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1
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Wang X, Yu H, Liu D, Hu B, Zhang R, Hu L, Hu G, Li C. The application of nanomaterials in tumor therapy based on the regulation of mechanical properties. NANOSCALE 2024; 16:13386-13398. [PMID: 38967103 DOI: 10.1039/d4nr01812e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/06/2024]
Abstract
Mechanical properties, as crucial physical properties, have a significant impact on the occurrence, development, and metastasis of tumors. Regulating the mechanical properties of tumors to enhance their sensitivity to radiotherapy and chemotherapy has become an important strategy in the field of cancer treatment. Over the past few decades, nanomaterials have made remarkable progress in cancer therapy, either based on their intrinsic properties or as drug delivery carriers. However, the investigation of nanomaterials of mechanical regulation in tumor therapy is currently in its initial stages. The mechanical properties of nanomaterials themselves, drug carrier targeting, and regulation of the mechanical environment of tumor tissue have far-reaching effects on the efficient uptake of drugs and clinical tumor treatment. Therefore, this review aims to comprehensively summarize the applications and research progress of nanomaterials in tumor therapy based on the regulation of mechanical properties, in order to provide strong support for further research and the development of treatment strategies in this field.
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Affiliation(s)
- Xiaolei Wang
- School of Engineering Medicine of Beihang University and Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of China, Beihang University, Beijing 100191, China.
| | - Hongxi Yu
- School of Engineering Medicine of Beihang University and Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of China, Beihang University, Beijing 100191, China.
| | - Dan Liu
- School of Engineering Medicine of Beihang University and Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of China, Beihang University, Beijing 100191, China.
| | - Boxian Hu
- School of Engineering Medicine of Beihang University and Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of China, Beihang University, Beijing 100191, China.
| | - Ruihang Zhang
- School of Engineering Medicine of Beihang University and Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of China, Beihang University, Beijing 100191, China.
| | - Lihua Hu
- Department of Cardiology, Peking University First Hospital, Beijing 100034, China
| | - Guiping Hu
- School of Engineering Medicine of Beihang University and Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of China, Beihang University, Beijing 100191, China.
| | - Cheng Li
- School of Engineering Medicine of Beihang University and Key Laboratory of Big Data-Based Precision Medicine (Beihang University), Ministry of Industry and Information Technology of China, Beihang University, Beijing 100191, China.
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Chu X, Zhong X, Zang S, Wang M, Li P, Ma Y, Tian X, Yang Y, Wang C, Yang Y. Stem cell-like circulating tumor cells identified by Pep@MNP and their clinical significance in pancreatic cancer metastasis. Front Oncol 2024; 14:1327280. [PMID: 38983932 PMCID: PMC11231205 DOI: 10.3389/fonc.2024.1327280] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Accepted: 06/10/2024] [Indexed: 07/11/2024] Open
Abstract
Objective The circulating tumor cells (CTCs) could be captured by the peptide functionalized magnetic nanoparticles (Pep@MNP) detection system in pancreatic ductal adenocarcinoma (PDAC). CTCs and the CXCR4 expression were detected to explore their clinical significance. The CXCR4+ CTCs, this is highly metastatic-prone stem cell-like subsets of CTCs (HM-CTCs), were found to be associated with the early recurrence and metastasis of PDAC. Methods CTCs were captured by Pep@MNP. CTCs were identified via immunofluorescence with CD45, cytokeratin antibodies, and the CXCR4 positive CTCs were assigned to be HM-CTCs. Results The over-expression of CXCR4 could promote the migration of pancreatic cancer cell in vitro and in vivo. In peripheral blood (PB), CTCs were detected positive in 79.0% of all patients (49/62, 9 (0-71)/2mL), among which 63.3% patients (31/49, 3 (0-23)/2mL) were HM-CTCs positive. In portal vein blood (PVB), CTCs were positive in 77.5% of patients (31/40, 10 (0-40)/2mL), and 67.7% of which (21/31, 4 (0-15)/2mL) were HM-CTCs positive CTCs enumeration could be used as diagnostic biomarker of pancreatic cancer (AUC = 0.862), and the combination of CTCs positive and CA19-9 increase shows improved diagnostic accuracy (AUC = 0.963). in addition, PVB HM-CTCs were more accurate to predict the early recurrence and liver metastasis than PB HM-CTCs (AUC 0.825 vs. 0.787 and 0.827 vs. 0.809, respectively). Conclusions The CTCs identified by Pep@MNP detection system could be used as diagnostic and prognostic biomarkers of PDAC patients. We identified and defined the CXCR4 over-expressed CTC subpopulation as highly metastatic-prone CTCs, which was proved to identify patients who were prone to suffering from early recurrence and metastasis.
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Affiliation(s)
- Xiangyu Chu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Xiejian Zhong
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Shouge Zang
- Department of General Surgery, Fuyang People's Hospital of Anhui Medical University, Fuyang, China
| | - Mengting Wang
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Ping Li
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
| | - Yongsu Ma
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Xiaodong Tian
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
| | - Yanlian Yang
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Chen Wang
- Chinese Academy of Sciences Key Laboratory of Biological Effects of Nanomaterials and Nanosafety, Chinese Academy of Sciences Key Laboratory of Standardization and Measurement for Nanotechnology, Chinese Academy of Sciences Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, China
- School of Nanoscience and Engineering, University of Chinese Academy of Sciences, Beijing, China
| | - Yinmo Yang
- Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, China
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Huang Y, Zhang R, Lyu H, Xiao S, Guo D, Chen XZ, Zhou C, Tang J. LncRNAs as nodes for the cross-talk between autophagy and Wnt signaling in pancreatic cancer drug resistance. Int J Biol Sci 2024; 20:2698-2726. [PMID: 38725864 PMCID: PMC11077374 DOI: 10.7150/ijbs.91832] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Accepted: 02/06/2024] [Indexed: 05/12/2024] Open
Abstract
Pancreatic cancer is a malignancy with high mortality. In addition to the few symptoms until the disease reaches an advanced stage, the high fatality rate is attributed to its rapid development, drug resistance and lack of appropriate treatment. In the selection and research of therapeutic drugs, gemcitabine is the first-line drug for pancreatic cancer. Solving the problem of gemcitabine resistance in pancreatic cancer will contribute to the progress of pancreatic cancer treatment. Long non coding RNAs (lncRNAs), which are RNA transcripts longer than 200 nucleotides, play vital roles in cellular physiological metabolic activities. Currently, our group and others have found that some lncRNAs are aberrantly expressed in pancreatic cancer cells, which can regulate the process of cancer through autophagy and Wnt/β-catenin pathways simultaneously and affect the sensitivity of cancer cells to therapeutic drugs. This review presents an overview of the recent evidence concerning the node of lncRNA for the cross-talk between autophagy and Wnt/β-catenin signaling in pancreatic cancer, together with the practicability of lncRNAs and the core regulatory factors as targets in therapeutic resistance.
