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1
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Kooshan Z, Cárdenas-Piedra L, Clements J, Batra J. Glycolysis, the sweet appetite of the tumor microenvironment. Cancer Lett 2024; 600:217156. [PMID: 39127341 DOI: 10.1016/j.canlet.2024.217156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 07/17/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Cancer cells display an altered metabolic phenotype, characterised by increased glycolysis and lactate production, even in the presence of sufficient oxygen - a phenomenon known as the Warburg effect. This metabolic reprogramming is a crucial adaptation that enables cancer cells to meet their elevated energy and biosynthetic demands. Importantly, the tumor microenvironment plays a pivotal role in shaping and sustaining this metabolic shift in cancer cells. This review explores the intricate relationship between the tumor microenvironment and the Warburg effect, highlighting how communication within this niche regulates cancer cell metabolism and impacts tumor progression and therapeutic resistance. We discuss the potential of targeting the Warburg effect as a promising therapeutic strategy, with the aim of disrupting the metabolic advantage of cancer cells and enhancing our understanding of this complex interplay within the tumor microenvironment.
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Affiliation(s)
- Zeinab Kooshan
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Lilibeth Cárdenas-Piedra
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia; ARC Training Centre for Cell & Tissue Engineering Technologies, Brisbane, Australia
| | - Judith Clements
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia
| | - Jyotsna Batra
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia; Center for Genomics and Personalised Health, Translational Research Institute, Queensland University of Technology, Brisbane, Australia; ARC Training Centre for Cell & Tissue Engineering Technologies, Brisbane, Australia.
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2
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Yao S, Liu X, Feng Y, Li Y, Xiao X, Han Y, Xia S. Unveiling the Role of HGF/c-Met Signaling in Non-Small Cell Lung Cancer Tumor Microenvironment. Int J Mol Sci 2024; 25:9101. [PMID: 39201787 PMCID: PMC11354629 DOI: 10.3390/ijms25169101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 08/15/2024] [Accepted: 08/19/2024] [Indexed: 09/03/2024] Open
Abstract
Non-small cell lung cancer (NSCLC) is characterized by several molecular alterations that contribute to its development and progression. These alterations include the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), human epidermal growth factor receptor 2 (HER2), and mesenchymal-epithelial transition factor (c-MET). Among these, the hepatocyte growth factor (HGF)/c-MET signaling pathway plays a crucial role in NSCLC. In spite of this, the involvement of the HGF/c-MET signaling axis in remodeling the tumor microenvironment (TME) remains relatively unexplored. This review explores the biological functions of the HGF/c-MET signaling pathway in both normal and cancerous cells, examining its multifaceted roles in the NSCLC tumor microenvironment, including tumor cell proliferation, migration and invasion, angiogenesis, and immune evasion. Furthermore, we summarize the current progress and clinical applications of MET-targeted therapies in NSCLC and discuss future research directions, such as the development of novel MET inhibitors and the potential of combination immunotherapy.
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Affiliation(s)
| | | | | | | | | | | | - Shu Xia
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China; (S.Y.); (X.L.); (Y.F.); (Y.L.); (X.X.); (Y.H.)
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3
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Davis JC, Waltz SE. The MET Family of Receptor Tyrosine Kinases Promotes a Shift to Pro-Tumor Metabolism. Genes (Basel) 2024; 15:953. [PMID: 39062731 PMCID: PMC11275592 DOI: 10.3390/genes15070953] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 07/16/2024] [Accepted: 07/19/2024] [Indexed: 07/28/2024] Open
Abstract
The development and growth of cancer is fundamentally dependent on pro-tumor changes in metabolism. Cancer cells generally shift away from oxidative phosphorylation as the primary source of energy and rely more heavily on glycolysis. Receptor tyrosine kinases (RTKs) are a type of receptor that is implicated in this shift to pro-tumor metabolism. RTKs are important drivers of cancer growth and metastasis. One such family of RTKs is the MET family, which consists of MET and RON (MST1R). The overexpression of either MET or RON has been associated with worse cancer patient prognosis in a variety of tumor types. Both MET and RON signaling promote increased glycolysis by upregulating the expression of key glycolytic enzymes via increased MYC transcription factor activity. Additionally, both MET and RON signaling promote increased cholesterol biosynthesis downstream of glycolysis by upregulating the expression of SREBP2-induced cholesterol biosynthesis enzymes via CTTNB1. These changes in metabolism, driven by RTK activity, provide potential targets in limiting tumor growth and metastasis via pharmacological inhibition or modifications in diet. This review summarizes pro-tumor changes in metabolism driven by the MET family of RTKs. In doing so, we will offer our unique perspective on metabolic pathways that drive worse patient prognosis and provide suggestions for future study.
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Affiliation(s)
- James C. Davis
- Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
| | - Susan E. Waltz
- Department of Cancer Biology, College of Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
- Research Service, Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220, USA
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Mohan CD, Shanmugam MK, Gowda SGS, Chinnathambi A, Rangappa KS, Sethi G. c-MET pathway in human malignancies and its targeting by natural compounds for cancer therapy. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2024; 128:155379. [PMID: 38503157 DOI: 10.1016/j.phymed.2024.155379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 01/03/2024] [Accepted: 01/17/2024] [Indexed: 03/21/2024]
Abstract
BACKGROUND c-MET is a receptor tyrosine kinase which is classically activated by HGF to activate its downstream signaling cascades such as MAPK, PI3K/Akt/mTOR, and STAT3. The c-MET modulates cell proliferation, epithelial-mesenchymal transition (EMT), immune response, morphogenesis, apoptosis, and angiogenesis. The c-MET has been shown to serve a prominent role in embryogenesis and early development. The c-MET pathway is deregulated in a broad range of malignancies, due to overexpression of ligands or receptors, genomic amplification, and MET mutations. The link between the deregulation of c-MET signaling and tumor progression has been well-documented. Overexpression or overactivation of c-MET is associated with dismal clinical outcomes and acquired resistance to targeted therapies. Since c-MET activation results in the triggering of oncogenic pathways, abrogating the c-MET pathway is considered to be a pivotal strategy in cancer therapeutics. Herein, an analysis of role of the c-MET pathway in human cancers and its relevance in bone metastasis and therapeutic resistance has been undertaken. Also, an attempt has been made to summarize the inhibitory activity of selected natural compounds towards c-MET signaling in cancers. METHODS The publications related to c-MET pathway in malignancies and its natural compound modulators were obtained from databases such as PubMed, Scopus, and Google Scholar and summarized based on PRISMA guidelines. Some of the keywords used for extracting relevant literature are c-MET, natural compound inhibitors of c-MET, c-MET in liver cancer, c-MET in breast cancer, c-MET in lung cancer, c-MET in pancreatic cancer, c-MET in head and neck cancer, c-MET in bone metastasis, c-MET in therapeutic resistance, and combination of c-MET inhibitors and chemotherapeutic agents. The chemical structure of natural compounds was verified in PubChem database. RESULTS The search yielded 3935 publications, of which 195 reference publications were used for our analysis. Clinical trials were referenced using ClinicalTrials.gov identifier. The c-MET pathway has been recognized as a prominent target to combat the growth, metastasis, and chemotherapeutic resistance in cancers. The key role of the c-MET in bone metastasis as well as therapeutic resistance has been elaborated. Also, suppressive effect of selected natural compounds on the c-MET pathway in clinical/preclinical studies has been discussed.
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Affiliation(s)
- Chakrabhavi Dhananjaya Mohan
- FEST Division, CSIR-Indian Institute of Toxicology Research, Vishvigyan Bhawan, 31, Mahatma Gandhi Marg, Lucknow, Uttar Pradesh 226 001, India
| | - Muthu K Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | | | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud University, Riyadh 11451, Saudi Arabia
| | - Kanchugarakoppal S Rangappa
- Institution of Excellence, Vijnana Bhavan, University of Mysore, Manasagangotri, Mysore, Karnataka 570006, India.
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore.
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Li J, Zhang X, Liu Y, Zhou J, Shen L, Yue G. Expressions and Clinical Significance of Met and YAP in Gastric Cancer Tissue Microarray. Gastroenterol Res Pract 2024; 2024:5591298. [PMID: 38634107 PMCID: PMC11022516 DOI: 10.1155/2024/5591298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2023] [Revised: 03/14/2024] [Accepted: 03/25/2024] [Indexed: 04/19/2024] Open
Abstract
Objective This study is aimed at investigating the expression of Met and YAP in gastric cancer and their impact on clinical prognosis. Methods Tissue samples and clinical data were collected from 89 patients with gastric cancer. Immunohistochemistry was performed to quantify the expression of Met and YAP using tissue microarray. The correlation between the expressions of Met, YAP, and clinicopathological characteristics of patients was determined using a chi-square test. Survival analysis was conducted using the Kaplan-Meier method, while multivariate survival analysis was performed using the Cox proportional hazard model. Bioinformatics analysis was carried out by downloading chip data from TCGA. Results The expression levels of both Met and YAP were significantly higher in gastric cancer tissues compared to adjacent tissues (P < 0.001). Met expression showed a positive association with P53 and CD133, whereas YAP expression correlated positively with tumor grade and CD133 (P < 0.05). Pearson's analysis revealed a significant correlation between Met expression and VEGFR as well as CD133, while YAP expression correlated with Ki67 and VEGFR (P < 0.05). Patients with high levels of both Met and YAP exhibited decreased survival time (P < 0.01). Furthermore, Met expression, N stage, and VEGFR were identified as independent risk factors for gastric cancer prognosis (P < 0.05), whereas no such association was observed for YAP expression. Bioinformatics analysis demonstrated a significant correlation between the expressions of Met and YAP; both proteins were highly expressed in gastric cancer patients accompanied by markedly reduced survival time. Conclusion The expressions of Met and YAP are closely associated with the survival outcomes as well as clinicopathological features in patients with gastric cancer. Moreover, our findings highlight that Met serves as an independent prognostic factor for gastric cancer.
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Affiliation(s)
- Jinxia Li
- Hunan University of Chinese Medicine, Changsha 410208, China
- Provincial Key Laboratory of TCM Diagnostics, Hunan University of Chinese Medicine, Changsha 410208, China
| | - Xinyun Zhang
- Hunan University of Chinese Medicine, Changsha 410208, China
| | - Ying Liu
- Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Jinyong Zhou
- Central Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing 210029, China
| | - Li Shen
- Institute of Basic Theory of TCM, China Academy of Chinese Medical Sciences, Beijing 100700, China
| | - Guangxin Yue
- Institute of Basic Theory of TCM, China Academy of Chinese Medical Sciences, Beijing 100700, China
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Crepaldi T, Gallo S, Comoglio PM. The MET Oncogene: Thirty Years of Insights into Molecular Mechanisms Driving Malignancy. Pharmaceuticals (Basel) 2024; 17:448. [PMID: 38675409 PMCID: PMC11054789 DOI: 10.3390/ph17040448] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2024] [Revised: 03/22/2024] [Accepted: 03/27/2024] [Indexed: 04/28/2024] Open
Abstract
The discovery and subsequent research on the MET oncogene's role in cancer onset and progression have illuminated crucial insights into the molecular mechanisms driving malignancy. The identification of MET as the hepatocyte growth factor (HGF) receptor has paved the path for characterizing the MET tyrosine kinase activation mechanism and its downstream signaling cascade. Over the past thirty years, research has established the importance of HGF/MET signaling in normal cellular processes, such as cell dissociation, migration, proliferation, and cell survival. Notably, genetic alterations that lead to the continuous activation of MET, known as constitutive activation, have been identified as oncogenic drivers in various cancers. The genetic lesions affecting MET, such as exon skipping, gene amplification, and gene rearrangements, provide valuable targets for therapeutic intervention. Moreover, the implications of MET as a resistance mechanism to targeted therapies emphasize the need for combination treatments that include MET inhibitors. The intriguing "flare effect" phenomenon, wherein MET inhibition can lead to post-treatment increases in cancer cell proliferation, underscores the dynamic nature of cancer therapeutics. In human tumors, increased protein expression often occurs without gene amplification. Various mechanisms may cause an overexpression: transcriptional upregulation induced by other oncogenes; environmental factors (such as hypoxia or radiation); or substances produced by the reactive stroma, such as inflammatory cytokines, pro-angiogenic factors, and even HGF itself. In conclusion, the journey to understanding MET's involvement in cancer onset and progression over the past three decades has not only deepened our knowledge, but has also paved the way for innovative therapeutic strategies. Selective pharmacological inactivation of MET stands as a promising avenue for achieving cancer remission, particularly in cases where MET alterations are the primary drivers of malignancy.
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Affiliation(s)
- Tiziana Crepaldi
- Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy; (T.C.); (S.G.)
- Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy
| | - Simona Gallo
- Department of Oncology, University of Turin, Regione Gonzole 10, 10143 Orbassano, Italy; (T.C.); (S.G.)
