS. Colon cancer stem cells: Potential target for the treatment of colorectal cancer. Cancer Biol Ther 2019; 20:1068-1082. [PMID: 31050577 DOI: 10.1080/15384047.2019.1599660] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Despite incessant research, colon cancer still is one of the most common causes of fatalities in both men and women worldwide. Also, nearly 50% of patients with colorectal cancer show tumor recurrence. Recent investigations have highlighted the involvement of colon cancer stem cells (CCSCs) in cancer relapse and chemoresistance. CCSCs deliver a significant protumorigenic niche through persistent overexpression of self-renewal capabilities. Moreover, CSCs cross network with stromal cells, immune infiltrates, and cyotokine-chemokine, which potentiate their aggressive proliferative potential. Targeting CCSCs through small molecule inhibitors, miRNAs, and monoclonal antibodies (mAbs) in in vivo studies has generated compelling evidence for the effectiveness of these various treatments. This review effectively compiles the role of CCSC surface markers and dysregulated and/or upregulated pathways in the pathogenesis of colorectal cancer that can be used to target CCSCs for effective colorectal cancer treatment.
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Affiliation(s)
- Riya Gupta
- a Department of Pharmacology , SVKM's Dr. Bhanuben Nanavati College of Pharmacy , Mumbai , India
| | - Lokesh Kumar Bhatt
- a Department of Pharmacology , SVKM's Dr. Bhanuben Nanavati College of Pharmacy , Mumbai , India
| | - Thomas P Johnston
- b Division of Pharmacology and Pharmaceutical Sciences , University of Missouri-Kansas City , Kansas City , MO , USA
| | - Kedar S Prabhavalkar
- a Department of Pharmacology , SVKM's Dr. Bhanuben Nanavati College of Pharmacy , Mumbai , India
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29
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Jia R, Yang L, Yuan X, Kong J, Liu Y, Yin W, Gao S, Zhang Y. GASC1 Promotes Stemness of Esophageal Squamous Cell Carcinoma via NOTCH1 Promoter Demethylation. JOURNAL OF ONCOLOGY 2019; 2019:1621054. [PMID: 31031809 PMCID: PMC6457298 DOI: 10.1155/2019/1621054] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Accepted: 02/25/2019] [Indexed: 12/31/2022]
Abstract
The highest incidence of esophageal squamous cell carcinoma (ESCC) occurs in China. Cancer stem cells play key roles for tumor progression. Gene amplified in squamous cell carcinoma 1 (GASC1) is essential to maintain self-renewal and differentiation potential of embryonic stem cells. This study aimed to reveal the effect and mechanism of GASC1 on ESCC stemness. The biological function of GASC1 in ESCC was evaluated both in vitro and in vivo. ChIP assay was performed to determine the molecular mechanism of GASC1 in epigenetic regulation of NOTCH1. We found that GASC1 expression was increased in poor differentiated ESCC cells and tissues. ESCC patients with a high level of GASC1 presented a significantly worse survival rate. GASC1 expression in purified ALDH+ ESCC cells was significantly higher than that in ALDH- cells. The stemness of ESCC was dramatically decreased after GASC1 blockade. Furthermore, blockade of GASC1 decreased NOTCH1 expression via increase of NOTCH1 promoter H3K9me2 and H3K9me3. Moreover, the impaired stemness after blockade of GASC1 could be reversed after transfection of NOTCH1 overexpression lentiviral vector. GASC1 promoted stemness in ESCC cells via NOTCH1 promoter demethylation. Therefore, GASC1/NOTCH1 signaling might be a potential therapeutic target for the treatment of ESCC patients.
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Affiliation(s)
- Ruinuo Jia
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan 450052, China
- Cancer Hospital, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Li Yang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan 450052, China
| | - Xiang Yuan
- Cancer Hospital, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Jinyu Kong
- Cancer Hospital, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Yiwen Liu
- Cancer Hospital, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Weijiao Yin
- Cancer Hospital, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Shegan Gao
- Cancer Hospital, The First Affiliated Hospital and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, Henan 471000, China
| | - Yi Zhang
- Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan 450052, China
- School of Life Sciences, Zhengzhou University, Zhengzhou, Henan 450001, China
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30
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Velasco-Velázquez MA, Velázquez-Quesada I, Vásquez-Bochm LX, Pérez-Tapia SM. Targeting Breast Cancer Stem Cells: A Methodological Perspective. Curr Stem Cell Res Ther 2019; 14:389-397. [PMID: 30147014 DOI: 10.2174/1574888x13666180821155701] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2018] [Revised: 08/01/2018] [Accepted: 08/09/2018] [Indexed: 02/07/2023]
Abstract
Cancer Stem Cells (CSCs) constitute a subpopulation at the top of the tumor cell hierarchy that contributes to tumor heterogeneity and is uniquely capable of seeding new tumors. Because of their biological properties, CSCs have been pointed out as therapeutic targets for the development of new therapies against breast cancer. The identification of drugs that selectively target breast CSCs requires a clear understanding of their biological functions and the experimental methods to evaluate such hallmarks. Herein, we review the methods to study breast CSCs properties and discuss their value in the preclinical evaluation of CSC-targeting drugs.