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Affiliation(s)
- Yuhan Huang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Rui Zhang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Hao Lyu
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Shuai Xiao
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Dong Guo
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Xing-Zhen Chen
- Membrane Protein Disease Research Group, Department of Physiology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada, T6G2R3
| | - Cefan Zhou
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
| | - Jingfeng Tang
- National "111" Center for Cellular Regulation and Molecular Pharmaceutics, Key Laboratory of Fermentation Engineering (Ministry of Education), Cooperative Innovation Center of Industrial Fermentation (Ministry of Education & Hubei Province), Hubei Key Laboratory of Industrial Microbiology, Hubei University of Technology, Wuhan, China, 430068
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Pan K, Li X, He J, Lei Y, Yang Y, Jiang D, Tang Y. Value of the NF-κB signalling pathway and the DNA repair gene PARP1 in predicting distant metastasis after breast cancer surgery. Sci Rep 2024; 14:4402. [PMID: 38388665 PMCID: PMC10883999 DOI: 10.1038/s41598-023-49156-4] [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: 07/11/2023] [Accepted: 12/05/2023] [Indexed: 02/24/2024] Open
Abstract
The DNA repair gene PARP1 and NF-κB signalling pathway affect the metastasis of breast cancer by influencing the drug resistance of cancer cells. Therefore, this study focused on the value of the DNA repair gene PARP1 and NF-κB pathway proteins in predicting the postoperative metastasis of breast cancer. A nested case‒control study was performed. Immunohistochemical methods were used to detect the expression of these genes in patients. ROC curves were used to analyse the predictive effect of these factors on distant metastasis. The COX model was used to evaluate the effects of PARP1 and TNF-α on distant metastasis. The results showed that the expression levels of PARP1, IKKβ, p50, p65 and TNF-α were significantly increased in the metastasis group (P < 0.001). PARP1 was correlated with IKKβ, p50, p65 and TNF-α proteins (P < 0.001). There was a correlation between IKKβ, p50, p65 and TNF-α proteins (P < 0.001). ROC curve analysis showed that immunohistochemical scores for PARP1 of > 6, IKKβ of > 4, p65 of > 4, p50 of > 2, and TNF-α of > 4 had value in predicting distant metastasis (SePARP1 = 78.35%, SpPARP1 = 79.38%, AUCPARP1 = 0.843; Sep50 = 64.95%, Spp50 = 70.10%, AUCp50 = 0.709; SeTNF-α = 60.82%, SpTNF-α = 69.07%, AUCTNF-α = 0.6884). Cox regression analysis showed that high expression levels of PARP1 and TNF-α were a risk factor for distant metastasis after breast cancer surgery (RRPARP1 = 4.092, 95% CI 2.475-6.766, P < 0.001; RRTNF-α = 1.825, 95% CI 1.189-2.799, P = 0.006). Taken together, PARP1 > 6, p50 > 2, and TNF-α > 4 have a certain value in predicting breast cancer metastasis, and the predictive value is better when they are combined for diagnosis (Secombine = 97.94%, Spcombine = 71.13%).
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Affiliation(s)
- Kaiyong Pan
- School of Public Health, Southwest Medical University, 1 Xianglin Road, Luzhou, 646000, Sichuan, China
| | - Xiabin Li
- Department of Pathology, The First Affiliated Hospital of Southwest Medical University, 25 Taiping Road, Luzhou, 646000, Sichuan, China
| | - Junfang He
- School of Public Health, Southwest Medical University, 1 Xianglin Road, Luzhou, 646000, Sichuan, China
| | - Yuxi Lei
- School of Public Health, Southwest Medical University, 1 Xianglin Road, Luzhou, 646000, Sichuan, China
| | - Yongxin Yang
- Guizhou QianNan People's Hospital, 9 Enfeng Road, Duyun, 558099, Guizhou, China
| | - Deyong Jiang
- Sichuan Luzhou Center for Disease Control, 31 Datong Road, Luzhou, 646000, Sichuan, China
| | - Yan Tang
- School of Public Health, Southwest Medical University, 1 Xianglin Road, Luzhou, 646000, Sichuan, China.
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Feng P, Xue X, Bukhari I, Qiu C, Li Y, Zheng P, Mi Y. Gut microbiota and its therapeutic implications in tumor microenvironment interactions. Front Microbiol 2024; 15:1287077. [PMID: 38322318 PMCID: PMC10844568 DOI: 10.3389/fmicb.2024.1287077] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 01/08/2024] [Indexed: 02/08/2024] Open
Abstract
The development of cancer is not just the growth and proliferation of a single transformed cell, but its tumor microenvironment (TME) also coevolves with it, which is primarily involved in tumor initiation, development, metastasis, and therapeutic responses. Recent years, TME has been emerged as a potential target for cancer diagnosis and treatment. However, the clinical efficacy of treatments targeting the TME, especially its specific components, remains insufficient. In parallel, the gut microbiome is an essential TME component that is crucial in cancer immunotherapy. Thus, assessing and constructing frameworks between the gut microbiota and the TME can significantly enhance the exploration of effective treatment strategies for various tumors. In this review the role of the gut microbiota in human cancers, including its function and relationship with various tumors was summarized. In addition, the interaction between the gut microbiota and the TME as well as its potential applications in cancer therapeutics was described. Furthermore, it was summarized that fecal microbiota transplantation, dietary adjustments, and synthetic biology to introduce gut microbiota-based medical technologies for cancer treatment. This review provides a comprehensive summary for uncovering the mechanism underlying the effects of the gut microbiota on the TME and lays a foundation for the development of personalized medicine in further studies.