- Candiolo Cancer Institute, FPO-IRCCS, SP142, Km 3.95, 10060 Candiolo, Italy
| | - Paolo Maria Comoglio
- IFOM ETS—The AIRC Institute of Molecular Oncology, Via Adamello 16, 20139 Milano, Italy
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Xu H, Wu D, Xiao M, Lei Y, Lei Y, Yu X, Shi S. PP2A complex disruptor SET prompts widespread hypertranscription of growth-essential genes in the pancreatic cancer cells. SCIENCE ADVANCES 2024; 10:eadk6633. [PMID: 38277454 PMCID: PMC10816699 DOI: 10.1126/sciadv.adk6633] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 12/26/2023] [Indexed: 01/28/2024]
Abstract
Hyperactivation of the oncogenic transcription reflects the epigenetic plasticity of the cancer cells. Su(var)3-9, enhancer of zeste, Trithorax (SET) was described as a nuclear factor that stimulated transcription from the chromatin template. However, the mechanisms of SET-dependent transcription are unknown. Here, we found that overexpression of SET and CDK9 induced very similar transcriptome signatures in multiple cancer cell lines. SET localized in the transcription start site (TSS)-proximal regions and supported the RNA transcription. SET specifically bound the PP2A-C subunit and induced PP2A-A subunit repulsion from the C subunit, which indicated the role of SET as a PP2A-A/C complex disruptor in the TSS-proximal regions. Through blocking PP2A activity, SET assisted CDK9 to maintain Pol II CTD phosphorylation and activated mRNA transcription. Our findings position SET as a key factor that modulates chromatin PP2A activity, promoting the oncogenic transcription in the pancreatic cancer.
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Affiliation(s)
- He Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Di Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Mingming Xiao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Yubin Lei
- Key Laboratory of Growth Regulation and Translational Research of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou, Zhejiang Province 310024, China
| | - Yalan Lei
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Shanghai Pancreatic Cancer Institute, Shanghai 200032, China
- Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
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Zhang N, Li Y. Receptor tyrosine kinases: biological functions and anticancer targeted therapy. MedComm (Beijing) 2023; 4:e446. [PMID: 38077251 PMCID: PMC10701465 DOI: 10.1002/mco2.446] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 11/23/2023] [Accepted: 11/24/2023] [Indexed: 10/16/2024] Open
Abstract
Receptor tyrosine kinases (RTKs) are a class of protein kinases that play crucial roles in various cellular processes, including cell migration, morphological differentiation, cell growth, and angiogenesis. In humans, 58 RTKs have been identified and categorized into 20 distinct families based on the composition of their extracellular regions. RTKs are primarily activated by specific ligands that bind to their extracellular region. They not only regulate tumor transformation, proliferation, metastasis, drug resistance, and angiogenesis, but also initiate and maintain the self-renewal and cloning ability of cancer stem cells. Accurate diagnosis and grading of tumors with dysregulated RTKs are essential in clinical practice. There is a growing body of evidence supporting the benefits of RTKs-targeted therapies for cancer patients, and researchers are actively exploring new targets and developing targeted agents. However, further optimization of RTK inhibitors is necessary to effectively target the diverse RTK alterations observed in human cancers. This review provides insights into the classification, structure, activation mechanisms, and expression of RTKs in tumors. It also highlights the research advances in RTKs targeted anticancer therapy and emphasizes their significance in optimizing cancer diagnosis and treatment strategies.
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Affiliation(s)
- Nan Zhang
- Chongqing University Cancer Hospital, School of MedicineChongqing UniversityChongqingChina
| | - Yongsheng Li
- Chongqing University Cancer Hospital, School of MedicineChongqing UniversityChongqingChina
- Department of Medical OncologyChongqing University Cancer HospitalChongqingChina
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9
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Du Y, Sun H, Shi Z, Sui X, Liu B, Zheng Z, Liu Y, Xuan Z, Zhong M, Fu M, Bai Y, Zhang Q, Shao C. Targeting the hedgehog pathway in MET mutation cancers and its effects on cells associated with cancer development. Cell Commun Signal 2023; 21:313. [PMID: 37919751 PMCID: PMC10623711 DOI: 10.1186/s12964-023-01333-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 09/25/2023] [Indexed: 11/04/2023] Open
Abstract
The mutation of MET plays a crucial role in the initiation of cancer, while the Hedgehog (Hh) pathway also plays a significant role in cell differentiation and the maintenance of tumor stem cells. Conventional chemotherapy drugs are primarily designed to target the majority of cell populations within tumors rather than tumor stem cells. Consequently, after a brief period of remission, tumors often relapse. Moreover, the exclusive targeting of tumor stemness cell disregards the potential for other tumor cells to regain stemness and acquire drug resistance. As a result, current drugs that solely target the HGF/c-MET axis and the Hh pathway demonstrate only moderate efficacy in specific types of cancer. Mounting evidence indicates that these two pathways not only play important roles in cancer but also exert significant influence on the development of resistance to single-target therapies through the secretion of their own ligands. In this comprehensive review, we analyze and compare the potential impact of the Hh pathway on the tumor microenvironment (TME) in HGF/c-MET-driven tumor models, as well as the interplay between different cell types. Additionally, we further substantiate the potential and necessity of dual-pathway combination therapy as a critical target in MET addicted cancer treatment. Video Abstract.
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Affiliation(s)
- Yifan Du
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Huimin Sun
- Central Laboratory, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Zhiyuan Shi
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Xiuyuan Sui
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Bin Liu
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Zeyuan Zheng
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Yankuo Liu
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Zuodong Xuan
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Min Zhong
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Meiling Fu
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Yang Bai
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China
| | - Qian Zhang
- Department of Endocrinology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361000, China
| | - Chen Shao
- Department of Urology, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361101, China.
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Zhao Y, Qin C, Zhao B, Wang Y, Li Z, Li T, Yang X, Wang W. Pancreatic cancer stemness: dynamic status in malignant progression. J Exp Clin Cancer Res 2023; 42:122. [PMID: 37173787 PMCID: PMC10182699 DOI: 10.1186/s13046-023-02693-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Accepted: 04/30/2023] [Indexed: 05/15/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive malignancies worldwide. Increasing evidence suggests that the capacity for self-renewal, proliferation, and differentiation of pancreatic cancer stem cells (PCSCs) contribute to major challenges with current PC therapies, causing metastasis and therapeutic resistance, leading to recurrence and death in patients. The concept that PCSCs are characterized by their high plasticity and self-renewal capacities is central to this review. We focused specifically on the regulation of PCSCs, such as stemness-related signaling pathways, stimuli in tumor cells and the tumor microenvironment (TME), as well as the development of innovative stemness-targeted therapies. Understanding the biological behavior of PCSCs with plasticity and the molecular mechanisms regulating PC stemness will help to identify new treatment strategies to treat this horrible disease.
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Affiliation(s)
- Yutong Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Cheng Qin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Bangbo Zhao
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Yuanyang Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Zeru Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Tianyu Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Xiaoying Yang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China
| | - Weibin Wang
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- Key Laboratory of Research in Pancreatic Tumor, Chinese Academy of Medical Sciences, Beijing, 100023, People's Republic of China.
- National Science and Technology Key Infrastructure On Translational Medicine in, Peking Union Medical College Hospital, Beijing, 100023, People's Republic of China.
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11
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Bubin R, Uljanovs R, Strumfa I. Cancer Stem Cells in Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2023; 24:ijms24087030. [PMID: 37108193 PMCID: PMC10138709 DOI: 10.3390/ijms24087030] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 04/05/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
The first discovery of cancer stem cells (CSCs) in leukaemia triggered active research on stemness in neoplastic tissues. CSCs represent a subpopulation of malignant cells, defined by unique properties: a dedifferentiated state, self-renewal, pluripotency, an inherent resistance to chemo- and radiotherapy, the presence of certain epigenetic alterations, as well as a higher tumorigenicity in comparison with the general population of cancer cells. A combination of these features highlights CSCs as a high-priority target during cancer treatment. The presence of CSCs has been confirmed in multiple malignancies, including pancreatic ductal adenocarcinoma, an entity that is well known for its dismal prognosis. As the aggressive course of pancreatic carcinoma is partly attributable to treatment resistance, CSCs could contribute to adverse outcomes. The aim of this review is to summarize the current information regarding the markers and molecular features of CSCs in pancreatic ductal adenocarcinoma and the therapeutic options to remove them.
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Affiliation(s)
- Roman Bubin
- Faculty of Medicine, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia
| | - Romans Uljanovs
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia
| | - Ilze Strumfa
- Department of Pathology, Riga Stradins University, 16 Dzirciema Street, LV-1007 Riga, Latvia
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12
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Köseer AS, Di Gaetano S, Arndt C, Bachmann M, Dubrovska A. Immunotargeting of Cancer Stem Cells. Cancers (Basel) 2023; 15:1608. [PMID: 36900399 PMCID: PMC10001158 DOI: 10.3390/cancers15051608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/24/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
The generally accepted view is that CSCs hijack the signaling pathways attributed to normal stem cells that regulate the self-renewal and differentiation processes. Therefore, the development of selective targeting strategies for CSC, although clinically meaningful, is associated with significant challenges because CSC and normal stem cells share many important signaling mechanisms for their maintenance and survival. Furthermore, the efficacy of this therapy is opposed by tumor heterogeneity and CSC plasticity. While there have been considerable efforts to target CSC populations by the chemical inhibition of the developmental pathways such as Notch, Hedgehog (Hh), and Wnt/β-catenin, noticeably fewer attempts were focused on the stimulation of the immune response by CSC-specific antigens, including cell-surface targets. Cancer immunotherapies are based on triggering the anti-tumor immune response by specific activation and targeted redirecting of immune cells toward tumor cells. This review is focused on CSC-directed immunotherapeutic approaches such as bispecific antibodies and antibody-drug candidates, CSC-targeted cellular immunotherapies, and immune-based vaccines. We discuss the strategies to improve the safety and efficacy of the different immunotherapeutic approaches and describe the current state of their clinical development.
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Affiliation(s)
- Ayse Sedef Köseer
- National Center for Tumor Diseases (NCT), Partner Site Dresden: German Cancer Research Center (DKFZ), Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01309 Dresden, Germany
| | - Simona Di Gaetano
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01309 Dresden, Germany
| | - Claudia Arndt
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
- Mildred Scheel Early Career Center, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, 01307 Dresden, Germany
| | - Michael Bachmann
- National Center for Tumor Diseases (NCT), Partner Site Dresden: German Cancer Research Center (DKFZ), Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiopharmaceutical Cancer Research, 01328 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Anna Dubrovska
- National Center for Tumor Diseases (NCT), Partner Site Dresden: German Cancer Research Center (DKFZ), Heidelberg, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01307 Dresden, Germany
- OncoRay–National Center for Radiation Research in Oncology, Faculty of Medicine and University Hospital Carl Gustav Carus, Technische Universität Dresden, Helmholtz-Zentrum Dresden-Rossendorf (HZDR), 01309 Dresden, Germany
- German Cancer Consortium (DKTK), Partner Site Dresden and German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Helmholtz-Zentrum Dresden-Rossendorf, Institute of Radiooncology-OncoRay, 01328 Dresden, Germany
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13
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Sarkar M, Nguyen T, Gundre E, Ogunlusi O, El-Sobky M, Giri B, Sarkar TR. Cancer-associated fibroblasts: The chief architect in the tumor microenvironment. Front Cell Dev Biol 2023; 11:1089068. [PMID: 36793444 PMCID: PMC9923123 DOI: 10.3389/fcell.2023.1089068] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 01/12/2023] [Indexed: 01/31/2023] Open
Abstract
Stromal heterogeneity of tumor microenvironment (TME) plays a crucial role in malignancy and therapeutic resistance. Cancer-associated fibroblasts (CAFs) are one of the major players in tumor stroma. The heterogeneous sources of origin and subsequent impacts of crosstalk with breast cancer cells flaunt serious challenges before current therapies to cure triple-negative breast cancer (TNBC) and other cancers. The positive and reciprocal feedback of CAFs to induce cancer cells dictates their mutual synergy in establishing malignancy. Their substantial role in creating a tumor-promoting niche has reduced the efficacy of several anti-cancer treatments, including radiation, chemotherapy, immunotherapy, and endocrine therapy. Over the years, there has been an emphasis on understanding CAF-induced therapeutic resistance in order to enhance cancer therapy results. CAFs, in the majority of cases, employ crosstalk, stromal management, and other strategies to generate resilience in surrounding tumor cells. This emphasizes the significance of developing novel strategies that target particular tumor-promoting CAF subpopulations, which will improve treatment sensitivity and impede tumor growth. In this review, we discuss the current understanding of the origin and heterogeneity of CAFs, their role in tumor progression, and altering the tumor response to therapeutic agents in breast cancer. In addition, we also discuss the potential and possible approaches for CAF-mediated therapies.