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Affiliation(s)
- Marco A Velasco-Velázquez
- Departamento de Farmacologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (UNAM), Ciudad de Mexico, Mexico
- Unidad Periférica de Investigación en Biomedicina Traslacional, Facultad de Medicina, UNAM, Ciudad de México, México
| | - Inés Velázquez-Quesada
- Departamento de Farmacologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (UNAM), Ciudad de Mexico, Mexico
- Unidad de Desarrollo e Investigacion en Bioprocesos, ENCB, Instituto Politecnico Nacional, Ciudad de Mexico, Mexico
| | - Luz X Vásquez-Bochm
- Departamento de Farmacologia, Facultad de Medicina, Universidad Nacional Autonoma de Mexico (UNAM), Ciudad de Mexico, Mexico
- Posgrado en Ciencias Químicas, UNAM, Ciudad de México, México
| | - Sonia M Pérez-Tapia
- Unidad de Desarrollo e Investigacion en Bioprocesos, ENCB, Instituto Politecnico Nacional, Ciudad de Mexico, Mexico
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31
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Steinbichler TB, Dudás J, Skvortsov S, Ganswindt U, Riechelmann H, Skvortsova II. Therapy resistance mediated by cancer stem cells. Semin Cancer Biol 2018; 53:156-167. [PMID: 30471331 DOI: 10.1016/j.semcancer.2018.11.006] [Citation(s) in RCA: 203] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 11/19/2018] [Accepted: 11/19/2018] [Indexed: 12/13/2022]
Abstract
Cancer stem cells (CSC) possess abilities generally associated with embryonic or adult stem cells, especially self-renewal and differentiation. The CSC model assumes that this subpopulation of cells sustains malignant growth, which suggests a hierarchical organization of tumors in which CSCs are on top and responsible for the generation of intratumoral heterogeneity. Effective tumor therapy requires the eradication of CSC as they can support regrowth of the tumor resulting in recurrence. However, eradication of CSC is difficult because they frequently are therapy resistant. Therapy resistance is mediated by the acquisition of dormancy, increased DNA repair and drug efflux capacity, decreased apoptosis as well as the interaction between CSC and their supporting microenvironment, the CSC niche. This review highlights the role of CSC in chemo- and radiotherapy resistance as well as possible ways to overcome CSC mediated therapy resistance.
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Affiliation(s)
| | - József Dudás
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Sergej Skvortsov
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria
| | - Ute Ganswindt
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Riechelmann
- Department of Otorhinolaryngology, Head and Neck Surgery, Medical University of Innsbruck, Innsbruck, Austria
| | - Ira-Ida Skvortsova
- Department of Therapeutic Radiology and Oncology, Medical University of Innsbruck, Innsbruck, Austria; EXTRO-Lab, Tyrolean Cancer Research Institute, Innsbruck, Austria.
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32
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Tulchinsky E, Demidov O, Kriajevska M, Barlev NA, Imyanitov E. EMT: A mechanism for escape from EGFR-targeted therapy in lung cancer. Biochim Biophys Acta Rev Cancer 2018; 1871:29-39. [PMID: 30419315 DOI: 10.1016/j.bbcan.2018.10.003] [Citation(s) in RCA: 138] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2018] [Revised: 10/07/2018] [Accepted: 10/21/2018] [Indexed: 02/08/2023]
Abstract
Epithelial mesenchymal transition (EMT) is a reversible developmental genetic programme of transdifferentiation of polarised epithelial cells to mesenchymal cells. In cancer, EMT is an important factor of tumour cell plasticity and has received increasing attention for its role in the resistance to conventional and targeted therapies. In this paper we provide an overview of EMT in human malignancies, and discuss contribution of EMT to the development of the resistance to Epidermal Growth Factor Receptor (EGFR)-targeted therapies in non-small cell lung cancer (NSCLC). Patients with the tumours bearing specific mutations in EGFR have a good clinical response to selective EGFR inhibitors, but the resistance inevitably develops. Several mechanisms responsible for the resistance include secondary mutations in the EGFR gene, genetic or non-mutational activation of alternative survival pathways, transdifferentiation of NSCLC to the small cell lung cancer histotype, or formation of resistant tumours with mesenchymal characteristics. Mechanistically, application of an EGFR inhibitor does not kill all cancer cells; some cells survive the exposure to a drug, and undergo genetic evolution towards resistance. Here, we present a theory that these quiescent or slow-proliferating drug-tolerant cell populations, or so-called "persisters", are generated via EMT pathways. We review the EMT-activated mechanisms of cell survival in NSCLC, which include activation of ABC transporters and EMT-associated receptor tyrosine kinase AXL, immune evasion, and epigenetic reprogramming. We propose that therapeutic inhibition of these pathways would eliminate pools of persister cells and prevent or delay cancer recurrence when applied in combination with the agents targeting EGFR.
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Affiliation(s)
- Eugene Tulchinsky
- Leicester Cancer Research Centre, Leicester University, UK; Moscow Institute of Physics and Technology, Dolgoprudny, Moscow, region, 117303, Russia.
| | - Oleg Demidov
- Instutute of Cytology, Russian Academy of Sciences, Saint-Petersburg 194064, Russia
| | | | - Nickolai A Barlev
- Moscow Institute of Physics and Technology, Dolgoprudny, Moscow, region, 117303, Russia; Instutute of Cytology, Russian Academy of Sciences, Saint-Petersburg 194064, Russia
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Crous A, Chizenga E, Hodgkinson N, Abrahamse H. Targeted Photodynamic Therapy: A Novel Approach to Abolition of Human Cancer Stem Cells. INTERNATIONAL JOURNAL OF OPTICS 2018; 2018:1-9. [DOI: 10.1155/2018/7317063] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/02/2023]
Abstract
Cancer is a global burden that has prompted extensive research into prevention and treatment, over many decades. Scientific studies have shown that subset of cells within a tumour, known as cancer stem cells (CSCs), are responsible for tumourigenesis, metastasis, drug resistance, and recurrences. CSCs have characteristic features of enhanced self-renewal, proliferation, and limited but multidirectional differentiation capacity. The discovery of CSCs has initiated extensive research into novel cancer treatment regimes. Evidence indicates that CSCs are resistant to conventional chemo- and radiation therapy leading to treatment failures, cancer metastasis, secondary cancer formation, and relapse. Because of the observed phenomena in the course of cancer prognosis, a need for treatment modalities targeting CSCs is important. Photodynamic therapy (PDT) is a clinically approved, minimally invasive, therapeutic procedure that can exert a selective cytotoxic activity toward cancerous cells while reducing toxicity to normal cells. It uses a photosensitizer (PS) that becomes excited when subjected to light at a specific wavelength, and the PS forms reactive oxygen species (ROS) killing malignant cells. Currently, PDT is being investigated as a target specific treatment for CSCs by the addition of carrier molecules and antibody conjugates bound to the PS. Targeted PDT (TPDT) may be able to not only eradicate the tumour mass but kill CSCs as well.