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Affiliation(s)
- Pengya Feng
- Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Children Rehabilitation Medicine, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xia Xue
- Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Ihtisham Bukhari
- Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chunjing Qiu
- Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yingying Li
- Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Pengyuan Zheng
- Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yang Mi
- Key Laboratory of Helicobacter Pylori, Microbiota and Gastrointestinal Cancer of Henan Province, Marshall Medical Research Center, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
- Department of Gastroenterology, Fifth Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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Zhang T, Gu Z, Ni R, Wang X, Jiang Q, Tao R. An Update on Gemcitabine-Based Chemosensitization Strategies in Pancreatic Ductal Adenocarcinoma. FRONT BIOSCI-LANDMRK 2023; 28:361. [PMID: 38179740 DOI: 10.31083/j.fbl2812361] [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: 06/01/2023] [Revised: 07/22/2023] [Accepted: 08/10/2023] [Indexed: 01/06/2024]
Abstract
Pancreatic cancer is the seventh leading cause of cancer-related deaths, and chemotherapy is one of the most important treatments for pancreatic cancer. Unfortunately, pancreatic cancer cells can block chemotherapy drugs from entering the tumor. This is owing to interactions between the tumor's environment and the cancer cells. Here, we review the latest research on the mechanisms by which pancreatic cancer cells block the chemotherapy drug, gemcitabine. The results of our review can help identify potential therapeutic targets for the blocking of gemcitabine by pancreatic cancer cells and may provide new strategies to help chemotherapy drugs penetrate tumors.
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Affiliation(s)
- Tianpeng Zhang
- Department of Surgery, Bengbu Medical College, 233030 Bengbu, AnHui, China
| | - Zongting Gu
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, 310000 Hangzhou, Zhejiang, China
| | - Ran Ni
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, 310000 Hangzhou, Zhejiang, China
| | - Xiao Wang
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, 310000 Hangzhou, Zhejiang, China
| | - Qitao Jiang
- Department of Surgery, Bengbu Medical College, 233030 Bengbu, AnHui, China
| | - Ran Tao
- General Surgery, Cancer Center, Department of Hepatobiliary & Pancreatic Surgery and Minimally Invasive Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital), Hangzhou Medical College, 310000 Hangzhou, Zhejiang, China
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Govindarajan B, Sbrissa D, Pressprich M, Kim S, Rishi AK, Vaishampayan U, Cher ML, Chinni SR. Adaptor proteins mediate CXCR4 and PI4KA crosstalk in prostate cancer cells and the significance of PI4KA in bone tumor growth. Sci Rep 2023; 13:20634. [PMID: 37996444 PMCID: PMC10667255 DOI: 10.1038/s41598-023-47633-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Accepted: 11/16/2023] [Indexed: 11/25/2023] Open
Abstract
The chemokine receptor, CXCR4 signaling regulates cell growth, invasion, and metastasis to the bone-marrow niche in prostate cancer (PCa). Previously, we established that CXCR4 interacts with phosphatidylinositol 4-kinase IIIα (PI4KIIIα encoded by PI4KA) through its adaptor proteins and PI4KA overexpressed in the PCa metastasis. To further characterize how the CXCR4-PI4KIIIα axis promotes PCa metastasis, here we identify CXCR4 binds to PI4KIIIα adaptor proteins TTC7 and this interaction induce plasma membrane PI4P production in prostate cancer cells. Inhibiting PI4KIIIα or TTC7 reduces plasma membrane PI4P production, cellular invasion, and bone tumor growth. Using metastatic biopsy sequencing, we found PI4KA expression in tumors correlated with overall survival and contributes to immunosuppressive bone tumor microenvironment through preferentially enriching non-activated and immunosuppressive macrophage populations. Altogether we have characterized the chemokine signaling axis through CXCR4-PI4KIIIα interaction contributing to the growth of prostate cancer bone metastasis.
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Affiliation(s)
- Barani Govindarajan
- Department of Pathology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA
| | - Diego Sbrissa
- Department of Urology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Mark Pressprich
- Department of Urology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Seongho Kim
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
- Biostatistics and Bioinformatics Core, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Arun K Rishi
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Ulka Vaishampayan
- Department of Oncology, University of Michigan, 7217 Rogel Cancer Center, Ann Arbor, MI, USA
| | - Michael L Cher
- Department of Pathology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA
- Department of Urology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA
| | - Sreenivasa R Chinni
- Department of Pathology, Wayne State University, School of Medicine, 9245 Scott Hall, 540 E. Canfield Avenue, Detroit, MI, 48201, USA.
- Department of Urology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA.
- Department of Oncology, Wayne State University, School of Medicine, Detroit, MI, 48201, USA.
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Anand S, Khan MA, Zubair H, Sudan SK, Vikramdeo KS, Deshmukh SK, Azim S, Srivastava SK, Singh S, Singh AP. MYB sustains hypoxic survival of pancreatic cancer cells by facilitating metabolic reprogramming. EMBO Rep 2023; 24:e55643. [PMID: 36592158 PMCID: PMC9986821 DOI: 10.15252/embr.202255643] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 01/03/2023] Open
Abstract
Extensive desmoplasia and poor vasculature renders pancreatic tumors severely hypoxic, contributing to their aggressiveness and therapy resistance. Here, we identify the HuR/MYB/HIF1α axis as a critical regulator of the metabolic plasticity and hypoxic survival of pancreatic cancer cells. HuR undergoes nuclear-to-cytoplasmic translocation under hypoxia and stabilizes MYB transcripts, while MYB transcriptionally upregulates HIF1α. Upon MYB silencing, pancreatic cancer cells fail to survive and adapt metabolically under hypoxia, despite forced overexpression of HIF1α. MYB induces the transcription of several HIF1α-regulated glycolytic genes by directly binding to their promoters, thus enhancing the recruitment of HIF1α to hypoxia-responsive elements through its interaction with p300-dependent histone acetylation. MYB-depleted pancreatic cancer cells exhibit a dramatic reduction in tumorigenic ability, glucose-uptake and metabolism in orthotopic mouse model, even after HIF1α restoration. Together, our findings reveal an essential role of MYB in metabolic reprogramming that supports pancreatic cancer cell survival under hypoxia.