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Affiliation(s)
- Mrinmoy Sarkar
- Department of Biology, Texas A&M University, College Station, TX, United States
- Cancer Biology and Inflammatory Disorder Division, CSIR-Indian Institute of Chemical Biology, Kolkata, India
| | - Tristan Nguyen
- Department of Biology, Texas A&M University, College Station, TX, United States
| | - Esheksha Gundre
- Department of Biology, Texas A&M University, College Station, TX, United States
| | - Olajumoke Ogunlusi
- Department of Biology, Texas A&M University, College Station, TX, United States
| | - Mohanad El-Sobky
- Department of Biology, Texas A&M University, College Station, TX, United States
| | - Biplab Giri
- Department of Physiology, University of Gour Banga, English Bazar, India
| | - Tapasree Roy Sarkar
- Department of Biology, Texas A&M University, College Station, TX, United States
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14
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Sequential Treatment with Activin and Hepatocyte Growth Factor Induces FOXM1 to Promote Colorectal Cancer Liver Metastasis. Can J Gastroenterol Hepatol 2022; 2022:8996203. [PMID: 36591565 PMCID: PMC9803576 DOI: 10.1155/2022/8996203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 11/23/2022] [Accepted: 12/03/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Cancer stem cells (CSCs) are involved in liver metastasis in colorectal cancer (CRC). Activin and hepatocyte growth factor (HGF) are important regulators of stem cell properties. This study was performed to explore the effect of activin and HGF on CRC invasion and metastasis. The key genes involved in the action of activin and HGF in CRC were identified. METHODS HCT116 CRC cells were sequentially treated with activin and HGF and examined for migration and invasion in vitro and liver metastasis in vivo. RNA sequencing was performed to identify differentially expressed genes in response to activin and HGF. RESULTS Sequential treatment with activin and HGF-enhanced CRC cell migration, invasion, and metastasis. CXCR4 and AFP expressions were increased by activin and HGF treatment. Knockdown of FOXM1 blocked liver metastasis from HCT116 cells pretreated with activin and HGF and suppressed CXCR4 and AFP expression. Activin alone increased the mRNA and protein expression of FOXM1. In contrast, HGF alone enhanced the phosphorylation of FOXM1, without altering the total protein level of FOXM1. SMAD2 was required for activin-mediated FOXM1 induction. FOXM1 transactivated CXCR4 by directly binding to the promoter of CXCR4. Additionally, CXCR4 regulated AFP expression through the NF-κB pathway. CONCLUSIONS Sequential treatment with activin and HGF accelerates CRC invasion and liver metastasis, which involves the upregulation and activation of FOXM1 and induction of CXCR4 and AFP.
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15
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Cancer-Associated Fibroblast Diversity Shapes Tumor Metabolism in Pancreatic Cancer. Cancers (Basel) 2022; 15:cancers15010061. [PMID: 36612058 PMCID: PMC9817728 DOI: 10.3390/cancers15010061] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2022] [Revised: 12/14/2022] [Accepted: 12/20/2022] [Indexed: 12/24/2022] Open
Abstract
Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF/cancer cell crosstalk could pave the way for new therapeutic strategies.
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16
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Ervin EH, French R, Chang CH, Pauklin S. Inside the stemness engine: Mechanistic links between deregulated transcription factors and stemness in cancer. Semin Cancer Biol 2022; 87:48-83. [PMID: 36347438 DOI: 10.1016/j.semcancer.2022.11.001] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/22/2022] [Accepted: 11/03/2022] [Indexed: 11/07/2022]
Abstract
Cell identity is largely determined by its transcriptional profile. In tumour, deregulation of transcription factor expression and/or activity enables cancer cell to acquire a stem-like state characterised by capacity to self-renew, differentiate and form tumours in vivo. These stem-like cancer cells are highly metastatic and therapy resistant, thus warranting a more complete understanding of the molecular mechanisms downstream of the transcription factors that mediate the establishment of stemness state. Here, we review recent research findings that provide a mechanistic link between the commonly deregulated transcription factors and stemness in cancer. In particular, we describe the role of master transcription factors (SOX, OCT4, NANOG, KLF, BRACHYURY, SALL, HOX, FOX and RUNX), signalling-regulated transcription factors (SMAD, β-catenin, YAP, TAZ, AP-1, NOTCH, STAT, GLI, ETS and NF-κB) and unclassified transcription factors (c-MYC, HIF, EMT transcription factors and P53) across diverse tumour types, thereby yielding a comprehensive overview identifying shared downstream targets, highlighting unique mechanisms and discussing complexities.
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Affiliation(s)
- Egle-Helene Ervin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Rhiannon French
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Chao-Hui Chang
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Old Road, Headington, Oxford, OX3 7LD, United Kingdom.
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17
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Zhang T, Ren Y, Yang P, Wang J, Zhou H. Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma. Cell Death Dis 2022; 13:897. [PMID: 36284087 PMCID: PMC9596464 DOI: 10.1038/s41419-022-05351-1] [Citation(s) in RCA: 86] [Impact Index Per Article: 28.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 10/11/2022] [Accepted: 10/14/2022] [Indexed: 11/06/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a prominent extracellular matrix (ECM) deposition and poor prognosis. High levels of ECM proteins derived from tumour cells reduce the efficacy of conventional cancer treatment paradigms and contribute to tumour progression and metastasis. As abundant tumour-promoting cells in the ECM, cancer-associated fibroblasts (CAFs) are promising targets for novel anti-tumour interventions. Nonetheless, related clinical trials are hampered by the lack of specific markers and elusive differences between CAF subtypes. Here, we review the origins and functional diversity of CAFs and show how they create a tumour-promoting milieu, focusing on the crosstalk between CAFs, tumour cells, and immune cells in the tumour microenvironment. Furthermore, relevant clinical advances and potential therapeutic strategies relating to CAFs are discussed.
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Affiliation(s)
- Tianyi Zhang
- grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China ,grid.450259.f0000 0004 1804 2516Key Laboratory of Space Radiobiology of Gansu Province & Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Yanxian Ren
- grid.412643.60000 0004 1757 2902Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China
| | - Pengfei Yang
- grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China ,grid.450259.f0000 0004 1804 2516Key Laboratory of Space Radiobiology of Gansu Province & Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Jufang Wang
- grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China ,grid.450259.f0000 0004 1804 2516Key Laboratory of Space Radiobiology of Gansu Province & Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
| | - Heng Zhou
- grid.410726.60000 0004 1797 8419University of Chinese Academy of Sciences, Beijing, China ,grid.450259.f0000 0004 1804 2516Key Laboratory of Space Radiobiology of Gansu Province & Key Laboratory of Heavy Ion Radiation Biology and Medicine, Institute of Modern Physics, Chinese Academy of Sciences, Lanzhou, China
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18
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Zhou B, Lei JH, Wang Q, Qu TF, Cha LC, Zhan HX, Liu SL, Hu X, Sun CD, Guo WD, Qiu FB, Cao JY. Cancer-associated fibroblast-secreted miR-421 promotes pancreatic cancer by regulating the SIRT3/H3K9Ac/HIF-1α axis. Kaohsiung J Med Sci 2022; 38:1080-1092. [PMID: 36200682 DOI: 10.1002/kjm2.12590] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 07/18/2022] [Accepted: 08/09/2022] [Indexed: 11/10/2022] Open
Abstract
This study was designed to explore the effects of exosomal miR-421 secreted by cancer-associated fibroblasts (CAFs) on pancreatic cancer (PC) progression and the mechanisms involved. CAFs and exosomes (exos) were isolated and identified. PC cells were treated with CAF-derived exos (CAF-exos). Western blotting and quantitative polymerase chain reaction (qPCR) were used to measure miR-421, sirtuin-3 (SIRT3), and hypoxia duciblefactors-1 alpha (HIF-1α) levels. Cell counting kit-8 (CCK-8), wound-healing, and transwell migration assays were used to measure proliferation, migration, and invasion abilities of the cells. Dual-luciferase assay and RNA immunoprecipitation (RIP) experiment analyzed the relationship between miR-421 and SIRT3. Chromatin immunoprecipitation (f)-verified H3K9Ac enrichment in the HIF-1α promoter region. In vivo tumorigenesis experiments were performed to further explore the effects of exosomal miR-421 from CAFs on PC. CAFs and exos were successfully isolated. CAF-exo-treated PC cells highly expressed miR-421 and had increased cell proliferation, migration, and invasion abilities. Knocking down miR-421 increased the expression of SIRT3. SIRT3 is a target of miR-421, and inhibiting the expression of SIRT3 reversed the negative effects of miR-421 knockdown on PC cell. Knocking down miR-421 in CAF-exo inhibited the expression of HIF-1α in PC cells. Moreover, SIRT3-mediated HIF-1α expression by regulating H3K9Ac. HIF-1α overexpression reversed the inhibiting effects of SIRT3 overexpression on PC progression and counteracted the inhibiting effects of miR-421 knockdown on glycolysis. Moreover, in vivo tumorigenesis experiments showed that knocking down miR-421 attenuated CAF-exo induced tumor growth. Exosomal miR-421 from CAFs promoted PC progression by regulating the SIRT3/H3K9Ac/HIF-1α axis. This study provided insights into the molecular mechanism of PC.
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Affiliation(s)
- Bin Zhou
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Jing-Hao Lei
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Qiang Wang
- Department of Anesthesiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Teng-Fei Qu
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Li-Chao Cha
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Han-Xiang Zhan
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, Shandong Province, People's Republic of China
| | - Shang-Long Liu
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Xiao Hu
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Chuan-Dong Sun
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Wei-Dong Guo
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Fa-Bo Qiu
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
| | - Jing-Yu Cao
- Department of Hepatobiliary and Pancreatic Surgery and Retroperitoneal Tumor Surgery, the Affiliated Hospital of Qingdao University, Qingdao, People's Republic of China
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Nishimura T, Takadate T, Maeda S, Suzuki T, Minowa T, Fukuda T, Bando Y, Unno M. Disease-related protein co-expression networks are associated with the prognosis of resectable node-positive pancreatic ductal adenocarcinoma. Sci Rep 2022; 12:14709. [PMID: 36038612 PMCID: PMC9424258 DOI: 10.1038/s41598-022-19182-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 08/25/2022] [Indexed: 12/05/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a multifactorial disease, the molecular profile of which remains unclear. This study aimed at unveiling the disease-related protein networks associated with different outcomes of resectable, node-positive PDAC cases. We assessed laser-microdissected cancerous cells from PDAC tissues of a poor outcome group (POG; n = 4) and a better outcome group (BOG; n = 4). Noncancerous pancreatic duct tissues (n = 5) were used as the reference. We identified four representative network modules by applying a weighted network correlation analysis to the obtained quantitative PDAC proteome datasets. Two network modules that were significant for POG were associated with the heat shock response to hypoxia-related stress; in the latter, a large involvement of the non-canonical Hedgehog pathway (regulated by GLI1), the internal ribosome entry site-mediated cap-independent translation, the inositol requiring enzyme 1-alpha (IRE1α)/X-box binding protein 1 pathway of the unfolding protein response (UPR), and the aerobic glycolysis was observed. By contrast, the BOG characteristic module was involved in the inactivation of the UPR pathway via the synoviolin 1-dependent proteasomal degradation of IRE1α, the activation of SOX2, and the loss of PALB2 (partner and localizer of BRCA2) function, all potentially suppressing malignant tumor development. Our findings might facilitate future therapeutic strategies for PDAC.
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Affiliation(s)
- Toshihide Nishimura
- Department of Translational Medicine Informatics, St. Marianna University School of Medicine, Kawasaki, Kanagawa, 216-8511, Japan. .,Biosys Technologies, Inc., Tokyo, Tokyo, 153-8904, Japan.
| | - Tatsuyuki Takadate
- Department of Surgery, National Hospital Organization Sendai Medical Center, Sendai, Miyagi, 983-8520, Japan
| | - Shimpei Maeda
- Department of Surgery, Saitama Medical Center, Jichi Medical University, Shimotsuke, Tochigi, 329-0498, Japan
| | - Takashi Suzuki
- Department of Pathology and Histotechnology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8574, Japan
| | - Takashi Minowa
- Nanotechnology Innovation Station, National Institute for Materials Science, Tsukuba, Ibaraki, Japan
| | - Tetsuya Fukuda
- Biosys Technologies, Inc., Tokyo, Tokyo, 153-8904, Japan
| | - Yasuhiko Bando
- Biosys Technologies, Inc., Tokyo, Tokyo, 153-8904, Japan
| | - Michiaki Unno
- Department of Surgery, National Hospital Organization Sendai Medical Center, Sendai, Miyagi, 983-8520, Japan.,Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, 980-8574, Japan
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20
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In Vitro Differentiation of Human Amniotic Epithelial Cells into Hepatocyte-like Cells. Cells 2022; 11:cells11142138. [PMID: 35883581 PMCID: PMC9317663 DOI: 10.3390/cells11142138] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 06/29/2022] [Accepted: 07/04/2022] [Indexed: 02/05/2023] Open
Abstract
Human amniotic epithelial cells (hAECs) represent an interesting clinical alternative to human embryonic (hESCs) and induced pluripotent (hiPSCs) stem cells in regenerative medicine. The potential of hAECs can be enhanced ex vivo by their partial pre-differentiation. The aim of this study was to evaluate the effectiveness of 18-day differentiation of hAECs into endodermal cells, hepatic precursor cells, and cells showing functional features of hepatocytes using culture media supplemented with high (100 ng/mL) concentrations of EGF or HGF. The cells obtained after differentiation showed changes in morphology and increased expression of AFP, ALB, CYP3A4, CYP3A7, and GSTP1 genes. HGF was more effective than EGF in increasing the expression of liver-specific genes in hAECs. However, EGF stimulated the differentiation process more efficiently and yielded more hepatocyte-like cells capable of synthesizing α-fetoprotein during differentiation. Additionally, after 18 days, GST transferases, albumin, and CYP P450s, which proved their partial functionality, were expressed. In summary, HGF and EGF at a dose of 100 ng/mL can be successfully used to obtain hepatocyte-like cells between days 7 and 18 of hAEC differentiation. However, the effectiveness of this process is lower compared with hiPSC differentiation; therefore, optimization of the composition of the medium requires further research.