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Affiliation(s)
- Anine Crous
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg 2028, Room 5308, John Orr Building, South Africa
| | - Elvin Chizenga
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg 2028, Room 5308, John Orr Building, South Africa
| | - Natasha Hodgkinson
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg 2028, Room 5308, John Orr Building, South Africa
| | - Heidi Abrahamse
- Laser Research Centre, Faculty of Health Sciences, University of Johannesburg, P.O. Box 17011, Doornfontein, Johannesburg 2028, Room 5308, John Orr Building, South Africa
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Gao JP, Xu W, Liu WT, Yan M, Zhu ZG. Tumor heterogeneity of gastric cancer: From the perspective of tumor-initiating cell. World J Gastroenterol 2018; 24:2567-2581. [PMID: 29962814 PMCID: PMC6021770 DOI: 10.3748/wjg.v24.i24.2567] [Citation(s) in RCA: 101] [Impact Index Per Article: 14.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2018] [Revised: 04/30/2018] [Accepted: 05/26/2018] [Indexed: 02/06/2023] Open
Abstract
Gastric cancer (GC) remains one of the most common and malignant types of cancer due to its rapid progression, distant metastasis, and resistance to conventional chemotherapy, although efforts have been made to understand the underlying mechanism of this resistance and to improve clinical outcome. It is well recognized that tumor heterogeneity, a fundamental feature of malignancy, plays an essential role in the cancer development and chemoresistance. The model of tumor-initiating cell (TIC) has been proposed to explain the genetic, histological, and phenotypical heterogeneity of GC. TIC accounts for a minor subpopulation of tumor cells with key characteristics including high tumorigenicity, maintenance of self-renewal potential, giving rise to both tumorigenic and non-tumorigenic cancer cells, and resistance to chemotherapy. Regarding tumor-initiating cell of GC (GATIC), substantial studies have been performed to (1) identify the putative specific cell markers for purification and functional validation of GATICs; (2) trace the origin of GATICs; and (3) decode the regulatory mechanism of GATICs. Furthermore, recent studies demonstrate the plasticity of GATIC and the interaction between GATIC and its surrounding factors (TIC niche or tumor microenvironment). All these investigations pave the way for the development of GATIC-targeted therapy, which is in the phase of preclinical studies and clinical trials. Here, we interpret the heterogeneity of GC from the perspectives of TIC by reviewing the above-mentioned fundamental and clinical studies of GATICs. Problems encountered during the GATIC investigations and the potential solutions are also discussed.
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Affiliation(s)
- Jian-Peng Gao
- Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Wei Xu
- Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Wen-Tao Liu
- Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Min Yan
- Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
| | - Zheng-Gang Zhu
- Department of Surgery, Shanghai Institute of Digestive Surgery, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai 200025, China
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35
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Wang H, Agarwal P, Zhao G, Ji G, Jewell CM, Fisher JP, Lu X, He X. Overcoming Ovarian Cancer Drug Resistance with a Cold Responsive Nanomaterial. ACS CENTRAL SCIENCE 2018; 4:567-581. [PMID: 29806003 PMCID: PMC5968444 DOI: 10.1021/acscentsci.8b00050] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/18/2018] [Indexed: 05/21/2023]
Abstract
Drug resistance due to overexpression of membrane transporters in cancer cells and the existence of cancer stem cells (CSCs) is a major hurdle to effective and safe cancer chemotherapy. Nanoparticles have been explored to overcome cancer drug resistance. However, drug slowly released from nanoparticles can still be efficiently pumped out of drug-resistant cells. Here, a hybrid nanoparticle of phospholipid and polymers is developed to achieve cold-triggered burst release of encapsulated drug. With ice cooling to below ∼12 °C for both burst drug release and reduced membrane transporter activity, binding of the drug with its target in drug-resistant cells is evident, while it is minimal in the cells kept at 37 °C. Moreover, targeted drug delivery with the cold-responsive nanoparticles in combination with ice cooling not only can effectively kill drug-resistant ovarian cancer cells and their CSCs in vitro but also destroy both subcutaneous and orthotopic ovarian tumors in vivo with no evident systemic toxicity.
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Affiliation(s)
- Hai Wang
- Fischell Department of Bioengineering and Robert E. Fischell Institute for Biomedical
Devices, University of Maryland, College Park, Maryland 20742, United States
- Department of Biomedical Engineering and Comprehensive Cancer
Center, The Ohio State University, Columbus, Ohio 43210, United States
| | - Pranay Agarwal
- Department of Biomedical Engineering and Comprehensive Cancer
Center, The Ohio State University, Columbus, Ohio 43210, United States
| | - Gang Zhao
- Center
for Biomedical Engineering, Department of Electronic Science and Technology, University of Science and Technology of China, Hefei, Anhui 230027, China
| | - Guang Ji
- Institute
of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200032, China
| | - Christopher M. Jewell
- Fischell Department of Bioengineering and Robert E. Fischell Institute for Biomedical
Devices, University of Maryland, College Park, Maryland 20742, United States
- Marlene
and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland 21201, United States
- Department
of Microbiology and Immunology, University
of Maryland School of Medicine, Baltimore, Maryland 21201, United States
- United
States Department of Veterans Affairs, Maryland
VA Health Care System, Baltimore, Maryland 21201, United States
| | - John P. Fisher
- Fischell Department of Bioengineering and Robert E. Fischell Institute for Biomedical
Devices, University of Maryland, College Park, Maryland 20742, United States
| | - Xiongbin Lu
- Department
of Medical and Molecular Genetics and Melvin and Bren Simon Cancer
Center, Indiana University School of Medicine, Indianapolis, Indiana 46202, United States
| | - Xiaoming He
- Fischell Department of Bioengineering and Robert E. Fischell Institute for Biomedical
Devices, University of Maryland, College Park, Maryland 20742, United States
- Department of Biomedical Engineering and Comprehensive Cancer
Center, The Ohio State University, Columbus, Ohio 43210, United States
- Marlene
and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland, Baltimore, Maryland 21201, United States
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36
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MiR-514 attenuates proliferation and increases chemoresistance by targeting ATP binding cassette subfamily in ovarian cancer. Mol Genet Genomics 2018; 293:1159-1167. [PMID: 29752546 DOI: 10.1007/s00438-018-1447-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2018] [Accepted: 05/07/2018] [Indexed: 12/14/2022]
Abstract
Cisplatin is one of the most popular chemotherapeutic drugs in treating ovarian cancer. Resistance to cisplatin is a common clinical challenge that needs to be solved to increase its anti-tumor effects. The relation of miR-514 expression with prognosis in ovarian cancer patients was analyzed based on GSE73584 datasets. The regulation of miR-514 on proliferation and cisplatin chemosensitivity of ovarian cells was examined by MTT assay, colony-formation assay and soft-agar colony-formation assay. Dual luciferase assay was performed to detect the direct interaction of miR-514 with its downstream targets. Immunobloting and qRT-PCR were performed for target gene expression analysis. Low expression of miR-514 was related to poor prognosis in ovarian cancer patients. MiR-514 repressed proliferation and decreased cisplatin chemosensitivity in ovarian cancer cells by targeting ATP binding cassette subfamily. MiR-514 is of clinically significance in ovarian cancer by attenuating proliferation of ovarian cancer cells and decreasing chemoresistance of cisplatin by targeting ATP binding cassette subfamily.