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Affiliation(s)
- Shashi Anand
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Mohammad Aslam Khan
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Haseeb Zubair
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Sarabjeet Kour Sudan
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Kunwar Somesh Vikramdeo
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Sachin Kumar Deshmukh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Shafquat Azim
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Sanjeev Kumar Srivastava
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Seema Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA
| | - Ajay Pratap Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA
- Cancer Biology Program, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA
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Govindarajan B, Sbrissa D, Pressprich M, Kim S, Vaishampayan U, Cher ML, Chinni S. Adaptor proteins mediate CXCR4 and PI4KA crosstalk in prostate cancer cells and the significance of PI4KA in bone tumor growth. RESEARCH SQUARE 2023:rs.3.rs-2590830. [PMID: 36865146 PMCID: PMC9980273 DOI: 10.21203/rs.3.rs-2590830/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/25/2023]
Abstract
The chemokine receptor, CXCR4 signaling regulates cell growth, invasion, and metastasis to the bone-marrow niche in prostate cancer (PCa). Previously, we established that CXCR4 interacts with phosphatidylinositol 4-kinase IIIα (PI4KIIIα encoded by PI4KA) through its adaptor proteins and PI4KA overexpressed in the PCa metastasis. To further characterize how the CXCR4-PI4KIIIα axis promotes PCa metastasis, here we identify CXCR4 binds to PI4KIIIα adaptor proteins TTC7 and this interaction induce plasma membrane PI4P production in prostate cancer cells. Inhibiting PI4KIIIα or TTC7 reduces plasma membrane PI4P production, cellular invasion, and bone tumor growth. Using metastatic biopsy sequencing, we found PI4KA expression in tumors correlated with overall survival and contributes to immunosuppressive bone tumor microenvironment through preferentially enriching non-activated and immunosuppressive macrophage populations. Altogether we have characterized the chemokine signaling axis through CXCR4-PI4KIIIα interaction contributing to the growth of prostate cancer bone metastasis.
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10
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Zhou H, Zhang Q, Huang W, Zhou S, Wang Y, Zeng X, Wang H, Xie W, Kong H. NLRP3 Inflammasome Mediates Silica-induced Lung Epithelial Injury and Aberrant Regeneration in Lung Stem/Progenitor Cell-derived Organotypic Models. Int J Biol Sci 2023; 19:1875-1893. [PMID: 37063430 PMCID: PMC10092774 DOI: 10.7150/ijbs.80605] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Accepted: 03/03/2023] [Indexed: 04/18/2023] Open
Abstract
Silica-induced lung epithelial injury and fibrosis are vital pathogeneses of silicosis. Although the NOD-like receptor protein 3 (NLRP3) inflammasome contributes to silica-induced chronic lung inflammation, its role in epithelial injury and regeneration remains unclear. Here, using mouse lung stem/progenitor cell-derived organotypic systems, including 2D air-liquid interface and 3D organoid cultures, we investigated the effects of the NLRP3 inflammasome on airway epithelial phenotype and function, cellular injury and regeneration, and the potential mechanisms. Our data showed that silica-induced NLRP3 inflammasome activation disrupted the epithelial architecture, impaired mucociliary clearance, induced cellular hyperplasia and the epithelial-mesenchymal transition in 2D culture, and inhibited organoid development in 3D system. Moreover, abnormal expression of the stem/progenitor cell markers SOX2 and SOX9 was observed in the 2D and 3D organotypic models after sustained silica stimulation. Notably, these silica-induced structural and functional abnormalities were ameliorated by MCC950, a selective NLRP3 inflammasome inhibitor. Further studies indicated that the NF-κB, Shh-Gli and Wnt/β-catenin pathways were involved in NLRP3 inflammasome-mediated abnormal differentiation and dysfunction of the airway epithelium. Thus, prolonged NLRP3 inflammasome activation caused injury and aberrant lung epithelial regeneration, suggesting that the NLRP3 inflammasome is a pivotal target for regulating tissue repair in chronic inflammatory lung diseases.
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Affiliation(s)
| | | | | | | | | | | | | | - Weiping Xie
- ✉ Corresponding authors: Hui Kong, M.D., Ph.D., . Weiping Xie, M.D., Ph.D., . Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, P.R. China. Tel: +86-25-68136426; Fax: +86-25-68136269
| | - Hui Kong
- ✉ Corresponding authors: Hui Kong, M.D., Ph.D., . Weiping Xie, M.D., Ph.D., . Department of Pulmonary & Critical Care Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu 210029, P.R. China. Tel: +86-25-68136426; Fax: +86-25-68136269
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11
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A Comprehensive Characterization of Stemness in Cell Lines and Primary Cells of Pancreatic Ductal Adenocarcinoma. Int J Mol Sci 2022; 23:ijms231810663. [PMID: 36142575 PMCID: PMC9503169 DOI: 10.3390/ijms231810663] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/08/2022] [Accepted: 09/09/2022] [Indexed: 01/18/2023] Open
Abstract
The aim of this study is to provide a comprehensive characterization of stemness in pancreatic ductal adenocarcinoma (PDAC) cell lines. Seventeen cell lines were evaluated for the expression of cancer stem cell (CSC) markers. The two putative pancreatic CSC phenotypes were expressed heterogeneously ranging from 0 to 99.35% (median 3.46) for ESA+CD24+CD44+ and 0 to 1.94% (median 0.13) for CXCR4+CD133+. Cell lines were classified according to ESA+CD24+CD44+ expression as: Low-Stemness (LS; <5%, n = 9, median 0.31%); Medium-Stemness (MS; 6−20%, n = 4, median 12.4%); and High-Stemness (HS; >20%, n = 4, median 95.8%) cell lines. Higher degree of stemness was associated with in vivo tumorigenicity but not with in vitro growth kinetics, clonogenicity, and chemo-resistance. A wide characterization (chemokine receptors, factors involved in pancreatic organogenesis, markers of epithelial−mesenchymal transition, and secretome) revealed that the degree of stemness was associated with KRT19 and NKX2.2 mRNA expression, with CD49a and CA19.9/Tie2 protein expression, and with the secretion of VEGF, IL-7, IL-12p70, IL-6, CCL3, IL-10, and CXCL9. The expression of stem cell markers was also evaluated on primary tumor cells from 55 PDAC patients who underwent pancreatectomy with radical intent, revealing that CXCR4+/CD133+ and CD24+ cells, but not ESA+CD24+CD44+, are independent predictors of mortality.