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21
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Wang SY, Hu QC, Wu T, Xia J, Tao XA, Cheng B. Abnormal lipid synthesis as a therapeutic target for cancer stem cells. World J Stem Cells 2022; 14:146-162. [PMID: 35432735 PMCID: PMC8963380 DOI: 10.4252/wjsc.v14.i2.146] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/19/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.
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Affiliation(s)
- Si-Yu Wang
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Qin-Chao Hu
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Tong Wu
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Juan Xia
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Xiao-An Tao
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Bin Cheng
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
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22
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Yang Z, Deng W, Zhang X, An Y, Liu Y, Yao H, Zhang Z. Opportunities and Challenges of Nanoparticles in Digestive Tumours as Anti-Angiogenic Therapies. Front Oncol 2022; 11:789330. [PMID: 35083147 PMCID: PMC8784389 DOI: 10.3389/fonc.2021.789330] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 12/10/2021] [Indexed: 01/04/2023] Open
Abstract
Digestive tumours, a common kind of malignancy worldwide, have recently led to the most tumour-related deaths. Angiogenesis, the process of forming novel blood vessels from pre-existing vessels, is involved in various physiological and pathological processes in the body. Many studies suggest that abnormal angiogenesis plays an important role in the growth, progression, and metastasis of digestive tumours. Therefore, anti-angiogenic therapy is considered a promising target for improving therapeutic efficacy. Traditional strategies such as bevacizumab and regorafenib can target and block the activity of proangiogenic factors to treat digestive tumours. However, due to resistance and some limitations, such as poor pharmacokinetics, their efficacy is not always satisfactory. In recent years, nanotechnology-based anti-angiogenic therapies have emerged as a new way to treat digestive tumours. Compared with commonly used drugs, nanoparticles show great potential in tumour targeted delivery, controlled drug release, prolonged cycle time, and increased drug bioavailability. Therefore, anti-angiogenic nanoparticles may be an effective complementary therapy to treat digestive tumours. In this review, we outline the different mechanisms of angiogenesis, the effects of nanoparticles on angiogenesis, and their biomedical applications in various kinds of digestive tumours. In addition, the opportunities and challenges are briefly discussed.
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Affiliation(s)
| | | | | | | | | | - Hongwei Yao
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University and National Clinical Research Center for Digestive Diseases, Beijing, China
| | - Zhongtao Zhang
- Department of General Surgery, Beijing Friendship Hospital, Capital Medical University and National Clinical Research Center for Digestive Diseases, Beijing, China
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23
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Zhang Z, Zhang HJ. Glycometabolic rearrangements-aerobic glycolysis in pancreatic ductal adenocarcinoma (PDAC): roles, regulatory networks, and therapeutic potential. Expert Opin Ther Targets 2021; 25:1077-1093. [PMID: 34874212 DOI: 10.1080/14728222.2021.2015321] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Glycometabolic rearrangements (aerobic glycolysis) is a hallmark of pancreatic ductal adenocarcinoma (PDAC) and contributes to tumorigenesis and progression through numerous mechanisms. The targeting of aerobic glycolysis is recognized as a potential therapeutic strategy which offers the possibility of improving treatment outcomes for PDAC patients. AREAS COVERED In this review, the role of aerobic glycolysis and its regulatory networks in PDAC are discussed. The targeting of aerobic glycolysis in PDAC is examined, and its therapeutic potential is evaluated. The relevant literature published from 2001 to 2021 was searched in databases including PubMed, Scopus, and Embase. EXPERT OPINION Regulatory networks of aerobic glycolysis in PDAC are based on key factors such as c-Myc, hypoxia-inducible factor 1α, the mammalian target of rapamycin pathway, and non-coding RNAs. Experimental evidence suggests that modulators or inhibitors of aerobic glycolysis promote therapeutic effects in preclinical tumor models. Nevertheless, successful clinical translation of drugs that target aerobic glycolysis in PDAC is an obstacle. Moreover, it is necessary to identify the potential targets for future interventions from regulatory networks to design efficacious and safer agents.
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Affiliation(s)
- Zhong Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, People's Republic of China
| | - Hai-Jun Zhang
- Department of Oncology, Zhongda Hospital, Medical School of Southeast University, Nanjing, People's Republic of China
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24
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Loh JJ, Ma S. The Role of Cancer-Associated Fibroblast as a Dynamic Player in Mediating Cancer Stemness in the Tumor Microenvironment. Front Cell Dev Biol 2021; 9:727640. [PMID: 34760886 PMCID: PMC8573407 DOI: 10.3389/fcell.2021.727640] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 09/24/2021] [Indexed: 01/15/2023] Open
Abstract
The enrichment of cancer-associated fibroblast (CAFs) in a tumor microenvironment (TME) cultivates a pro-tumorigenic niche via aberrant paracrine signaling and matrix remodeling. A favorable niche is critical to the maintenance of cancer stem cells (CSCs), a population of cells that are characterized by their enhanced ability to self-renew, metastasis, and develop therapy resistance. Mounting evidence illustrates the interplay between CAF and cancer cells expedites malignant progression. Therefore, targeting the key cellular components and factors in the niche may promote a more efficacious treatment. In this study, we discuss how CAF orchestrates a niche that enhances CSC features and the potential therapeutic implication.
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Affiliation(s)
- Jia Jian Loh
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong
| | - Stephanie Ma
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Pokfulam, Hong Kong, SAR China
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25
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Brisset M, Grandin M, Bernet A, Mehlen P, Hollande F. Dependence receptors: new targets for cancer therapy. EMBO Mol Med 2021; 13:e14495. [PMID: 34542930 PMCID: PMC8573599 DOI: 10.15252/emmm.202114495] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 08/11/2021] [Accepted: 08/11/2021] [Indexed: 12/22/2022] Open
Abstract
Dependence receptors are known to promote survival and positive signaling such as proliferation, migration, and differentiation when activated, but to actively trigger apoptosis when unbound to their ligand. Their abnormal regulation was shown to be an important feature of tumorigenesis, allowing cancer cells to escape apoptosis triggered by these receptors while promoting in parallel major aspects of tumorigenesis such as proliferation, angiogenesis, invasiveness, and chemoresistance. This involvement in multiple cancer hallmarks has raised interest in dependence receptors as targets for cancer therapy. Although additional studies remain necessary to fully understand the complexity of signaling pathways activated by these receptors and to target them efficiently, it is now clear that dependence receptors represent very exciting targets for future cancer treatment. This manuscript reviews current knowledge on the contribution of dependence receptors to cancer and highlights the potential for therapies that activate pro-apoptotic functions of these proteins.
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Affiliation(s)
- Morgan Brisset
- Department of Clinical Pathology, Victorian Comprehensive Cancer CentreThe University of MelbourneMelbourneVic.Australia
- University of Melbourne Centre for Cancer ResearchVictorian Comprehensive Cancer CentreMelbourneVic.Australia
| | - Mélodie Grandin
- Department of Clinical Pathology, Victorian Comprehensive Cancer CentreThe University of MelbourneMelbourneVic.Australia
- University of Melbourne Centre for Cancer ResearchVictorian Comprehensive Cancer CentreMelbourneVic.Australia
| | - Agnès Bernet
- Apoptosis, Cancer and Development LaboratoryCentre de Recherche en Cancérologie de Lyon, INSERM U1052‐CNRS UMR5286Centre Léon BérardUniversité de LyonLyonFrance
| | - Patrick Mehlen
- Apoptosis, Cancer and Development LaboratoryCentre de Recherche en Cancérologie de Lyon, INSERM U1052‐CNRS UMR5286Centre Léon BérardUniversité de LyonLyonFrance
| | - Frédéric Hollande
- Department of Clinical Pathology, Victorian Comprehensive Cancer CentreThe University of MelbourneMelbourneVic.Australia
- University of Melbourne Centre for Cancer ResearchVictorian Comprehensive Cancer CentreMelbourneVic.Australia
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26
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Tao Y, Shao F, Cai M, Liu Z, Peng Y, Huang Q, Meng F. Activated Pancreatic Stellate Cells Enhance the Warburg Effect to Cause the Malignant Development in Chronic Pancreatitis. Front Oncol 2021; 11:714598. [PMID: 34540683 PMCID: PMC8446660 DOI: 10.3389/fonc.2021.714598] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2021] [Accepted: 08/16/2021] [Indexed: 12/03/2022] Open
Abstract
Chronic pancreatitis (CP) is a precancerous condition associated with pancreatic ductal adenocarcinoma (PDAC), but its evolutionary mechanism is unclear. Pancreatic stellate cells (PSCs) are closely related to the occurrence and development of CP and PDAC, but it is not clear whether PSCs play a key role in this “inflammation-cancer transition”. Our research found that co-culture with activated PSCs promoted the proliferation, migration and invasion of normal pancreatic duct epithelial cells and pancreatic cancer cells. At the same time, activated PSCs had a significant effect on the expression of the glycolysis markers (pyruvate kinase M2, lactate dehydrogenase A, glucose transporter 1, hexokinase-II and monocarboxylate transporter 4; PKM2, LDHA, GLUT1, HK2 and MCT4) in normal pancreatic duct epithelial cells and pancreatic cancer cells and increased lactic acid production and glucose consumption in these two cells. In vivo experiments showed that the expression of the glycolysis markers in pancreatic duct epithelial cells and the marker protein (α-SMA) of activated PSCs in the pancreatic duct peripancreatic interstitium were higher in pancreatic cancer tissues and chronic pancreatitis tissues than in normal pancreatic tissues in both animals and humans. In addition, analysis of human tissue specimens showed that there is a correlation between the expression of glycolysis markers and α-SMA. These findings indicate that activated PSCs play an important role in the development and progression of chronic pancreatitis into pancreatic cancer by regulating and promoting aerobic glycolysis. Our research provides a new theoretical basis for further understanding the mechanism of CP malignancy and the selection of targets for reversing CP malignancy.
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Affiliation(s)
- Ye Tao
- Department of General Surgery, Anhui Provincial Hospital Affiliated of Anhui Medical University, Hefei, China
| | - Feng Shao
- Department of General Surgery, The First Affiliated Hospital of University of Science & Technology of China, Anhui Provincial Hospital, Hefei, China
| | - Ming Cai
- Department of General Surgery, Anhui Provincial Hospital Affiliated of Anhui Medical University, Hefei, China
| | - Zhen Liu
- Department of General Surgery, The First Affiliated Hospital of University of Science & Technology of China, Anhui Provincial Hospital, Hefei, China
| | - Yao Peng
- Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Qiang Huang
- Department of General Surgery, Anhui Provincial Hospital Affiliated of Anhui Medical University, Hefei, China
| | - Futao Meng
- Department of General Surgery, The First Affiliated Hospital of University of Science & Technology of China, Anhui Provincial Hospital, Hefei, China.,Department of Surgical Oncology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China
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27
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Shi C, Zhang S, Guo C, Tie J. Yap-Hippo Signaling Activates Mitochondrial Protection and Sustains Breast Cancer Viability under Hypoxic Stress. JOURNAL OF ONCOLOGY 2021; 2021:5212721. [PMID: 34567116 PMCID: PMC8463197 DOI: 10.1155/2021/5212721] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 11/17/2022]
Abstract
Yes-associated protein (Yap) is a transcriptional regulator that upregulates oncogenes and downregulates tumor repressor genes. In this study, we analyzed protein expression, RNA transcription, and signaling pathways to determine the function and mechanism of Yap in breast cancer survival during hypoxic stress. Yap transcription was drastically upregulated by hypoxia in a time-dependent manner. siRNA-mediated Yap knockdown attenuated breast cancer viability and impaired cell proliferation under hypoxic conditions. Yap knockdown induced mitochondrial stress, including mitochondrial membrane potential reduction, mitochondrial oxidative stress, and ATP exhaustion after exposure to hypoxia. It also repressed mitochondrial protective systems, including mitophagy and mitochondrial fusion upon exposure to hypoxia. Finally, our data showed that Yap knockdown suppresses MCF-7 cell migration by inhibiting F-actin transcription and promoting lamellipodium degradation under hypoxic stress. Taken together, Yap maintenance of mitochondrial function and activation of F-actin/lamellipodium signaling is required for breast cancer survival, migration, and proliferation under hypoxic stress.
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Affiliation(s)
- Chen Shi
- Department of Radiation Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Siyuan Zhang
- Department of Radiation Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Changkuo Guo
- Department of Radiation Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
| | - Jian Tie
- Department of Radiation Oncology, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital and Institute, Beijing 100142, China
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28
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The metabolic flexibility of quiescent CSC: implications for chemotherapy resistance. Cell Death Dis 2021; 12:835. [PMID: 34482364 PMCID: PMC8418609 DOI: 10.1038/s41419-021-04116-6] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 08/10/2021] [Accepted: 08/20/2021] [Indexed: 12/11/2022]
Abstract
Quiescence has been observed in stem cells (SCs), including adult SCs and cancer SCs (CSCs). Conventional chemotherapies mostly target proliferating cancer cells, while the quiescent state favors CSCs escape to chemotherapeutic drugs, leaving risks for tumor recurrence or metastasis. The tumor microenvironment (TME) provides various signals that maintain resident quiescent CSCs, protect them from immune surveillance, and facilitates their recurrence potential. Since the TME has the potential to support and initiate stem cell-like programs in cancer cells, targeting the TME components may prove to be a powerful modality for the treatment of chemotherapy resistance. In addition, an increasing number of studies have discovered that CSCs exhibit the potential of metabolic flexibility when metabolic substrates are limited, and display increased robustness in response to stress. Accompanied by chemotherapy that targets proliferative cancer cells, treatments that modulate CSC quiescence through the regulation of metabolic pathways also show promise. In this review, we focus on the roles of metabolic flexibility and the TME on CSCs quiescence and further discuss potential treatments of targeting CSCs and the TME to limit chemotherapy resistance.