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37
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Chaurasiya S, Chen NG, Warner SG. Oncolytic Virotherapy versus Cancer Stem Cells: A Review of Approaches and Mechanisms. Cancers (Basel) 2018; 10:E124. [PMID: 29671772 PMCID: PMC5923379 DOI: 10.3390/cancers10040124] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 04/11/2018] [Accepted: 04/14/2018] [Indexed: 12/26/2022] Open
Abstract
A growing body of evidence suggests that a subset of cells within tumors are resistant to conventional treatment modalities and may be responsible for disease recurrence. These cells are called cancer stem cells (CSC), which share properties with normal stem cells including self-renewal, pluripotency, drug resistance, and the ability to maintain quiescence. While most conventional therapies can efficiently destroy rapidly dividing cancer cells comprising the bulk of a tumor, they often fail to kill the less abundant and quiescent CSCs. Furthermore, killing of only differentiated cells in the tumor may actually allow for enrichment of CSCs and thereby portend a bad prognosis. Therefore, targeting of CSCs is important to achieve long-term success in cancer therapy. Oncolytic viruses represent a completely different class of therapeutics that can kill cancer cells in a variety of ways, which differ from those of conventional therapies. Hence, CSCs that are inherently resistant to conventional therapies may be susceptible to oncolytic virus-mediated killing. Recent studies have shown that oncolytic viruses can efficiently kill CSCs in many types of cancer. Here, we discuss the mechanism through which CSCs can escape conventional therapies and how they may still be susceptible to different classes of oncolytic viruses. Furthermore, we provide a summary of recent studies that have tested oncolytic viruses on CSCs of different origins and discuss possible future directions for this fascinating subset of oncolytic virus research.
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Affiliation(s)
- Shyambabu Chaurasiya
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA.
| | - Nanhai G Chen
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA.
- Center for Gene Therapy, Department of Hematologic and Hematopoietic Cell Transplantation, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
- Gene Editing and Viral Vector Core, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.
| | - Susanne G Warner
- Department of Surgery, Division of Surgical Oncology, City of Hope National Medical Center, Duarte, CA 91010, USA.
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38
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Skoda AM, Simovic D, Karin V, Kardum V, Vranic S, Serman L. The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosn J Basic Med Sci 2018; 18:8-20. [PMID: 29274272 DOI: 10.17305/bjbms.2018.2756] [Citation(s) in RCA: 489] [Impact Index Per Article: 69.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 12/01/2017] [Indexed: 12/14/2022] Open
Abstract
The Hedgehog (Hh) signaling pathway was first identified in the common fruit fly. It is a highly conserved evolutionary pathway of signal transmission from the cell membrane to the nucleus. The Hh signaling pathway plays an important role in the embryonic development. It exerts its biological effects through a signaling cascade that culminates in a change of balance between activator and repressor forms of glioma-associated oncogene (Gli) transcription factors. The components of the Hh signaling pathway involved in the signaling transfer to the Gli transcription factors include Hedgehog ligands (Sonic Hh [SHh], Indian Hh [IHh], and Desert Hh [DHh]), Patched receptor (Ptch1, Ptch2), Smoothened receptor (Smo), Suppressor of fused homolog (Sufu), kinesin protein Kif7, protein kinase A (PKA), and cyclic adenosine monophosphate (cAMP). The activator form of Gli travels to the nucleus and stimulates the transcription of the target genes by binding to their promoters. The main target genes of the Hh signaling pathway are PTCH1, PTCH2, and GLI1. Deregulation of the Hh signaling pathway is associated with developmental anomalies and cancer, including Gorlin syndrome, and sporadic cancers, such as basal cell carcinoma, medulloblastoma, pancreatic, breast, colon, ovarian, and small-cell lung carcinomas. The aberrant activation of the Hh signaling pathway is caused by mutations in the related genes (ligand-independent signaling) or by the excessive expression of the Hh signaling molecules (ligand-dependent signaling - autocrine or paracrine). Several Hh signaling pathway inhibitors, such as vismodegib and sonidegib, have been developed for cancer treatment. These drugs are regarded as promising cancer therapies, especially for patients with refractory/advanced cancers.
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Affiliation(s)
- Ana Marija Skoda
- Department of Biology, School of Medicine, University of Zagreb, Zagreb, Croatia.