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12
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Quatannens D, Verhoeven Y, Van Dam P, Lardon F, Prenen H, Roeyen G, Peeters M, Smits ELJ, Van Audenaerde J. Targeting hedgehog signaling in pancreatic ductal adenocarcinoma. Pharmacol Ther 2022; 236:108107. [PMID: 34999181 DOI: 10.1016/j.pharmthera.2022.108107] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 12/15/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer related death. The urgent need for effective therapies is highlighted by the lack of adequate targeting. In PDAC, hedgehog (Hh) signaling is known to be aberrantly activated, which prompted the pathway as a possible target for effective treatment for PDAC patients. Unfortunately, specific targeting of upstream molecules within the Hh signaling pathway failed to bring clinical benefit. This led to the ongoing debate on Hh targeting as a therapeutic treatment for PDAC patients. Additionally, concurrent non-canonical activation routes also result in translocation of Gli transcription factors into the nucleus. Therefore, different downstream targets of the Hh signaling pathway were identified and evaluated in preclinical and clinical research. In this review we summarize the variety of Hh signaling antagonists in different preclinical models of PDAC. Furthermore, we discuss published and ongoing clinical trials that evaluated Hh antagonists and point out the current hurdles and future perspectives in the light of redesigning Hh-targeting therapies for the treatment of PDAC patients.
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Affiliation(s)
- Delphine Quatannens
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Yannick Verhoeven
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Peter Van Dam
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Unit of Gynecologic Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Filip Lardon
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Hans Prenen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Geert Roeyen
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Hepatobiliary Transplantation and Endocrine Surgery, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Marc Peeters
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium; Department of Oncology, University Hospital Antwerp (UZA), Antwerp, Belgium.
| | - Evelien L J Smits
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
| | - Jonas Van Audenaerde
- Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Antwerp, Belgium.
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13
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Malik S, Westcott JM, Brekken RA, Burrows FJ. CXCL12 in Pancreatic Cancer: Its Function and Potential as a Therapeutic Drug Target. Cancers (Basel) 2021; 14:cancers14010086. [PMID: 35008248 PMCID: PMC8750050 DOI: 10.3390/cancers14010086] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 12/10/2021] [Accepted: 12/21/2021] [Indexed: 12/19/2022] Open
Abstract
Simple Summary Pancreatic cancer is a challenging disease to treat effectively. Fibroblasts associated with pancreatic cancer contribute to disease progression by secreting factors that enhance tumor cell survival and help tumor cells avoid detection by the immune system. This overview focuses on a chemokine, CXCL12, produced by cancer-associated fibroblasts and how CXCL12 signaling enhances pancreatic cancer progression by contributing to various hallmarks of cancer including, but not limited to, tumor growth and evasion of immune response. These pro-oncogenic functions of CXCL12 make it an attractive target in pancreatic cancer. We discuss the different approaches in development to therapeutically target CXCL12 and finally propose a novel approach, the use of the farnesyl transferase inhibitor tipifarnib to inhibit CXCL12 expression in pancreatic fibroblasts. Abstract Pancreatic ductal adenocarcinoma (PDAC) is a disease with limited therapeutic options and dismal long-term survival. The unique tumor environment of PDAC, consisting of desmoplastic stroma, immune suppressive cells, and activated fibroblasts, contributes to its resistance to therapy. Activated fibroblasts (cancer-associated fibroblasts and pancreatic stellate cells) secrete chemokines and growth factors that support PDAC growth, spread, chemoresistance, and immune evasion. In this review, we focus on one such chemokine, CXCL12, secreted by the cancer-associated fibroblasts and discuss its contribution to several of the classical hallmarks of PDAC and other tumors. We review the various therapeutic approaches in development to target CXCL12 signaling in PDAC. Finally, we propose an unconventional use of tipifarnib, a farnesyl transferase inhibitor, to inhibit CXCL12 production in PDAC.
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Affiliation(s)
| | - Jill M. Westcott
- Division of Surgical Oncology, Department of Surgery, and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
| | - Rolf A. Brekken
- Division of Surgical Oncology, Department of Surgery, and Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA;
- Correspondence: (R.A.B.); (F.J.B.)
| | - Francis J. Burrows
- Kura Oncology, Inc., San Diego, CA 92130, USA;
- Correspondence: (R.A.B.); (F.J.B.)
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14
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The Hedgehog Signaling Pathway in Idiopathic Pulmonary Fibrosis: Resurrection Time. Int J Mol Sci 2021; 23:ijms23010171. [PMID: 35008597 PMCID: PMC8745434 DOI: 10.3390/ijms23010171] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Revised: 12/20/2021] [Accepted: 12/22/2021] [Indexed: 02/07/2023] Open
Abstract
The hedgehog (Hh) pathway is a sophisticated conserved cell signaling pathway that plays an essential role in controlling cell specification and proliferation, survival factors, and tissue patterning formation during embryonic development. Hh signal activity does not entirely disappear after development and may be reactivated in adulthood within tissue-injury-associated diseases, including idiopathic pulmonary fibrosis (IPF). The dysregulation of Hh-associated activating transcription factors, genomic abnormalities, and microenvironments is a co-factor that induces the initiation and progression of IPF.
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15
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Brunty S, Clower L, Mitchell B, Fleshman T, Zgheib NB, Santanam N. Peritoneal Modulators of Endometriosis-Associated Ovarian Cancer. Front Oncol 2021; 11:793297. [PMID: 34900746 PMCID: PMC8655857 DOI: 10.3389/fonc.2021.793297] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2021] [Accepted: 11/04/2021] [Indexed: 12/13/2022] Open
Abstract
Ovarian cancer is the 4th largest cause of cancer death in women. Approximately 10-15% of women of childbearing age suffer from endometriosis. Endometriosis is defined by the growth and presence of endometrial tissue (lesions) outside of the uterus. The women with endometriosis also have an increased presence of peritoneal fluid (PF) that comprises of inflammatory cells, growth factors, cytokines/chemokines, etc. Epidemiological studies have shown that >3% of women with endometriosis develop ovarian cancer (low-grade serous or endometrioid types). Our hypothesis is that the PF from women with endometriosis induces transformative changes in the ovarian cells, leading to ovarian cancer development. PF from women with and without endometriosis was collected after IRB approval and patient consent. IOSE (human normal ovarian epithelial cells) and TOV-21G cells (human ovarian clear cell carcinoma cell line) were treated with various volumes of PF (no endometriosis or endometriosis) for 48 or 96 h and proliferation measured. Expression levels of epigenetic regulators and FoxP3, an inflammatory tumor suppressor, were determined. A Human Cancer Inflammation and Immunity Crosstalk RT2 Profiler PCR array was used to measure changes in cancer related genes in treated cells. Results showed increased growth of TOV-21G cells treated with PF from women with endometriosis versus without endometriosis and compared to IOSE cells. Endo PF treatment induced EZH2, H3K27me3, and FoxP3. The RT2 PCR array of TOV-21G cells treated with endo PF showed upregulation of various inflammatory genes (TLRs, Myd88, etc.). These studies indicate that PF from women with endometriosis can both proliferate and transform ovarian cells and hence this microenvironment plays a major mechanistic role in the progression of endometriosis to ovarian cancer.