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29
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Najafi M, Majidpoor J, Toolee H, Mortezaee K. The current knowledge concerning solid cancer and therapy. J Biochem Mol Toxicol 2021; 35:e22900. [PMID: 34462987 DOI: 10.1002/jbt.22900] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 07/29/2021] [Accepted: 08/20/2021] [Indexed: 12/25/2022]
Abstract
Solid cancers comprise a large number of new cases and deaths from cancer each year globally. There are a number of strategies for addressing tumors raised from solid organs including surgery, chemotherapy, radiotherapy, targeted therapy, immunotherapy, combinational therapy, and stem cell and extracellular vesicle (EV) therapy. Surgery, radiotherapy, and chemotherapy are the dominant cures, but are not always effective, in which even in a localized tumor there is a possibility of tumor relapse after surgical resection. Over half of the cancer patients will receive radiotherapy as a part of their therapeutic schedule. Radiotherapy can cause an abscopal response for boosting the activity of the immune system outside the local field of radiation, but it may also cause an unwanted bystander effect, predisposing nonradiated cells into carcinogenesis. In the context of immunotherapy, immune checkpoint inhibition is known as the standard-of-care, but the major concern is in regard with cold cancers that show low responses to such therapy. Stem-cell therapy can be used to send prodrugs toward the tumor area; this strategy, however, has its own predicaments, such as unwanted attraction toward the other sites including healthy tissues and its instability. A substitute to such therapy and quite a novel strategy is to use EVs, by virtue of their stability and potential to cross biological barriers and long-term storage of contents. Combination therapy is the current focus. Despite advances in the field, there are still unmet concerns in the area of effective cancer therapy, raising challenges and opportunities for future investigations.
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Affiliation(s)
- Masoud Najafi
- Medical Technology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran.,Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah, Iran
| | - Jamal Majidpoor
- Department of Anatomy, School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Heidar Toolee
- Department of Anatomy, School of Medicine, Shahroud University of Medical Sciences, Shahroud, Iran
| | - Keywan Mortezaee
- Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
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30
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Mizuno M, Khaledian B, Maeda M, Hayashi T, Mizuno S, Munetsuna E, Watanabe T, Kono S, Okada S, Suzuki M, Takao S, Minami H, Asai N, Sugiyama F, Takahashi S, Shimono Y. Adipsin-Dependent Secretion of Hepatocyte Growth Factor Regulates the Adipocyte-Cancer Stem Cell Interaction. Cancers (Basel) 2021; 13:cancers13164238. [PMID: 34439392 PMCID: PMC8393397 DOI: 10.3390/cancers13164238] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/18/2021] [Accepted: 08/19/2021] [Indexed: 01/18/2023] Open
Abstract
Simple Summary Obesity, which is characterized by the excess of adipose tissue, is associated with an increased risk of multiple cancers. We have previously reported that adipsin, a secreted factor from adipocytes, enhances cancer cell proliferation and stem cell properties. In this study, we found that adipsin affected adipocytes themselves and enhanced their secretion of hepatocyte growth factor (HGF). We found that HGF enhanced the adipocyte-cancer cell interactions as a downstream effector of adipsin. Understanding the adipocyte-cancer cell interaction will provide a novel strategy to treat cancers whose initiation, invasion, and metastatic progression are associated with adipose tissues. Abstract Adipose tissue is a component of the tumor microenvironment and is involved in tumor progression. We have previously shown that adipokine adipsin (CFD) functions as an enhancer of tumor proliferation and cancer stem cell (CSC) properties in breast cancers. We established the Cfd-knockout (KO) mice and the mammary adipose tissue-derived stem cells (mADSCs) from them. Cfd-KO in mADSCs significantly reduced their ability to enhance tumorsphere formation of breast cancer patient-derived xenograft (PDX) cells, which was restored by the addition of Cfd in the culture medium. Hepatocyte growth factor (HGF) was expressed and secreted from mADSCs in a Cfd-dependent manner. HGF rescued the reduced ability of Cfd-KO mADSCs to promote tumorsphere formation in vitro and tumor formation in vivo by breast cancer PDX cells. These results suggest that HGF is a downstream effector of Cfd in mADSCs that enhances the CSC properties in breast cancers.
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Affiliation(s)
- Masahiro Mizuno
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
| | - Behnoush Khaledian
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
| | - Masao Maeda
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
- Department of Pathology, Fujita Health University School of Medicine, Toyoake 4701192, Japan;
| | - Takanori Hayashi
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
| | - Seiya Mizuno
- Laboratory Animal Resource Center, Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba 3058575, Japan; (S.M.); (F.S.); (S.T.)
| | - Eiji Munetsuna
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
| | - Takashi Watanabe
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
| | - Seishi Kono
- Division of Breast and Endocrine Surgery, Kobe University Graduate School of Medicine, Kobe 6500017, Japan; (S.K.); (S.T.)
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 8600811, Japan;
| | - Motoshi Suzuki
- Department of Molecular Oncology, Fujita Health University School of Medicine, Toyoake 4701192, Japan;
| | - Shintaro Takao
- Division of Breast and Endocrine Surgery, Kobe University Graduate School of Medicine, Kobe 6500017, Japan; (S.K.); (S.T.)
| | - Hironobu Minami
- Division of Medical Oncology/Hematology, Kobe University Graduate School of Medicine, Kobe 6500017, Japan;
| | - Naoya Asai
- Department of Pathology, Fujita Health University School of Medicine, Toyoake 4701192, Japan;
| | - Fumihiro Sugiyama
- Laboratory Animal Resource Center, Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba 3058575, Japan; (S.M.); (F.S.); (S.T.)
| | - Satoru Takahashi
- Laboratory Animal Resource Center, Transborder Medical Research Center, Faculty of Medicine, University of Tsukuba, Tsukuba 3058575, Japan; (S.M.); (F.S.); (S.T.)
| | - Yohei Shimono
- Department of Biochemistry, Fujita Health University School of Medicine, Toyoake 4701192, Japan or (M.M.); (B.K.); (M.M.); (T.H.); (E.M.); (T.W.)
- Correspondence: ; Tel.: +81-562-932-450
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31
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Fu J, Su X, Li Z, Deng L, Liu X, Feng X, Peng J. HGF/c-MET pathway in cancer: from molecular characterization to clinical evidence. Oncogene 2021; 40:4625-4651. [PMID: 34145400 DOI: 10.1038/s41388-021-01863-w] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 05/17/2021] [Accepted: 05/24/2021] [Indexed: 02/07/2023]
Abstract
This review provides a comprehensive landscape of HGF/c-MET (hepatocyte growth factor (HGF) /mesenchymal-epithelial transition factor (c-MET)) signaling pathway in cancers. First, we generalize the compelling influence of HGF/c-MET pathway on multiple cellular processes. Then, we present the genomic characterization of HGF/c-MET pathway in carcinogenesis. Furthermore, we extensively illustrate the malignant biological behaviors of HGF/c-MET pathway in cancers, in which hyperactive HGF/c-MET signaling is considered as a hallmark. In addition, we investigate the current clinical trials of HGF/c-MET-targeted therapy in cancers. We find that although HGF/c-MET-targeted therapy has led to breakthroughs in certain cancers, monotherapy of targeting HGF/c-MET has failed to demonstrate significant clinical efficacy in most cancers. With the advantage of the combinations of HGF/c-MET-targeted therapy, the exploration of more options of combinational targeted therapy in cancers may be the major challenge in the future.
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Affiliation(s)
- Jianjiang Fu
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Xiaorui Su
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Zhihua Li
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
- Department of Fetal Medicine and Prenatal Diagnosis, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Ling Deng
- Department of Molecular Diagnostics, Sun Yat-sen University Cancer Center, Guangzhou, China
| | - Xiawei Liu
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China
| | - Xuancheng Feng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China.
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China.
| | - Juan Peng
- Department of Pathology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
- The Third Clinical School of Guangzhou Medical University, Guangzhou, China.
- Key Laboratory of Reproduction and Genetics of Guangdong Higher Education Institutes, Guangzhou, China.
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32
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Song W, He X, Gong P, Yang Y, Huang S, Zeng Y, Wei L, Zhang J. Glycolysis-Related Gene Expression Profiling Screen for Prognostic Risk Signature of Pancreatic Ductal Adenocarcinoma. Front Genet 2021; 12:639246. [PMID: 34249078 PMCID: PMC8261051 DOI: 10.3389/fgene.2021.639246] [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: 02/14/2021] [Accepted: 05/25/2021] [Indexed: 12/21/2022] Open
Abstract
Objective: Pancreatic ductal adenocarcinoma (PDAC) is highly lethal. Although progress has been made in the treatment of PDAC, its prognosis remains unsatisfactory. This study aimed to develop novel prognostic genes related to glycolysis in PDAC and to apply these genes to new risk stratification. Methods: In this study, based on the Cancer Genome Atlas (TCGA) PAAD cohort, the expression level of glycolysis-related gene at mRNA level in PAAD and its relationship with prognosis were analyzed. Non-negative matrix decomposition (NMF) clustering was used to cluster PDAC patients according to glycolytic genes. Prognostic glycolytic genes, screened by univariate Cox analysis and LASSO regression analysis were established to calculate risk scores. The differentially expressed genes (DEGs) in the high-risk group and the low-risk group were analyzed, and the signal pathway was further enriched to analyze the correlation between glycolysis genes. In addition, based on RNA-seq data, CIBERSORT was used to evaluate the infiltration degree of immune cells in PDAC samples, and ESTIMATE was used to calculate the immune score of the samples. Results: A total of 319 glycolysis-related genes were retrieved, and all PDAC samples were divided into two clusters by NMF cluster analysis. Survival analysis showed that PDAC patients in cluster 1 had shorter survival time and worse prognosis compared with cluster 2 samples (P < 0.001). A risk prediction model based on 11 glycolysis genes was constructed, according to which patients were divided into two groups, with significantly poorer prognosis in high-risk group than in low-risk group (P < 0.001). Both internal validation and external dataset validation demonstrate good predictive ability of the model (AUC = 0.805, P < 0.001; AUC = 0.763, P < 0.001). Gene aggregation analysis showed that DEGs highly expressed in high-risk group were mainly concentrated in the glycolysis level, immune status, and tumor cell proliferation, etc. In addition, the samples in high-risk group showed immunosuppressed status and infiltrated by relatively more macrophages and less CD8+T cell. Conclusions: These findings suggested that the gene signature based on glycolysis-related genes had potential diagnostic, therapeutic, and prognostic value for PDAC.
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Affiliation(s)
- Wenjing Song
- Department of Breast and Thyroid Surgery, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Xin He
- Department of Breast and Thyroid Surgery, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Pengju Gong
- Department of Breast and Thyroid Surgery, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Yan Yang
- Department of Breast and Thyroid Surgery, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Sirui Huang
- Department of Breast and Thyroid Surgery, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Yifan Zeng
- Department of Breast and Thyroid Surgery, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital, Wuhan University, Wuhan, China
| | - Lei Wei
- Department of Pathology and Pathophysiology, School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Jingwei Zhang
- Department of Breast and Thyroid Surgery, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital, Wuhan University, Wuhan, China
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Zhou J, Zhang N, Zhang W, Lu C, Xu F. The YAP/HIF-1α/miR-182/EGR2 axis is implicated in asthma severity through the control of Th17 cell differentiation. Cell Biosci 2021; 11:84. [PMID: 33980319 PMCID: PMC8117288 DOI: 10.1186/s13578-021-00560-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2020] [Accepted: 02/18/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Asthma is a heterogeneous chronic inflammatory disease of the airway, involving reversible airflow limitation and airway remodeling. T helper 17 (Th17) cells play an important role in the pathogenesis of allergic asthma. However, there is limited understanding of the signaling pathways controlling Th17 cell differentiation in asthma. The aim of this study was to investigate if the Yes-associated protein (YAP)/hypoxia inducible factor-1α (HIF-1α)/microRNA-182 (miR-182)/early growth response 2 (EGR2) axis is involved in mediating Th17 cell differentiation and disease severity in asthma. METHODS The study included 29 pediatric patients with asthma, 22 healthy volunteers, ovalbumin-induced murine asthma models, and mouse naive CD4+ T cells. The subpopulation of Th17 cells was examined by flow cytometry. The levels of interleukin-17A were determined by enzyme linked immunosorbent assay. Chromatin immunoprecipitation-quantitative polymerase chain reaction assays and dual-luciferase reporter gene assays were performed to examine interactions between HIF-1α and miR-182, and between miR-182 and EGR2. RESULTS YAP, HIF-1α, and miR-182 were upregulated but EGR2 was downregulated in human and mouse peripheral blood mononuclear cells from the asthma group. Abundant expression of YAP and HIF-1α promoted miR-182 expression and then inhibited EGR2, a target of miR-182, thus enhancing Th17 differentiation and deteriorating asthma and lipid metabolism dysfunction. In addition, in vivo overexpression of EGR2 countered the promoting effect of the YAP/HIF-1α/miR-182 axis on asthma and lipid metabolism dysfunction. CONCLUSION These results indicate that activation of the YAP/HIF-1α/miR-182/EGR2 axis may promote Th17 cell differentiation, exacerbate asthma development, and aggravate lipid metabolism dysfunction, thus suggesting a potential therapeutic target for asthma.