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39
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‘Et tu, inhibitor?’: the potential for HIV inhibitors to prime P-gp-mediated chemoresistance in cancer. Future Sci OA 2018; 4:FSO269. [PMID: 29379643 PMCID: PMC5778385 DOI: 10.4155/fsoa-2017-0134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2017] [Accepted: 11/02/2017] [Indexed: 11/17/2022] Open
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40
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Su S, Chen J, Yao H, Liu J, Yu S, Lao L, Wang M, Luo M, Xing Y, Chen F, Huang D, Zhao J, Yang L, Liao D, Su F, Li M, Liu Q, Song E. CD10 +GPR77 + Cancer-Associated Fibroblasts Promote Cancer Formation and Chemoresistance by Sustaining Cancer Stemness. Cell 2018; 172:841-856.e16. [PMID: 29395328 DOI: 10.1016/j.cell.2018.01.009] [Citation(s) in RCA: 858] [Impact Index Per Article: 122.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 12/28/2017] [Accepted: 01/04/2018] [Indexed: 12/12/2022]
Abstract
Carcinoma-associated fibroblasts (CAFs) are abundant and heterogeneous stromal cells in tumor microenvironment that are critically involved in cancer progression. Here, we demonstrate that two cell-surface molecules, CD10 and GPR77, specifically define a CAF subset correlated with chemoresistance and poor survival in multiple cohorts of breast and lung cancer patients. CD10+GPR77+ CAFs promote tumor formation and chemoresistance by providing a survival niche for cancer stem cells (CSCs). Mechanistically, CD10+GPR77+ CAFs are driven by persistent NF-κB activation via p65 phosphorylation and acetylation, which is maintained by complement signaling via GPR77, a C5a receptor. Furthermore, CD10+GPR77+ CAFs promote successful engraftment of patient-derived xenografts (PDXs), and targeting these CAFs with a neutralizing anti-GPR77 antibody abolishes tumor formation and restores tumor chemosensitivity. Our study reveals a functional CAF subset that can be defined and isolated by specific cell-surface markers and suggests that targeting the CD10+GPR77+ CAF subset could be an effective therapeutic strategy against CSC-driven solid tumors.
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Affiliation(s)
- Shicheng Su
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Jianing Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Herui Yao
- Department of Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Jiang Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Shubin Yu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Liyan Lao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Minghui Wang
- Department of Thoracic Surgery, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Manli Luo
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Yue Xing
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Fei Chen
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Di Huang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Jinghua Zhao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Linbin Yang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Dan Liao
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Fengxi Su
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Mengfeng Li
- Department of Microbiology and Key Laboratory of Tropical Disease Control , Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China
| | - Qiang Liu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China
| | - Erwei Song
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Program of Molecular Medicine, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
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41
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Friedman R. Drug resistance in cancer: molecular evolution and compensatory proliferation. Oncotarget 2017; 7:11746-55. [PMID: 26909596 PMCID: PMC4914245 DOI: 10.18632/oncotarget.7459] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Accepted: 02/08/2016] [Indexed: 01/31/2023] Open
Abstract
Targeted therapies have revolutionized cancer treatment. Unfortunately, their success is limited due to the development of drug resistance within the tumor, which is an evolutionary process. Understanding how drug resistance evolves is a prerequisite to a better success of targeted therapies. Resistance is usually explained as a response to evolutionary pressure imposed by treatment. Thus, evolutionary understanding can and should be used in the design and treatment of cancer. In this article, drug-resistance to targeted therapies is reviewed from an evolutionary standpoint. The concept of apoptosis-induced compensatory proliferation (AICP) is developed. It is shown that AICP helps to explain some of the phenomena that are observed experimentally in cancers. Finally, potential drug targets are suggested in light of AICP.
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Affiliation(s)
- Ran Friedman
- Department of Chemistry and Biomedical Sciences, Linnæus University, Kalmar, Sweden
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42
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Davis W, Tew KD. ATP-binding cassette transporter-2 (ABCA2) as a therapeutic target. Biochem Pharmacol 2017; 151:188-200. [PMID: 29223352 DOI: 10.1016/j.bcp.2017.11.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 11/27/2017] [Indexed: 12/28/2022]
Abstract
The ATP binding cassette transporter ABCA2 is primarily an endolysosomal membrane protein that demonstrates pleiotropic functionalities, coalescing around the maintenance of homeostasis of sterols, sphingolipids and cholesterol. It is most highly expressed in brain tissue and ABCA2 knockout mice express neurological defects consistent with aberrant myelination. Increased expression of the transporter has been linked with resistance to cancer drugs, particularly those possessing a steroid backbone and gene expression (in concert with other genes involved in cholesterol metabolism) was found to be regulated by sterols. Moreover, in macrophages ABCA2 is influenced by sterols and has a role in regulating cholesterol sequestration, potentially important in cardiovascular disease. Accumulating data indicate the critical importance of ABCA2 in mediating movement of sphingolipids within cellular compartments and these have been implicated in various aspects of cholesterol trafficking. Perhaps because the functions of ABCA2 are linked with membrane building blocks, there are reports linking it with human pathologies, including, cholesterolemias and cardiovascular disease, Alzheimer's and cancer. The present review addresses whether there is now sufficient information to consider ABCA2 as a plausible therapeutic target.
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Affiliation(s)
- Warren Davis
- Dept. of Cell & Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, BSB, MSC 509, Charleston, SC 29425, United States
| | - Kenneth D Tew
- Dept. of Cell & Molecular Pharmacology & Experimental Therapeutics, Medical University of South Carolina, 173 Ashley Avenue, BSB, MSC 509, Charleston, SC 29425, United States.
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43
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Dosch J, Hadley E, Wiese C, Soderberg M, Houwman T, Ding K, Kharazova A, Collins JL, van Knippenberg B, Gregory C, Kofman A. Time-lapse microscopic observation of non-dividing cells in cultured human osteosarcoma MG-63 cell line. Cell Cycle 2017; 17:174-181. [PMID: 29169283 DOI: 10.1080/15384101.2017.1395535] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Cancer stem cells resemble normal tissue-specific stem cells in many aspects, such as self-renewal and plasticity. Like their non-malignant counterparts, cancer stem cells are suggested to exhibit a relative quiescence. The established cancer cell lines reportedly harbor slow-proliferating cells that are positive for some cancer stem cells markers. However, the fate of these cells and their progeny remains unknown. We used time-lapse microscopy and the contrast-based segmentation algorithm to identify and monitor actively dividing and non-dividing cells in human osteosarcoma MG-63 cell line. Within the monitored field of view the non-dividing cells were represented by three cells that never divided, and one cell that attempted to divide, but failed cytokinesis, and later, after significantly prolonged division, produced the progeny with enlarged segmented nuclei, thus pointing to a possible mitotic catastrophe. Together, these cells initially constituted about 6.2% of the total number of seeded cells, yet only 0.02% of all cells at the end of the observation period when cells became confluent. Non-dividing cells were characterized by rounded shape, dark nuclei, random cytoplasmic streaming and subtle oscillatory movement, however, they did not migrate and rarely formed cell-cell contacts as compared to actively dividing cells. Our data indicate that the observed non-dividing MG-63 cells do not have a growth advantage over other cells and, therefore, they do not contribute to the cancer stem cells pool.