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Affiliation(s)
- Sarah Brunty
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Lauren Clower
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Brenda Mitchell
- Department of Obstetrics & Gynecology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Taylor Fleshman
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Nadim Bou Zgheib
- Department of Obstetrics & Gynecology, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
| | - Nalini Santanam
- Department of Biomedical Sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, United States
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16
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Lee YS, Kim HS, Cho Y, Lee IJ, Kim HJ, Lee DE, Kang HW, Park JS. Intraoperative radiation therapy induces immune response activity after pancreatic surgery. BMC Cancer 2021; 21:1097. [PMID: 34641806 PMCID: PMC8507125 DOI: 10.1186/s12885-021-08807-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 09/23/2021] [Indexed: 11/10/2022] Open
Abstract
Background Pancreatic cancer has highly aggressive features, such as local recurrence that leads to significantly high morbidity and mortality and recurrence after successful tumour resection. Intraoperative radiation therapy (IORT), which delivers targeted radiation to a tumour bed, is known to reduce local recurrence by directly killing tumour cells and modifying the tumour microenvironment. Methods Among 30 patients diagnosed with pancreatic cancer, 17 patients received IORT immediately after surgical resection. We investigated changes in the immune response induced by IORT by analysing the peritoneal fluid (PF) and blood of patients with and without IORT treatment after pancreatic cancer surgery. Further, we treated three pancreatic cell lines with PF to observe proliferation and activity changes. Results Levels of cytokines involved in the PI3K/SMAD pathway were increased in the PF of IORT-treated patients. Moreover, IORT-treated PF inhibited the growth, migration, and invasiveness of pancreatic cancer cells. Changes in lymphocyte populations in the blood of IORT-treated patients indicated an increased immune response. Conclusions Based on the characterisation and quantification of immune cells in the blood and cytokine levels in the PF, we conclude that IORT induced an anti-tumour effect by activating the immune response, which may prevent pancreatic cancer recurrence. Clinical trial registration NCT03273374. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-08807-3.
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Affiliation(s)
- Yun Sun Lee
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University, Seoul, South Korea
| | - Hyung Sun Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea
| | - Yeona Cho
- Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, South Korea
| | - Ik Jae Lee
- Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, South Korea
| | - Hyo Jung Kim
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea
| | - Da Eun Lee
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University, Seoul, South Korea
| | - Hyeon Woong Kang
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea.,Brain Korea 21 FOUR Project for Medical Science, Yonsei University, Seoul, South Korea
| | - Joon Seong Park
- Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 20, Eonju-ro 63 gil, Gangnam-gu, Seoul, 06229, South Korea.
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17
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Ashry R, Elhussiny M, Abdellatif H, Elkashty O, Abdel-Ghaffar HA, Gaballa ET, Mousa SA. Genetic Interpretation of the Impacts of Honokiol and EGCG on Apoptotic and Self-Renewal Pathways in HEp-2 Human Laryngeal CD44 high Cancer Stem Cells. Nutr Cancer 2021; 74:2152-2173. [PMID: 34590505 DOI: 10.1080/01635581.2021.1981404] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Most current larynx cancer therapies are generally aimed at the global mass of tumor, targeting the non-tumorigenic cells, and unfortunately sparing the tumorigenic cancer stem cells (CSCs) that are responsible for sustained growth, metastasis, and chemo- and radioresistance. Phytochemicals and herbs have recently been introduced as therapeutic sources for eliminating CSCs. Therefore, we assessed the anti-tumor effects of two herbal ingredients, the green tea extract "Epigallocatechin-3-gallate (EGCG)" and Honokiol (HNK), on parental cells or CD44high CSCs of the human laryngeal squamous cell carcinoma cell line HEp-2. Results revealed that EGCG had a preeminent apoptotic potential on HEp-2 laryngeal CSCs. HNK conferred higher cytotoxic impacts on parental cells mostly by necrosis induction, especially with higher doses, but apoptosis induction with lower doses was also observed. The Notch signaling pathway genes were more potently suppressed by EGCG than HNK. However, HNK surpassed EGCG in downregulating the β-catenin and the Sonic Hedgehog signaling pathways genes. On a genetic basis, both agents engaged the BCL-2 family-regulated and caspase-dependent intrinsic apoptotic pathway, but EGCG and HNK triggered apoptosis via p53-independent and p53-dependent pathways, respectively. Taken together, EGCG and HNK eradicated HEp-2 human larynx cancer cells through targeting multiple self-renewal pathways and activating diverse cell death modalities.