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Affiliation(s)
- Jing Zhou
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanchang University, No. 17, Yongwai Street, Donghu District, Nanchang, 330006, People's Republic of China
| | - Ning Zhang
- Department of Imaging, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, People's Republic of China
| | - Wei Zhang
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanchang University, No. 17, Yongwai Street, Donghu District, Nanchang, 330006, People's Republic of China
| | - Caiju Lu
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanchang University, No. 17, Yongwai Street, Donghu District, Nanchang, 330006, People's Republic of China
| | - Fei Xu
- Department of Respiratory Medicine, The First Affiliated Hospital of Nanchang University, No. 17, Yongwai Street, Donghu District, Nanchang, 330006, People's Republic of China.
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Mu R, Zou YK, Tu K, Wang DB, Tang D, Yu Z, Zhao L. Hypoxia Promotes Pancreatic Cancer Cell Dedifferentiation to Stem-Like Cell Phenotypes With High Tumorigenic Potential by the HIF-1α/Notch Signaling Pathway. Pancreas 2021; 50:756-765. [PMID: 34016895 DOI: 10.1097/mpa.0000000000001828] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
OBJECTIVES This study aimed to investigate the effect and mechanism of hypoxia on pancreatic cancer (PC) cell dedifferentiation and tumorigenic potential. METHODS Inhibition of hypoxia-inducible factor 1α (HIF-1α) and overexpression of Notch1 in PC HS766T cell lines were by lentiviral transfection. The expression of stem cell-specific markers C-X-C motif chemokine receptor 4, CD44, and Nestin was detected by immunofluorescence and Western blot assays. Cell invasion capacity was examined by Transwell assay. Tumorigenic potential was measured in an in situ tumor transplantation experiment. The expression of HIF-1α, Notch signals, and apoptosis signals was examined by Western blot assay. RESULTS Hypoxia promoted PC cells to dedifferentiate into stem-like cells by upregulating HIF-1α and activating Notch signals. Silencing of HIF-1α significantly repressed cell dedifferentiation and invasion, whereas overexpression of Notch1 reversed the effect of HIF-1α repression. In situ tumor transplantation experiment further confirmed that hypoxia promoted tumorigenic ability through upregulating HIF-1α. Moreover, the expression of HIF-1α and Notch1 was significantly increased in human PC tissues, and high expression of HIF-1α was correlated with poor survival rate. CONCLUSIONS Hypoxia promoted PC cell dedifferentiation to stem-like cell phenotypes with high tumorigenic potential by activating HIF-1α/Notch signaling pathway, indicating a novel role in regulating PC progression.
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Affiliation(s)
- Rui Mu
- From the Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Zunyi Medical University
| | - Yong-Kang Zou
- From the Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Zunyi Medical University
| | - Kui Tu
- From the Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Zunyi Medical University
| | - Dian-Bei Wang
- From the Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Zunyi Medical University
| | - Dan Tang
- Department of Hepatopancreatobiliary Surgery, Second Affiliated Hospital of Zunyi Medical University
| | - Zhou Yu
- Zunyi Medical University, Zunyi, China
| | - Lijin Zhao
- From the Department of Hepatopancreatobiliary Surgery, Affiliated Hospital of Zunyi Medical University
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Demény MA, Virág L. The PARP Enzyme Family and the Hallmarks of Cancer Part 2: Hallmarks Related to Cancer Host Interactions. Cancers (Basel) 2021; 13:2057. [PMID: 33923319 PMCID: PMC8123211 DOI: 10.3390/cancers13092057] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 04/07/2021] [Accepted: 04/21/2021] [Indexed: 12/12/2022] Open
Abstract
Poly (ADP-ribose) polymerases (PARPs) modify target proteins with a single ADP-ribose unit or with a poly (ADP-ribose) (PAR) polymer. PARP inhibitors (PARPis) recently became clinically available for the treatment of BRCA1/2 deficient tumors via the synthetic lethality paradigm. This personalized treatment primarily targets DNA damage-responsive PARPs (PARP1-3). However, the biological roles of PARP family member enzymes are broad; therefore, the effects of PARPis should be viewed in a much wider context, which includes complex effects on all known hallmarks of cancer. In the companion paper (part 1) to this review, we presented the fundamental roles of PARPs in intrinsic cancer cell hallmarks, such as uncontrolled proliferation, evasion of growth suppressors, cell death resistance, genome instability, replicative immortality, and reprogrammed metabolism. In the second part of this review, we present evidence linking PARPs to cancer-associated inflammation, anti-cancer immune response, invasion, and metastasis. A comprehensive overview of the roles of PARPs can facilitate the identification of novel cancer treatment opportunities and barriers limiting the efficacy of PARPi compounds.
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Affiliation(s)
- Máté A. Demény
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- MTA-DE Cell Biology and Signaling Research Group, 4032 Debrecen, Hungary
| | - László Virág
- Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032 Debrecen, Hungary
- MTA-DE Cell Biology and Signaling Research Group, 4032 Debrecen, Hungary
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Goodwin JS, Tsai LL, Mwin D, Coutinho de Souza P, Dialani S, Moon JT, Zhang Z, Grant AK, Ahmed M. In vivo detection of distal tumor glycolytic flux stimulated by hepatic ablation in a breast cancer model using hyperpolarized 13C MRI. Magn Reson Imaging 2021; 80:90-97. [PMID: 33901585 DOI: 10.1016/j.mri.2021.04.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Revised: 04/11/2021] [Accepted: 04/21/2021] [Indexed: 11/30/2022]
Abstract
PURPOSE Hepatic thermal ablation therapy can result in c-Met-mediated off-target stimulation of distal tumor growth. The purpose of this study was to determine if a similar effect on tumor metabolism could be detected in vivo with hyperpolarized 13C MRI. MATERIALS AND METHODS In this prospective study, female Fisher rats (n = 28, 120-150 g) were implanted with R3230 rat breast adenocarcinoma cells and assigned to either: sham surgery, hepatic radiofrequency ablation (RFA), or hepatic RFA + adjuvant c-Met inhibition with PHA-665752 (RFA + PHA). PHA-665752 was administered at 0.83 mg/kg at 24 h post-RFA. Tumor growth was measured daily. MRI was performed 24 h before and 72 h after treatment on 14 rats, and the conversion of 13C-pyruvate into 13C-lactate within each tumor was quantified as lactate:pyruvate ratio (LPR). Comparisons of tumor growth and LPR were performed using paired and unpaired t-tests. RESULTS Hepatic RFA alone resulted in increased growth of the distant tumor compared to sham treatment (0.50 ± 0.13 mm/day versus 0.11 ± 0.07 mm/day; p < 0.001), whereas RFA + PHA (0.06 ± 0.13 mm/day) resulted in no significant change from sham treatment (p = 0.28). A significant increase in LPR was seen following hepatic RFA (+0.016 ± 0.010, p = 0.02), while LPR was unchanged for sham treatment (-0.048 ± 0.051, p = 0.10) or RFA + PHA (0.003 ± 0.041, p = 0.90). CONCLUSION In vivo hyperpolarized 13C MRI can detect hepatic RFA-induced increase in lactate flux within a distant R3230 tumor, which correlates with increased tumor growth. Adjuvant inhibition of c-Met suppresses these off-target effects, supporting a role for the HGF/c-Met signaling axis in these tumorigenic responses.
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Affiliation(s)
- J Scott Goodwin
- Beth Israel Deaconess Medical Center, Department of Radiology, 330 Brookline Avenue, Boston, MA 02215, USA; UT Austin Dell Medical School Transitional Program, 1400 IH-35, CEC 2.404, Austin, TX 78701, USA
| | - Leo L Tsai
- Beth Israel Deaconess Medical Center, Department of Radiology, 330 Brookline Avenue, Boston, MA 02215, USA.
| | - David Mwin
- Beth Israel Deaconess Medical Center, Department of Radiology, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Patricia Coutinho de Souza
- Beth Israel Deaconess Medical Center, Department of Radiology, 330 Brookline Avenue, Boston, MA 02215, USA; Genmab, 777 Scudders Mill Rd, Plainsboro, NJ 08536, USA
| | - Svayam Dialani
- Beth Israel Deaconess Medical Center, Department of Radiology, 330 Brookline Avenue, Boston, MA 02215, USA; Northwestern University, 2145 Ridge Ave, Evanston, IL 60201, USA
| | - John T Moon
- Beth Israel Deaconess Medical Center, Department of Radiology, 330 Brookline Avenue, Boston, MA 02215, USA; Division of Interventional Radiology, Emory University School of Medicine, Emory University Hospital, 1364 Clifton Road NE, Atlanta, GA 30322, USA
| | - Zheng Zhang
- Beth Israel Deaconess Medical Center, Department of Radiology, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Aaron K Grant
- Beth Israel Deaconess Medical Center, Department of Radiology, 330 Brookline Avenue, Boston, MA 02215, USA
| | - Muneeb Ahmed
- Beth Israel Deaconess Medical Center, Department of Radiology, 330 Brookline Avenue, Boston, MA 02215, USA
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Curcio C, Brugiapaglia S, Bulfamante S, Follia L, Cappello P, Novelli F. The Glycolytic Pathway as a Target for Novel Onco-Immunology Therapies in Pancreatic Cancer. Molecules 2021; 26:1642. [PMID: 33804240 PMCID: PMC7998946 DOI: 10.3390/molecules26061642] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Revised: 03/02/2021] [Accepted: 03/11/2021] [Indexed: 02/08/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of human cancer, characterized by unrestrained progression, invasiveness and treatment resistance. To date, there are limited curative options, with surgical resection as the only effective strategy, hence the urgent need to discover novel therapies. A platform of onco-immunology targets is represented by molecules that play a role in the reprogrammed cellular metabolism as one hallmark of cancer. Due to the hypoxic tumor microenvironment (TME), PDA cells display an altered glucose metabolism-resulting in its increased uptake-and a higher glycolytic rate, which leads to lactate accumulation and them acting as fuel for cancer cells. The consequent acidification of the TME results in immunosuppression, which impairs the antitumor immunity. This review analyzes the genetic background and the emerging glycolytic enzymes that are involved in tumor progression, development and metastasis, and how this represents feasible therapeutic targets to counteract PDA. In particular, as the overexpressed or mutated glycolytic enzymes stimulate both humoral and cellular immune responses, we will discuss their possible exploitation as immunological targets in anti-PDA therapeutic strategies.
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Affiliation(s)
- Claudia Curcio
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Silvia Brugiapaglia
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Sara Bulfamante
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Laura Follia
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Computer Science Department, University of Turin, 10126 Turin, Italy
| | - Paola Cappello
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
| | - Francesco Novelli
- Department of Molecular Biotechnology and Health Sciences, University of Turin, 10126 Turin, Italy; (C.C.); (S.B.); (S.B.); (L.F.); (P.C.)
- Centro Ricerche Medicina Sperimentale, Azienda Ospedaliera Universitaria, Città della Salute e della Scienza di Torino, 10126 Turin, Italy
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Abstract
Secretory proteins in tumor tissues are important components of the tumor microenvironment. Secretory proteins act on tumor cells or stromal cells or mediate interactions between tumor cells and stromal cells, thereby affecting tumor progression and clinical treatment efficacy. In this paper, recent research advances in secretory proteins in malignant tumors are reviewed.
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Affiliation(s)
- Na Zhang
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jiajie Hao
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yan Cai
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Mingrong Wang
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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HGF/c-Met Signalling in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1270:31-44. [PMID: 33123991 DOI: 10.1007/978-3-030-47189-7_2] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Recently, it has become clearer that tumor plasticity increases the chance that cancer cells could acquire new mechanisms to escape immune surveillance, become resistant to conventional drugs, and spread to distant sites.Effectively, tumor plasticity drives adaptive response of cancer cells to hypoxia and nutrient deprivation leading to stimulation of neoangionesis or tumor escape. Therefore, tumor plasticity is believed to be a great contributor in recurrence and metastatic dissemination of cancer cells. Importantly, it could be an Achilles' heel of cancer if we could identify molecular mechanisms dictating this phenotype.The reactivation of stem-like signalling pathways is considered a great determinant of tumor plasticity; in addition, a key role has been also attributed to tumor microenvironment (TME). Indeed, it has been proved that cancer cells interact with different cells in the surrounding extracellular matrix (ECM). Interestingly, well-established communication represents a potential allied in maintenance of a plastic phenotype in cancer cells supporting tumor growth and spread. An important signalling pathway mediating cancer cell-TME crosstalk is represented by the HGF/c-Met signalling.Here, we review the role of the HGF/c-Met signalling in tumor-stroma crosstalk focusing on novel findings underlying its role in tumor plasticity, immune escape, and development of adaptive mechanisms.