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Affiliation(s)
- John Dosch
- a Department of Biology , Dakota Wesleyan University , 219 Corrigan Science Center, 1200 W. University Ave, Mitchell , SD , U.S.A
| | - Elise Hadley
- a Department of Biology , Dakota Wesleyan University , 219 Corrigan Science Center, 1200 W. University Ave, Mitchell , SD , U.S.A
| | - Cal Wiese
- a Department of Biology , Dakota Wesleyan University , 219 Corrigan Science Center, 1200 W. University Ave, Mitchell , SD , U.S.A
| | - Marissa Soderberg
- a Department of Biology , Dakota Wesleyan University , 219 Corrigan Science Center, 1200 W. University Ave, Mitchell , SD , U.S.A
| | - Tori Houwman
- a Department of Biology , Dakota Wesleyan University , 219 Corrigan Science Center, 1200 W. University Ave, Mitchell , SD , U.S.A
| | - Kai Ding
- b Johns Hopkins School of Medicine , 401 N. Broadway / Suite 1471, Baltimore MD , U.S.A
| | | | - John L Collins
- d Department of Biology , University of Tennessee at Martin , 574 University Street, U.S.A
| | - Bart van Knippenberg
- e CytoSMART Technologies BV , De Lismortel 31 5612AR Eindhoven , The Netherlands
| | - Carl Gregory
- f Institute for Regenerative Medicine , Texas A&M Health Science Center 208B , Reynolds Medical Building, College Station , TX , U.S.A
| | - Alexander Kofman
- a Department of Biology , Dakota Wesleyan University , 219 Corrigan Science Center, 1200 W. University Ave, Mitchell , SD , U.S.A .,g Aging-Cancer Interface Group , LDS Medical Center , St. Petersburg , Russian Federation
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44
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Zhang Y, Wang Y, Zuo Q, Li D, Zhang W, Lian C, Tang B, Xiao T, Wang M, Wang K, Li B. Effects of the Transforming Growth Factor Beta Signaling Pathway on the Differentiation of Chicken Embryonic Stem Cells into Male Germ Cells. Cell Reprogram 2017; 18:401-410. [PMID: 27906584 DOI: 10.1089/cell.2016.0019] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The objectives of the present study were to screen for key gene and signaling pathways involved in the production of male germ cells in poultry and to investigate the effects of the transforming growth factor beta (TGF-β) signaling pathway on the differentiation of chicken embryonic stem cells (ESCs) into male germ cells. The ESCs, primordial germ cells, and spermatogonial stem cells (SSCs) were sorted using flow cytometry for RNA sequencing (RNA-seq) technology. Male chicken ESCs were induced using 40 ng/mL of bone morphogenetic protein 4 (BMP4). The effects of the TGF-β signaling pathway on the production of chicken SSCs were confirmed by morphology, quantitative real-time polymerase chain reaction, and immunocytochemistry. One hundred seventy-three key genes relevant to development, differentiation, and metabolism and 20 signaling pathways involved in cell reproduction, differentiation, and signal transduction were identified by RNA-seq. The germ cells formed agglomerates and increased in number 14 days after induction by BMP4. During the induction process, the ESCs, Nanog, and Sox2 marker gene expression levels decreased, whereas expression of the germ cell-specific genes Stra8, Dazl, integrin-α6, and c-kit increased. The results indicated that the TGF-β signaling pathway participated in the differentiation of chicken ESCs into male germ cells.
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Affiliation(s)
- Yani Zhang
- 1 College of Animal Science and Technology, Yangzhou University , Yangzhou, China .,2 Key Laboratory for Animal Genetics , Breeding, Reproduction, and Molecular Design of Jiangsu Province, Yangzhou, China
| | - Yingjie Wang
- 1 College of Animal Science and Technology, Yangzhou University , Yangzhou, China .,2 Key Laboratory for Animal Genetics , Breeding, Reproduction, and Molecular Design of Jiangsu Province, Yangzhou, China
| | - Qisheng Zuo
- 1 College of Animal Science and Technology, Yangzhou University , Yangzhou, China .,2 Key Laboratory for Animal Genetics , Breeding, Reproduction, and Molecular Design of Jiangsu Province, Yangzhou, China
| | - Dong Li
- 1 College of Animal Science and Technology, Yangzhou University , Yangzhou, China .,2 Key Laboratory for Animal Genetics , Breeding, Reproduction, and Molecular Design of Jiangsu Province, Yangzhou, China
| | - Wenhui Zhang
- 1 College of Animal Science and Technology, Yangzhou University , Yangzhou, China .,2 Key Laboratory for Animal Genetics , Breeding, Reproduction, and Molecular Design of Jiangsu Province, Yangzhou, China
| | - Chao Lian
- 1 College of Animal Science and Technology, Yangzhou University , Yangzhou, China .,2 Key Laboratory for Animal Genetics , Breeding, Reproduction, and Molecular Design of Jiangsu Province, Yangzhou, China
| | - Beibei Tang
- 1 College of Animal Science and Technology, Yangzhou University , Yangzhou, China .,2 Key Laboratory for Animal Genetics , Breeding, Reproduction, and Molecular Design of Jiangsu Province, Yangzhou, China
| | - Tianrong Xiao
- 1 College of Animal Science and Technology, Yangzhou University , Yangzhou, China .,2 Key Laboratory for Animal Genetics , Breeding, Reproduction, and Molecular Design of Jiangsu Province, Yangzhou, China
| | - Man Wang
- 1 College of Animal Science and Technology, Yangzhou University , Yangzhou, China .,2 Key Laboratory for Animal Genetics , Breeding, Reproduction, and Molecular Design of Jiangsu Province, Yangzhou, China
| | - Kehua Wang
- 3 Poultry Institute , Chinese Academy of Agricultural Sciences, Yangzhou, China
| | - Bichun Li
- 1 College of Animal Science and Technology, Yangzhou University , Yangzhou, China .,2 Key Laboratory for Animal Genetics , Breeding, Reproduction, and Molecular Design of Jiangsu Province, Yangzhou, China
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45
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Charafe-Jauffret E. [The concept of cancer stem cell]. Bull Cancer 2017; 104:1056-1059. [PMID: 29169654 DOI: 10.1016/j.bulcan.2017.10.020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2017] [Accepted: 10/25/2017] [Indexed: 12/25/2022]
Affiliation(s)
- Emmanuelle Charafe-Jauffret
- Université d'Aix-Marseille, CNRS, institut Paoli-Calmettes, centre de recherche en cancérologie de Marseille (CRCM), Inserm, 232, boulevard de Ste-Marguerite, 13009 Marseille, France.