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Affiliation(s)
- Ramy Ashry
- Institute of Toxicology, University Medical Center Mainz, Mainz, Germany.,Oral Pathology Department, Faculty of Dentistry, Mansoura University, Mansoura, Egypt
| | - Mahmoud Elhussiny
- Institute of Global Health and Human Ecology, American University in Cairo (AUC), Cairo, Egypt.,Medical Experimental Research Center (MERC), Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Hussein Abdellatif
- Department of Human and Clinical Anatomy, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Sultanate of Oman.,Anatomy and Embryology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Osama Elkashty
- Oral Pathology Department, Faculty of Dentistry, Mansoura University, Mansoura, Egypt.,Craniofacial Tissue and Stem Cell Laboratory, Faculty of Dentistry, McGill University, Montreal, Canada
| | - Hassan A Abdel-Ghaffar
- Hematology Laboratory, Oncology Center, Mansoura University, Mansoura, Egypt.,Hematology section, Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Essam T Gaballa
- Oral Pathology Department, Faculty of Dentistry, Mansoura University, Mansoura, Egypt.,Oral Pathology Department, Faculty of Dentistry, Delta University, Mansoura, Egypt
| | - Shaker A Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, New York, USA
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18
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Patil K, Khan FB, Akhtar S, Ahmad A, Uddin S. The plasticity of pancreatic cancer stem cells: implications in therapeutic resistance. Cancer Metastasis Rev 2021; 40:691-720. [PMID: 34453639 PMCID: PMC8556195 DOI: 10.1007/s10555-021-09979-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Accepted: 07/12/2021] [Indexed: 02/07/2023]
Abstract
The ever-growing perception of cancer stem cells (CSCs) as a plastic state rather than a hardwired defined entity has evolved our understanding of the functional and biological plasticity of these elusive components in malignancies. Pancreatic cancer (PC), based on its biological features and clinical evolution, is a prototypical example of a CSC-driven disease. Since the discovery of pancreatic CSCs (PCSCs) in 2007, evidence has unraveled their control over many facets of the natural history of PC, including primary tumor growth, metastatic progression, disease recurrence, and acquired drug resistance. Consequently, the current near-ubiquitous treatment regimens for PC using aggressive cytotoxic agents, aimed at ''tumor debulking'' rather than eradication of CSCs, have proven ineffective in providing clinically convincing improvements in patients with this dreadful disease. Herein, we review the key hallmarks as well as the intrinsic and extrinsic resistance mechanisms of CSCs that mediate treatment failure in PC and enlist the potential CSC-targeting 'natural agents' that are gaining popularity in recent years. A better understanding of the molecular and functional landscape of PCSC-intrinsic evasion of chemotherapeutic drugs offers a facile opportunity for treating PC, an intractable cancer with a grim prognosis and in dire need of effective therapeutic advances.
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Affiliation(s)
- Kalyani Patil
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Farheen B Khan
- Department of Biology, College of Science, The United Arab Emirates University, PO Box 15551, Al Ain, United Arab Emirates
| | - Sabah Akhtar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
| | - Aamir Ahmad
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar.
- Dermatology Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar.
- Laboratory Animal Research Center, Qatar University, Doha, Qatar.
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19
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ETV4 promotes breast cancer cell stemness by activating glycolysis and CXCR4-mediated sonic Hedgehog signaling. Cell Death Discov 2021; 7:126. [PMID: 34052833 PMCID: PMC8164634 DOI: 10.1038/s41420-021-00508-x] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 04/12/2021] [Accepted: 04/28/2021] [Indexed: 12/16/2022] Open
Abstract
Cancer stem cells (CSCs) are a major cause of tumor treatment resistance, relapse and metastasis. Cancer cells exhibit reprogrammed metabolism characterized by aerobic glycolysis, which is also critical for sustaining cancer stemness. However, regulation of cancer cell metabolism rewiring and stemness is not completely understood. Here, we report that ETV4 is a key transcription factor in regulating glycolytic gene expression. ETV4 loss significantly inhibits the expression of HK2, LDHA as well as other glycolytic enzymes, reduces glucose uptake and lactate release in breast cancer cells. In human breast cancer and hepatocellular carcinoma tissues, ETV4 expression is positively correlated with glycolytic signaling. Moreover, we confirm that breast CSCs (BCSCs) are glycolysis-dependent and show that ETV4 is required for BCSC maintenance. ETV4 is enriched in BCSCs, its knockdown and overexpression suppresses and promotes breast cancer cell stem-like traits, respectively. Mechanistically, on the one hand, we find that ETV4 may enhance glycolysis activity to facilitate breast cancer stemness; on the other, ETV4 activates Sonic Hedgehog signaling by transcriptionally promoting CXCR4 expression. A xenograft assay validates the tumor growth-impeding effect and inhibition of CXCR4/SHH/GLI1 signaling cascade after ETV4 depletion. Together, our study highlights the potential roles of ETV4 in promoting cancer cell glycolytic shift and BCSC maintenance and reveals the molecular basis.
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20
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Kakarla M, ChallaSivaKanaka S, Hayward SW, Franco OE. Race as a Contributor to Stromal Modulation of Tumor Progression. Cancers (Basel) 2021; 13:cancers13112656. [PMID: 34071280 PMCID: PMC8197868 DOI: 10.3390/cancers13112656] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Revised: 05/18/2021] [Accepted: 05/23/2021] [Indexed: 02/07/2023] Open
Abstract
Stromal cells play crucial roles in tumor development and are increasingly attractive targets for therapy. There are considerable racial disparities in the incidence and progression of many tumors, reflecting both environmental exposure and genetic differences existing between races. Tumorigenesis and tumor progression are linked to both the propensity to suffer an initiating event and the host response to such an event once it occurs, contributing to incidence and outcomes. In this review, we focused on racial disparities in the tumor microenvironment (TME) of different cancers as potential modulators of growth, metastasis, and response to treatment. Several studies suggest that the TME in AA has a distinct tumor biology and may facilitate both early onset and aggressive tumor growth while inhibiting anti-tumorigenic properties. The TME of AA patients often exhibits an immunosuppressive microenvironment with a substantial enrichment of immune inflammatory pathways and genes. As a result, AA patients can potentially benefit more from treatment strategies that modulate the immune system. Focusing on TME components for diagnostic and therapeutic purposes to address racial disparities is a promising area of investigation. Future basic and clinical research studies on personalized cancer diagnosis and treatment should acknowledge the significance of TME in racial disparities.
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21
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Mollaei M, Hassan ZM, Khorshidi F, Langroudi L. Chemotherapeutic drugs: Cell death- and resistance-related signaling pathways. Are they really as smart as the tumor cells? Transl Oncol 2021; 14:101056. [PMID: 33684837 PMCID: PMC7938256 DOI: 10.1016/j.tranon.2021.101056] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 02/05/2021] [Accepted: 02/22/2021] [Indexed: 02/07/2023] Open
Abstract
Chemotherapeutic drugs kill cancer cells or control their progression all over the patient's body, while radiation- and surgery-based treatments perform in a particular site. Based on their mechanisms of action, they are classified into different groups, including alkylating substrates, antimetabolite agents, anti-tumor antibiotics, inhibitors of topoisomerase I and II, mitotic inhibitors, and finally, corticosteroids. Although chemotherapeutic drugs have brought about more life expectancy, two major and severe complications during chemotherapy are chemoresistance and tumor relapse. Therefore, we aimed to review the underlying intracellular signaling pathways involved in cell death and resistance in different chemotherapeutic drug families to clarify the shortcomings in the conventional single chemotherapy applications. Moreover, we have summarized the current combination chemotherapy applications, including numerous combined-, and encapsulated-combined-chemotherapeutic drugs. We further discussed the possibilities and applications of precision medicine, machine learning, next-generation sequencing (NGS), and whole-exome sequencing (WES) in promoting cancer immunotherapies. Finally, some of the recent clinical trials concerning the application of immunotherapies and combination chemotherapies were included as well, in order to provide a practical perspective toward the future of therapies in cancer cases.