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Zhang Z, Zhang H, Liu T, Chen T, Wang D, Tang D. Heterogeneous Pancreatic Stellate Cells Are Powerful Contributors to the Malignant Progression of Pancreatic Cancer. Front Cell Dev Biol 2021; 9:783617. [PMID: 34988078 PMCID: PMC8722736 DOI: 10.3389/fcell.2021.783617] [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: 09/26/2021] [Accepted: 11/24/2021] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer is associated with highly malignant tumors and poor prognosis due to strong therapeutic resistance. Accumulating evidence shows that activated pancreatic stellate cells (PSC) play an important role in the malignant progression of pancreatic cancer. In recent years, the rapid development of single-cell sequencing technology has facilitated the analysis of PSC population heterogeneity, allowing for the elucidation of the relationship between different subsets of cells with tumor development and therapeutic resistance. Researchers have identified two spatially separated, functionally complementary, and reversible subtypes, namely myofibroblastic and inflammatory PSC. Myofibroblastic PSC produce large amounts of pro-fibroproliferative collagen fibers, whereas inflammatory PSC express large amounts of inflammatory cytokines. These distinct cell subtypes cooperate to create a microenvironment suitable for cancer cell survival. Therefore, further understanding of the differentiation of PSC and their distinct functions will provide insight into more effective treatment options for pancreatic cancer patients.
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Affiliation(s)
- Zhilin Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Huan Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Tian Liu
- Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Tian Chen
- Clinical Medical College, Yangzhou University, Yangzhou, China
| | - Daorong Wang
- Department of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical College, Institute of General Surgery, Yangzhou University, Yangzhou, China
| | - Dong Tang
- Department of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical College, Institute of General Surgery, Yangzhou University, Yangzhou, China
- *Correspondence: Dong Tang,
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Khalil MI, Ghosh I, Singh V, Chen J, Zhu H, De Benedetti A. NEK1 Phosphorylation of YAP Promotes Its Stabilization and Transcriptional Output. Cancers (Basel) 2020; 12:cancers12123666. [PMID: 33297404 PMCID: PMC7762262 DOI: 10.3390/cancers12123666] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2020] [Revised: 12/04/2020] [Accepted: 12/04/2020] [Indexed: 12/13/2022] Open
Abstract
Simple Summary We earlier described the involvement of the TLK1>NEK1>ATR>Chk1 axis as a key determinant of cell cycle arrest in androgen-dependent prostate cancer (PCa) cells after androgen deprivation. We now report that the TLK1>NEK1 axis is also involved in stabilization of yes-associated protein 1 (YAP1), the transcriptional co-activator in the Hippo pathway, presumably facilitating reprogramming of the cells toward castration-resistant PCa (CRPC). NEK1 interacts with YAP1 physically resulting in its phosphorylation of 6 residues, which enhance its stability and activity. Analyses of cancer Protein Atlas and TCGA expression panels revealed a link between activated NEK1 and YAP1 expression and several YAP transcription targets. Abstract Most prostate cancer (PCa) deaths result from progressive failure in standard androgen deprivation therapy (ADT), leading to metastatic castration-resistant PCa (mCRPC); however, the mechanism and key players leading to this are not fully understood. While studying the role of tousled-like kinase 1 (TLK1) and never in mitosis gene A (NIMA)-related kinase 1 (NEK1) in a DNA damage response (DDR)-mediated cell cycle arrest in LNCaP cells treated with bicalutamide, we uncovered that overexpression of wt-NEK1 resulted in a rapid conversion to androgen-independent (AI) growth, analogous to what has been observed when YAP1 is overexpressed. We now report that overexpression of wt-NEK1 results in accumulation of YAP1, suggesting the existence of a TLK1>NEK1>YAP1 axis that leads to adaptation to AI growth. Further, YAP1 is co-immunoprecipitated with NEK1. Importantly, NEK1 was able to phosphorylate YAP1 on six residues in vitro, which we believe are important for stabilization of the protein, possibly by increasing its interaction with transcriptional partners. In fact, knockout (KO) of NEK1 in NT1 PCa cells resulted in a parallel decrease of YAP1 level and reduced expression of typical YAP-regulated target genes. In terms of cancer potential implications, the expression of NEK1 and YAP1 proteins was found to be increased and correlated in several cancers. These include PCa stages according to Gleason score, head and neck squamous cell carcinoma, and glioblastoma, suggesting that this co-regulation is imparted by increased YAP1 stability when NEK1 is overexpressed or activated by TLK1, and not through transcriptional co-expression. We propose that the TLK1>NEK1>YAP1 axis is a key determinant for cancer progression, particularly during the process of androgen-sensitive to -independent conversion during progression to mCRPC.
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Affiliation(s)
- Md Imtiaz Khalil
- Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, LA 71130, USA; (M.I.K.); (I.G.); (V.S.)
| | - Ishita Ghosh
- Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, LA 71130, USA; (M.I.K.); (I.G.); (V.S.)
| | - Vibha Singh
- Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, LA 71130, USA; (M.I.K.); (I.G.); (V.S.)
| | - Jing Chen
- Department of Molecular and Cellular Biochemistry and Proteomics Core, Center for Structural Biology, University of Kentucky, Lexington, KY 40506, USA; (J.C.); (H.Z.)
| | - Haining Zhu
- Department of Molecular and Cellular Biochemistry and Proteomics Core, Center for Structural Biology, University of Kentucky, Lexington, KY 40506, USA; (J.C.); (H.Z.)
| | - Arrigo De Benedetti
- Department of Biochemistry and Molecular Biology, LSU Health Sciences Center, Shreveport, LA 71130, USA; (M.I.K.); (I.G.); (V.S.)
- Correspondence: ; Tel.: +1-31-8675-5668
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Tan Z, Lei Y, Xu J, Shi S, Hua J, Zhang B, Meng Q, Liu J, Zhang Y, Wei M, Yu X, Liang C. The value of a metabolic reprogramming-related gene signature for pancreatic adenocarcinoma prognosis prediction. Aging (Albany NY) 2020; 12:24228-24241. [PMID: 33226369 PMCID: PMC7762467 DOI: 10.18632/aging.104134] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Accepted: 09/09/2020] [Indexed: 12/11/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal malignancies worldwide. Extensive enhancement of glycolysis and reprogramming of lipid metabolism are both associated with the development and progression of PDAC. Previous studies have suggested that various gene signatures could convey prognostic information about PDAC. However, the use of these signatures has some limitations, perhaps because of a lack of knowledge regarding the genetic and energy supply backgrounds of PDAC. Therefore, we conducted multi-mRNA analysis based on metabolic reprogramming to identify novel signatures for accurate prognosis prediction in PDAC patients. In this study, a three-gene signature comprising MET, ENO3 and CD36 was established to predict the overall survival of PDAC patients. The three-gene signature could divide patients into high- and low-risk groups by disparities in overall survival verified by log-rank test in two independent validation cohorts and could differentiate tumors from normal tissues with excellent accuracy in four Gene Expression Omnibus (GEO) cohorts. We also found a positive correlation between the risk score of the gene signature and inherited germline mutations in PDAC predisposition genes. A glycolysis and lipid metabolism-based gene nomogram and corresponding calibration curves showed significant performance for survival prediction in the TCGA-PDAC dataset. The high-risk designation was closely connected with oncological signatures and multiple aggressiveness-related pathways, as determined by gene set enrichment analysis (GSEA). In summary, our study developed a three-gene signature and established a prognostic nomogram that objectively predicted overall survival in PDAC. The findings could provide a reference for the prediction of overall survival and could aid in individualized management for PDAC patients.
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Affiliation(s)
- Zhen Tan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Yubin Lei
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jie Hua
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Qingcai Meng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Yiyin Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Miaoyan Wei
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
| | - Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.,Shanghai Pancreatic Cancer Institute, Shanghai 200032, China.,Pancreatic Cancer Institute, Fudan University, Shanghai 200032, China
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Pan Q, Gao Z, Zhu C, Peng Z, Song M, Li L. Overexpression of histone deacetylase SIRT1 exerts an antiangiogenic role in diabetic retinopathy via miR-20a elevation and YAP/HIF1α/VEGFA depletion. Am J Physiol Endocrinol Metab 2020; 319:E932-E943. [PMID: 32776826 DOI: 10.1152/ajpendo.00051.2020] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
As a basic member of the Class III histone deacetylases, SIRT1 has been implicated in the occurrence and progression of diabetic retinopathy (DR). The current study aimed to investigate the roles of SIRT1/miR-20a/Yse-associated protein (YAP)/hypoxia-inducible factor 1 α (HIF1α)/vascular endothelial growth factor A (VEGFA) in DR. The expression of SIRT1 was initially determined through quantitative RT-PCR and Western blot analysis following the successful establishment of a DR mouse model, followed by detection of SIRT1 catalytic activity. Retinal microvascular endothelial cells (RMECs) were cultured in media supplemented with normal glucose (NG) or high glucose (HG). Thereafter, SIRT1 was either silenced or overexpressed in RMECs, after which EdU staining and Matrigel-based tube formation assay were performed to assess cell proliferation and tube formation. The binding relationship between YAP, HIF1α, and VEGFA was further illustrated using dual-luciferase reporter assay. Preretinal neovascular cell number was tallied with the IB4-positive vascular endothelial cells, as determined by immunofluorescence. SIRT1 was poorly expressed in mice with DR and HG-treated RMECs with low catalytic activity. The proliferation and tube formation capabilities of RMECs were elevated under HG conditions, which could be reversed following overexpression of SIRT1. SIRT1 was identified as positively regulating the expression of miR-20a with YAP detected as the key target gene of miR-20a. Our data suggested that YAP could upregulate VEGFA via induction of HIF1α. Moreover, SIRT1 overexpression strongly repressed RMEC proliferation and angiogenesis, which could be reversed via restoration of YAP/HIF1α/VEGFA expression. Taken together, the key findings of our study suggest that upregulation of SIRT1 inhibits the development of DR via miR-20a-induced downregulation of YAP/HIF1α/VEGFA.
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Affiliation(s)
- Qintuo Pan
- Department of Fundus Surgery, The Eye Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Zhiqiang Gao
- Department of Fundus Surgery, The Eye Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Chenlei Zhu
- Department of Fundus Surgery, The Eye Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Zijie Peng
- Department of Fundus Surgery, The Eye Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Minmin Song
- Department of Fundus Surgery, The Eye Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
| | - Lili Li
- Department of Radiation Oncology and Chemotherapy, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, People's Republic of China
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Iannelli F, Roca MS, Lombardi R, Ciardiello C, Grumetti L, De Rienzo S, Moccia T, Vitagliano C, Sorice A, Costantini S, Milone MR, Pucci B, Leone A, Di Gennaro E, Mancini R, Ciliberto G, Bruzzese F, Budillon A. Synergistic antitumor interaction of valproic acid and simvastatin sensitizes prostate cancer to docetaxel by targeting CSCs compartment via YAP inhibition. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2020; 39:213. [PMID: 33032653 PMCID: PMC7545949 DOI: 10.1186/s13046-020-01723-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Accepted: 09/30/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Despite the introduction of several novel therapeutic approaches that improved survival, metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease. Herein we report the synergistic antitumor interaction between two well-known drugs used for years in clinical practice, the antiepileptic agent with histone deacetylase inhibitory activity valproic acid and the cholesterol lowering agent simvastatin, in mCRPC models. METHODS Synergistic anti-tumor effect was assessed on PC3, 22Rv1, DU145, DU145R80, LNCaP prostate cancer cell lines and EPN normal prostate epithelial cells, by calculating combination index (CI), caspase 3/7 activation and colony formation assays as well as on tumor spheroids and microtissues scored with luminescence 3D-cell viability assay. Cancer stem cells (CSC) compartment was studied evaluating specific markers by RT-PCR, western blotting and flow cytometry as well as by limiting dilution assay. Cholesterol content was evaluated by 1H-NMR. Overexpression of wild-type YAP and constitutively active YAP5SA were obtained by lipofectamine-based transfection and evaluated by immunofluorescence, western blotting and RT-PCR. 22Rv1 R_39 docetaxel resistant cells were selected by stepwise exposure to increasing drug concentrations. In vivo experiments were performed on xenograft models of DU145R80, 22Rv1 parental and docetaxel resistant cells, in athymic mice. RESULTS We demonstrated the capacity of the combined approach to target CSC compartment by a novel molecular mechanism based on the inhibition of YAP oncogene via concurrent modulation of mevalonate pathway and AMPK. Because both CSCs and YAP activation have been associated with chemo-resistance, we tested if the combined approach can potentiate docetaxel, a standard of care in mCRCP treatment. Indeed, we demonstrated, both in vitro and in vivo models, the ability of valproic acid/simvastatin combination to sensitize mCRPC cells to docetaxel and to revert docetaxel-resistance, by mevalonate pathway/YAP axis modulation. CONCLUSION Overall, mCRPC progression and therapeutic resistance driven by CSCs via YAP, can be tackled by the combined repurposing of two generic and safe drugs, an approach that warrants further clinical development in this disease.
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Affiliation(s)
- Federica Iannelli
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Maria Serena Roca
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Rita Lombardi
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Chiara Ciardiello
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Laura Grumetti
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Simona De Rienzo
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Tania Moccia
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Carlo Vitagliano
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Angela Sorice
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Susan Costantini
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Maria Rita Milone
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Biagio Pucci
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Alessandra Leone
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Elena Di Gennaro
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy
| | - Rita Mancini
- Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Francesca Bruzzese
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy. .,Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via Ammiraglio Bianco, 83013, Mercogliano, AV, Italy.
| | - Alfredo Budillon
- Experimental Pharmacology Unit-Laboratory of Naples and Mercogliano (AV), Istituto Nazionale per lo Studio e la Cura dei Tumori "Fondazione G. Pascale" - IRCCS, Via M. Semmola, 80131, Naples, Italy.