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46
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Sen U, Shenoy P S, Bose B. Opposing effects of low versus high concentrations of water soluble vitamins/dietary ingredients Vitamin C and niacin on colon cancer stem cells (CSCs). Cell Biol Int 2017; 41:1127-1145. [DOI: 10.1002/cbin.10830] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 07/26/2017] [Indexed: 12/28/2022]
Affiliation(s)
- Utsav Sen
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya University; University Road; Mangalore 575018 Karnataka India
| | - Sudheer Shenoy P
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya University; University Road; Mangalore 575018 Karnataka India
| | - Bipasha Bose
- Stem Cells and Regenerative Medicine Centre, Yenepoya Research Centre, Yenepoya University; University Road; Mangalore 575018 Karnataka India
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47
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Roh YJ, Kim JH, Kim IW, Na K, Park JM, Choi MG. Photodynamic Therapy Using Photosensitizer-Encapsulated Polymeric Nanoparticle to Overcome ATP-Binding Cassette Transporter Subfamily G2 Function in Pancreatic Cancer. Mol Cancer Ther 2017; 16:1487-1496. [PMID: 28416605 DOI: 10.1158/1535-7163.mct-16-0642] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2016] [Revised: 02/01/2017] [Accepted: 04/05/2017] [Indexed: 12/27/2022]
Abstract
Chlorin-based photosensitizers are commonly used in photodynamic therapy (PDT). These drugs are effluxed by cell membrane transporters, such as the ATP-binding cassette subfamily G member 2 (ABCG2). PDT efficacy is limited in tumor cells expressing high levels of these proteins. Pancreatic cancer cell lines AsPC-1 and MIA PaCa-2, which have high and low ABCG2 expression, respectively, were used, and ABCG2-overexpressing MIA PaCa-2 cells were generated. We compared PDT efficacy between chlorin e6 (Ce6) and cationic photosensitizer-encapsulated polymeric nanoparticle (PS-pNP), which is comprised with Ce6, polyethylene glycol, and polyethylenimine. The intracellular concentration of Ce6 was significantly higher in MIA PaCa-2 cells than in AsPC-1 or ABCG2-overexpressing MIA PaCa-2 cells. PS-pNP increased intracellular levels of the photosensitizer in all cell lines. The cell viability experiments indicated increased Ce6 resistance in ABCG2-overexpressing cells. In contrast, PS-pNP produced similar levels of cytotoxicity in each of the cancer cell lines tested. Singlet oxygen production was higher in cells treated with PS-pNP than in those treated with Ce6. Furthermore, in heterotopic and orthotopic AsPC-1 xenograft mouse models, PDT using PS-pNP significantly reduced tumor volume in comparison with that of Ce6 treatment. PS-pNP could increase intracellular Ce6 concentration, which was related with reduced ABCG2-mediated efflux of Ce6, thereby enhancing the effects of PDT in pancreatic cancer cells. Mol Cancer Ther; 16(8); 1487-96. ©2017 AACR.
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Affiliation(s)
- Yoon Jin Roh
- Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
| | - Ju Hee Kim
- Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
| | - In-Wook Kim
- Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea
| | - Kun Na
- Department of Biotechnology, Center for Photomedicine, The Catholic University of Korea, Bucheon-si, Gyeonggi-do, Korea
| | - Jae Myung Park
- Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea. .,Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Myung-Gyu Choi
- Catholic Research Institute of Medical Science, The Catholic University of Korea, Seoul, Korea. .,Division of Gastroenterology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea
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48
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Abou-ElNaga A, Mutawa G, El-Sherbiny IM, Abd-ElGhaffar H, Allam AA, Ajarem J, Mousa SA. Novel Nano-Therapeutic Approach Actively Targets Human Ovarian Cancer Stem Cells after Xenograft into Nude Mice. Int J Mol Sci 2017; 18:E813. [PMID: 28417924 PMCID: PMC5412397 DOI: 10.3390/ijms18040813] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2017] [Revised: 03/16/2017] [Accepted: 03/24/2017] [Indexed: 01/06/2023] Open
Abstract
The power of tumorigenesis, chemo-resistance and metastasis in malignant ovarian tumors resides in a tiny population of cancer cells known as ovarian cancer stem cells (OCSCs). Developing nano-therapeutic targeting of OCSCs is considered a great challenge. The potential use of poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) was investigated as a drug delivery system for paclitaxel (PTX) against OCSCs in vitro and in vivo. PTX-loaded PLGA NPs were prepared by an emulsion solvent evaporation method, supported by incorporation of folic acid (FA) as the ligand. NPs were characterized for size, surface morphology, drug loading, and encapsulation efficiency. In vitro cytotoxicity of PTX-loaded FA/PLGA NPs was tested against OCSCs with MTT assay. In vivo anti-tumoral efficiency and active targeting potential of prepared NPs against tumors in nude mice were investigated. In vitro results revealed that IC50 of PTX was significantly reduced after loading on PLGA NPs. On the other hand, in vivo results showed that PLGA NPs enhanced the tumor suppression efficiency of PTX. Investigation with real time quantitative PCR analysis revealed the limiting expression of chemo-resistant genes (ABCG2 and MDR1) after applying PLGA NPs as a drug delivery system for PTX. Histopathological examination of tumors showed the effective biological influence of PTX-loaded FA/PLGA NPs through the appearance of reactive lymphoid follicles. Targeting potential of PTX was activated by FA/PLGA NPs through significant preservation of body weight (p < 0.0001) and minimizing the systemic toxicity in healthy tissues. Immunohistochemical investigation revealed a high expression of apoptotic markers in tumor tissue, supporting the targeting effect of FA/PLGA NPs. A drug delivery system based on FA/PLGA NPs can enhance PTX's in vitro cytotoxicity and in vivo targeting potential against OCSCs.
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Affiliation(s)
- Amoura Abou-ElNaga
- Zoology Department, Faculty of Sciences, Mansoura University, Mansoura 35516, Egypt.
| | - Ghada Mutawa
- Zoology Department, Faculty of Sciences, Mansoura University, Mansoura 35516, Egypt.
| | - Ibrahim M El-Sherbiny
- Center for Materials Science, Zewail City of Science and Technology, Cairo 12588, Egypt.
| | - Hassan Abd-ElGhaffar
- Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura 35516, Egypt.
| | - Ahmed A Allam
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
- Zoology Department, Faculty of Science, Beni-Suef University, Beni-Suef 62511, Egypt.
| | - Jamaan Ajarem
- Zoology Department, College of Science, King Saud University, Riyadh 11451, Saudi Arabia.
| | - Shaker A Mousa
- The Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY 12144, USA.
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49
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Lei Y, Yi Y, Liu Y, Liu X, Keller ET, Qian CN, Zhang J, Lu Y. Metformin targets multiple signaling pathways in cancer. CHINESE JOURNAL OF CANCER 2017; 36:17. [PMID: 28126011 PMCID: PMC5270304 DOI: 10.1186/s40880-017-0184-9] [Citation(s) in RCA: 101] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2016] [Accepted: 06/21/2016] [Indexed: 12/20/2022]
Abstract
Metformin, an inexpensive and well-tolerated oral agent commonly used in the first-line treatment of type 2 diabetes, has become the focus of intense research as a candidate anticancer agent. Here, we discuss the potential of metformin in cancer therapeutics, particularly its functions in multiple signaling pathways, including AMP-activated protein kinase, mammalian target of rapamycin, insulin-like growth factor, c-Jun N-terminal kinase/mitogen-activated protein kinase (p38 MAPK), human epidermal growth factor receptor-2, and nuclear factor kappaB pathways. In addition, cutting-edge targeting of cancer stem cells by metformin is summarized.
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Affiliation(s)
- Yong Lei
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, 530021, Guangxi, P. R. China.,Center for Translational Medicine, Guangxi Medical University, 14th Floor, Pharmacology and Biomedical Sciences Building, No. 22 Shuangyong Road, Nanning, 530021, Guangxi, P. R. China
| | - Yanhua Yi
- School for International Education, Guangxi Medical University, Nanning, 530021, Guangxi, P. R. China
| | - Yang Liu
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, 530021, Guangxi, P. R. China.,Center for Translational Medicine, Guangxi Medical University, 14th Floor, Pharmacology and Biomedical Sciences Building, No. 22 Shuangyong Road, Nanning, 530021, Guangxi, P. R. China
| | - Xia Liu
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, 530021, Guangxi, P. R. China.,Center for Translational Medicine, Guangxi Medical University, 14th Floor, Pharmacology and Biomedical Sciences Building, No. 22 Shuangyong Road, Nanning, 530021, Guangxi, P. R. China
| | - Evan T Keller
- Department of Urology and Pathology, School of Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Chao-Nan Qian
- Department of Nasopharyngeal Carcinoma, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510060, Guangdong, P. R. China
| | - Jian Zhang
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, 530021, Guangxi, P. R. China. .,Center for Translational Medicine, Guangxi Medical University, 14th Floor, Pharmacology and Biomedical Sciences Building, No. 22 Shuangyong Road, Nanning, 530021, Guangxi, P. R. China. .,Department of Urology and Pathology, School of Medicine, University of Michigan, Ann Arbor, MI, 48109, USA.
| | - Yi Lu
- Key Laboratory of Longevity and Ageing-related Diseases, Ministry of Education, Nanning, 530021, Guangxi, P. R. China. .,Center for Translational Medicine, Guangxi Medical University, 14th Floor, Pharmacology and Biomedical Sciences Building, No. 22 Shuangyong Road, Nanning, 530021, Guangxi, P. R. China.
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Deshmukh A, Deshpande K, Arfuso F, Newsholme P, Dharmarajan A. Cancer stem cell metabolism: a potential target for cancer therapy. Mol Cancer 2016; 15:69. [PMID: 27825361 PMCID: PMC5101698 DOI: 10.1186/s12943-016-0555-x] [Citation(s) in RCA: 143] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 11/01/2016] [Indexed: 12/19/2022] Open
Abstract
Cancer Stem cells (CSCs) are a unipotent cell population present within the tumour cell mass. CSCs are known to be highly chemo-resistant, and in recent years, they have gained intense interest as key tumour initiating cells that may also play an integral role in tumour recurrence following chemotherapy. Cancer cells have the ability to alter their metabolism in order to fulfil bio-energetic and biosynthetic requirements. They are largely dependent on aerobic glycolysis for their energy production and also are associated with increased fatty acid synthesis and increased rates of glutamine utilisation. Emerging evidence has shown that therapeutic resistance to cancer treatment may arise due to dysregulation in glucose metabolism, fatty acid synthesis, and glutaminolysis. To propagate their lethal effects and maintain survival, tumour cells alter their metabolic requirements to ensure optimal nutrient use for their survival, evasion from host immune attack, and proliferation. It is now evident that cancer cells metabolise glutamine to grow rapidly because it provides the metabolic stimulus for required energy and precursors for synthesis of proteins, lipids, and nucleic acids. It can also regulate the activities of some of the signalling pathways that control the proliferation of cancer cells. This review describes the key metabolic pathways required by CSCs to maintain a survival advantage and highlights how a combined approach of targeting cellular metabolism in conjunction with the use of chemotherapeutic drugs may provide a promising strategy to overcome therapeutic resistance and therefore aid in cancer therapy.
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Affiliation(s)
- Abhijeet Deshmukh
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, 6102, Australia
| | - Kedar Deshpande
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Frank Arfuso
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, 6102, Australia
| | - Philip Newsholme
- School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Arun Dharmarajan
- Stem Cell and Cancer Biology Laboratory, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, 6102, Australia.
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