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Han X, Zhang WH, Wang WQ, Yu XJ, Liu L. Cancer-associated fibroblasts in therapeutic resistance of pancreatic cancer: Present situation, predicaments, and perspectives. Biochim Biophys Acta Rev Cancer 2020; 1874:188444. [PMID: 33031899 DOI: 10.1016/j.bbcan.2020.188444] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Revised: 09/30/2020] [Accepted: 09/30/2020] [Indexed: 12/24/2022]
Abstract
Pancreatic cancer is highly lethal, and the most effective treatment is curative resection followed by chemotherapy. Unfortunately, chemoresistance is an extremely common occurrence, and novel treatment modalities, such as immunotherapy and molecular targeted therapy, have shown limited success in clinical practice. Pancreatic cancer is characterized by an abundant stromal compartment. Cancer-associated fibroblasts (CAFs) and the extracellular matrix they deposit account for a large portion of the pancreatic tumor stroma. CAFs interact directly and indirectly with pancreatic cancer cells and can compromise the effects of, and even promote tumorigenic responses to, various treatment approaches. To eliminate these adverse effects, CAFs depletion strategies were developed. Instead of the anticipated antitumor effects of CAFs depletion, more aggressive tumor phenotypes were occasionally observed. The failure of universal stromal depletion led to the investigation of CAFs heterogeneity that forms the foundation for stromal remodeling and normalization. This review analyzes the role of CAFs in therapeutic resistance of pancreatic cancer and discusses potential CAFs-targeting strategies basing on the diverse biological functions of CAFs, thus to improve the outcome of pancreatic cancer treatment.
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Affiliation(s)
- Xuan Han
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wu-Hu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Shanghai Pancreatic Cancer Institute, Shanghai, China; Pancreatic Cancer Institute, Fudan University, Shanghai, China.
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Wang M, Zhao HY, Zhang JL, Wan DM, Li YM, Jiang ZX. Dysregulation of LncRNA ANRIL mediated by miR-411-3p inhibits the malignant proliferation and tumor stem cell like property of multiple myeloma via hypoxia-inducible factor 1α. Exp Cell Res 2020; 396:112280. [PMID: 32961145 DOI: 10.1016/j.yexcr.2020.112280] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2020] [Revised: 09/03/2020] [Accepted: 09/07/2020] [Indexed: 11/25/2022]
Abstract
Long non-coding RNA (lncRNA) ANRIL has been reported to be closely related to the relapse of multiple myeloma patients. However, the functional role and underlying mechanism of lncRNA ANRIL in multiple myeloma are not known. This study aims to investigate the biological function of lncRNA ANRIL in multiple myeloma. In this study, compared with normal tissues from healthy donors, lncRNA ANRIL and HIF-1α expressions were up-regulated in tumor tissues from multiple myeloma patients. miR-411-3p expression was down-regulated in tumor tissues from multiple myeloma patients. Besides, lncRNA ANRIL can interact with miR-411-3p. HIF-1α was confirmed to be a target of miR-411-3p. Correlation analysis showed that lncRNA ANRIL expression was negatively correlated with miR-411-3p expression. HIF-1α expression was negatively correlated with miR-411-3p expression. Further transfection experiments showed that knockdown of ANRIL or overexpression of miR-411-3p significantly inhibited cell proliferation, tumor formation ability and tumor stem cell like property, promoted cell apoptosis in vitro. Finally, miR-411-3p mimic reduced tumor volume, improved survival rate, suppressed malignant proliferation and tumor stem cell like property in U266 xenograft model. Our results demonstrate that lncRNA ANRIL mediated by miR-411-3p promotes the malignant proliferation and tumor stem cell like property of multiple myeloma through regulating HIF-1α.
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Affiliation(s)
- Meng Wang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China
| | - Hua-Yan Zhao
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China
| | - Jing-Lan Zhang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China
| | - Ding-Ming Wan
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China
| | - Ying-Mei Li
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China
| | - Zhong-Xing Jiang
- Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 452000, China.
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Puthenveetil A, Dubey S. Metabolic reprograming of tumor-associated macrophages. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:1030. [PMID: 32953830 PMCID: PMC7475460 DOI: 10.21037/atm-20-2037] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 06/20/2020] [Indexed: 12/11/2022]
Abstract
A large body of scientific evidence corroborated by clinical and animal model experiments indicates that tumor-associated macrophages (TAMs) play a crucial role in tumor development and progression. TAMs are a key immune cell type present in tumor microenvironment (TME) and associated with poor prognosis, drug resistance, enhanced angiogenesis and metastasis in cancer. TAMs are a phenotypically diverse population of myeloid cells which display tremendous plasticity and dynamic metabolic nature. A complete interpretation of pro-tumoral and anti-tumoral metabolic switch in TAMs is essential to understand immune evasion mechanisms in cancer. Recent studies have also implicated epigenetic mechanisms as significantly regulators of TAM functions. In this review we provide an overview of metabolic circuitry in TAMs, its impact on immune effector cells and interventions aimed at rewiring the metabolic circuits in TAMs. Mechanisms responsible for TAM polarization in cancer are also discussed.
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Affiliation(s)
- Abhishek Puthenveetil
- Amity Institute of Virology & Immunology, Amity University Uttar Pradesh, Noida, India
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Azad T, Rezaei R, Surendran A, Singaravelu R, Boulton S, Dave J, Bell JC, Ilkow CS. Hippo Signaling Pathway as a Central Mediator of Receptors Tyrosine Kinases (RTKs) in Tumorigenesis. Cancers (Basel) 2020; 12:cancers12082042. [PMID: 32722184 PMCID: PMC7463967 DOI: 10.3390/cancers12082042] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 07/21/2020] [Accepted: 07/22/2020] [Indexed: 12/18/2022] Open
Abstract
The Hippo pathway plays a critical role in tissue and organ growth under normal physiological conditions, and its dysregulation in malignant growth has made it an attractive target for therapeutic intervention in the fight against cancer. To date, its complex signaling mechanisms have made it difficult to identify strong therapeutic candidates. Hippo signaling is largely carried out by two main activated signaling pathways involving receptor tyrosine kinases (RTKs)—the RTK/RAS/PI3K and the RTK-RAS-MAPK pathways. However, several RTKs have also been shown to regulate this pathway to engage downstream Hippo effectors and ultimately influence cell proliferation. In this text, we attempt to review the diverse RTK signaling pathways that influence Hippo signaling in the context of oncogenesis.
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Affiliation(s)
- Taha Azad
- Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; (T.A.); (R.R.); (A.S.); (R.S.); (S.B.); (J.D.); (J.C.B.)
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Reza Rezaei
- Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; (T.A.); (R.R.); (A.S.); (R.S.); (S.B.); (J.D.); (J.C.B.)
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Abera Surendran
- Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; (T.A.); (R.R.); (A.S.); (R.S.); (S.B.); (J.D.); (J.C.B.)
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Ragunath Singaravelu
- Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; (T.A.); (R.R.); (A.S.); (R.S.); (S.B.); (J.D.); (J.C.B.)
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Stephen Boulton
- Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; (T.A.); (R.R.); (A.S.); (R.S.); (S.B.); (J.D.); (J.C.B.)
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Jaahnavi Dave
- Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; (T.A.); (R.R.); (A.S.); (R.S.); (S.B.); (J.D.); (J.C.B.)
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - John C. Bell
- Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; (T.A.); (R.R.); (A.S.); (R.S.); (S.B.); (J.D.); (J.C.B.)
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Carolina S. Ilkow
- Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada; (T.A.); (R.R.); (A.S.); (R.S.); (S.B.); (J.D.); (J.C.B.)
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Correspondence: ; Tel.: +1-613-737-8899 (ext. 75208)
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Shao S, Qin T, Qian W, Yue Y, Xiao Y, Li X, Zhang D, Wang Z, Ma Q, Lei J. Positive feedback in Cav-1-ROS signalling in PSCs mediates metabolic coupling between PSCs and tumour cells. J Cell Mol Med 2020; 24:9397-9408. [PMID: 32633891 PMCID: PMC7417714 DOI: 10.1111/jcmm.15596] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 06/09/2020] [Accepted: 06/12/2020] [Indexed: 12/18/2022] Open
Abstract
Caveolin-1 (Cav-1) is the principal structural component of caveolae, and its dysregulation occurs in cancer. However, the role of Cav-1 in pancreatic cancer (PDAC) tumorigenesis and metabolism is largely unknown. In this study, we aimed to investigate the effect of pancreatic stellate cell (PSC) Cav-1 on PDAC metabolism and aggression. We found that Cav-1 is expressed at low levels in PDAC stroma and that the loss of stromal Cav-1 is associated with poor survival. In PSCs, knockdown of Cav-1 promoted the production of reactive oxygen species (ROS), while ROS production further reduced the expression of Cav-1. Positive feedback occurs in Cav-1-ROS signalling in PSCs, which promotes PDAC growth and induces stroma-tumour metabolic coupling in PDAC. In PSCs, positive feedback in Cav-1-ROS signalling induced a shift in energy metabolism to glycolysis, with up-regulated expression of glycolytic enzymes (hexokinase 2 (HK-2), 6-phosphofructokinase (PFKP) and pyruvate kinase isozyme type M2 (PKM2)) and transporter (Glut1) expression and down-regulated expression of oxidative phosphorylation (OXPHOS) enzymes (translocase of outer mitochondrial membrane 20 (TOMM20) and NAD(P)H dehydrogenase [quinone] 1 (NQO1)). These events resulted in high levels of glycolysis products such as lactate, which was secreted by up-regulated monocarboxylate transporter 4 (MCT4) in PSCs. Simultaneously, PDAC cells took up these glycolysis products (lactate) through up-regulated MCT1 to undergo OXPHOS, with down-regulated expression of glycolytic enzymes (HK-2, PFKP and PKM2) and up-regulated expression of OXPHOS enzymes (TOMM20 and NQO1). Interrupting the metabolic coupling between the stroma and tumour cells may be an effective method for tumour therapy.
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Affiliation(s)
- Shan Shao
- Department of Oncology, First affiliated hospital of Xi'an Jiaotong University, Xi'an, China
| | - Tao Qin
- Department of Hepatobiliary Surgery, First affiliated hospital of Xi'an Jiaotong University, Xi'an, China
| | - Weikun Qian
- Department of Hepatobiliary Surgery, First affiliated hospital of Xi'an Jiaotong University, Xi'an, China
| | - Yangyang Yue
- Department of Hepatobiliary Surgery, First affiliated hospital of Xi'an Jiaotong University, Xi'an, China
| | - Ying Xiao
- Department of Hepatobiliary Surgery, First affiliated hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xuqi Li
- Department of General Surgery, First affiliated hospital of Xi'an Jiaotong University, Xi'an, China
| | - Dong Zhang
- Department of Hepatobiliary Surgery, First affiliated hospital of Xi'an Jiaotong University, Xi'an, China
| | - Zheng Wang
- Department of Hepatobiliary Surgery, First affiliated hospital of Xi'an Jiaotong University, Xi'an, China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First affiliated hospital of Xi'an Jiaotong University, Xi'an, China
| | - Jianjun Lei
- Department of Hepatobiliary Surgery, First affiliated hospital of Xi'an Jiaotong University, Xi'an, China
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Zhao C, Zeng C, Ye S, Dai X, He Q, Yang B, Zhu H. Yes-associated protein (YAP) and transcriptional coactivator with a PDZ-binding motif (TAZ): a nexus between hypoxia and cancer. Acta Pharm Sin B 2020; 10:947-960. [PMID: 32642404 PMCID: PMC7332664 DOI: 10.1016/j.apsb.2019.12.010] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2019] [Revised: 09/27/2019] [Accepted: 10/31/2019] [Indexed: 02/07/2023] Open
Abstract
Hypoxia is a common feature of solid tumors. As transcription factors, hypoxia-inducible factors (HIFs) are the master regulators of the hypoxic microenvironment; their target genes function in tumorigenesis and tumor development. Intriguingly, both yes-associated protein (YAP) and its paralog transcriptional coactivator with a PDZ-binding motif (TAZ) play fundamental roles in the malignant progression of hypoxic tumors. As downstream effectors of the mammalian Hippo pathway, YAP and/or TAZ (YAP/TAZ) are phosphorylated and sequestered in the cytoplasm by the large tumor suppressor kinase 1/2 (LATS1/2)-MOB kinase activator 1 (MOB1) complex, which restricts the transcriptional activity of YAP/TAZ. However, dephosphorylated YAP/TAZ have the ability to translocate to the nucleus where they induce transcription of target genes, most of which are closely related to cancer. Herein we review the tumor-related signaling crosstalk between YAP/TAZ and hypoxia, describe current agents and therapeutic strategies targeting the hypoxia–YAP/TAZ axis, and highlight questions that might have a potential impact in the future.
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Affiliation(s)
- Chenxi Zhao
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Chenming Zeng
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Song Ye
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China
| | - Xiaoyang Dai
- Center for Drug Safety Evaluation and Research of Zhejiang University, Hangzhou 310058, China
| | - Qiaojun He
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Bo Yang
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
| | - Hong Zhu
- Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China
- Corresponding author. Tel.: +86 571 882028401; fax: +86 571 88208400.
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