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Affiliation(s)
- Mojtaba Mollaei
- Department of Immunology, School of Medicine, Tarbiat Modares University, Tehran, Iran.
| | | | - Fatemeh Khorshidi
- Department of Immunology, School of Medicine, Tarbiat Modares University, Tehran, Iran; Department of Immunology, Pasteur Institute of Iran, Tehran, Iran
| | - Ladan Langroudi
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
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22
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Fani G, Mannini B, Vecchi G, Cascella R, Cecchi C, Dobson CM, Vendruscolo M, Chiti F. Aβ Oligomers Dysregulate Calcium Homeostasis by Mechanosensitive Activation of AMPA and NMDA Receptors. ACS Chem Neurosci 2021; 12:766-781. [PMID: 33538575 PMCID: PMC7898266 DOI: 10.1021/acschemneuro.0c00811] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Accepted: 01/25/2021] [Indexed: 12/15/2022] Open
Abstract
Alzheimer's disease, which is the most common form of dementia, is characterized by the aggregation of the amyloid β peptide (Aβ) and by an impairment of calcium homeostasis caused by excessive activation of glutamatergic receptors (excitotoxicity). Here, we studied the effects on calcium homeostasis caused by the formation of Aβ oligomeric assemblies. We found that Aβ oligomers cause a rapid influx of calcium ions (Ca2+) across the cell membrane by rapidly activating extrasynaptic N-methyl-d-aspartate (NMDA) receptors and, to a lower extent, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. We also observed, however, that misfolded oligomers do not interact directly with these receptors. Further experiments with lysophosphatidylcholine and arachidonic acid, which cause membrane compression and stretch, respectively, indicated that these receptors are activated through a change in membrane tension induced by the oligomers and transmitted mechanically to the receptors via the lipid bilayer. Indeed, lysophosphatidylcholine is able to neutralize the oligomer-induced activation of the NMDA receptors, whereas arachidonic acid activates the receptors similarly to the oligomers with no additive effects. An increased rotational freedom observed for a fluorescent probe embedded within the membrane in the presence of the oligomers also indicates a membrane stretch. These results reveal a mechanism of toxicity of Aβ oligomers in Alzheimer's disease through the perturbation of the mechanical properties of lipid membranes sensed by NMDA and AMPA receptors.
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Affiliation(s)
- Giulia Fani
- Department
of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
- Centre
for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
| | - Benedetta Mannini
- Centre
for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
| | - Giulia Vecchi
- Centre
for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
| | - Roberta Cascella
- Department
of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Cristina Cecchi
- Department
of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
| | - Christopher M. Dobson
- Centre
for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
| | - Michele Vendruscolo
- Centre
for Misfolding Diseases, Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, U.K.
| | - Fabrizio Chiti
- Department
of Experimental and Clinical Biomedical Sciences, Section of Biochemistry, University of Florence, Viale Morgagni 50, 50134 Florence, Italy
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23
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Shi Y, Riese DJ, Shen J. The Role of the CXCL12/CXCR4/CXCR7 Chemokine Axis in Cancer. Front Pharmacol 2020; 11:574667. [PMID: 33363463 PMCID: PMC7753359 DOI: 10.3389/fphar.2020.574667] [Citation(s) in RCA: 186] [Impact Index Per Article: 37.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 10/29/2020] [Indexed: 12/27/2022] Open
Abstract
Chemokines are a family of small, secreted cytokines which regulate a variety of cell functions. The C-X-C motif chemokine ligand 12 (CXCL12) binds to C-X-C chemokine receptor type 4 (CXCR4) and C-X-C chemokine receptor type 7 (CXCR7). The interaction of CXCL12 and its receptors subsequently induces downstream signaling pathways with broad effects on chemotaxis, cell proliferation, migration, and gene expression. Accumulating evidence suggests that the CXCL12/CXCR4/CXCR7 axis plays a pivotal role in tumor development, survival, angiogenesis, metastasis, and tumor microenvironment. In addition, this chemokine axis promotes chemoresistance in cancer therapy via complex crosstalk with other pathways. Multiple small molecules targeting CXCR4/CXCR7 have been developed and used for preclinical and clinical cancer treatment. In this review, we describe the roles of the CXCL12/CXCR4/CXCR7 axis in cancer progression and summarize strategies to develop novel targeted cancer therapies.
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Affiliation(s)
| | | | - Jianzhong Shen
- Department of Drug Discovery and Development, Harrison School of Pharmacy, Auburn University, Auburn, AL, United States
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24
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Gong J, Song Y, Xu L, Che X, Hou K, Guo T, Cheng Y, Liu Y, Qu X. Upregulation of Serine Proteinase Inhibitor Clade B Member 3 (SERPINB3) Expression by Stromal Cell-Derived Factor (SDF-1)/CXCR4/Nuclear Factor kappa B (NF-κB) Promotes Migration and Invasion of Gastric Cancer Cells. Med Sci Monit 2020; 26:e927411. [PMID: 33110054 PMCID: PMC7604976 DOI: 10.12659/msm.927411] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2020] [Accepted: 09/25/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Serine proteinase inhibitor clade B member 3 (SERPINB3) is a neutral glycoprotein. Its overexpression is related to the promotion of cell proliferation and activation via the nuclear factor kappa B (NF-kappaB) pathway in several tumors. Whether it can participate in stromal cell-derived factor (SDF-1)/NF-kappaB-induced metastasis of gastric cancer has not been reported. MATERIAL AND METHODS We analyzed the ability of SDF-1 to induce migration and invasion in vitro by knocking down the expression of SERPINB3 with siRNAs in gastric cancer cells. We also explored the effects of a CXCR4 antagonist and NF-kappaB inhibitor on SERPINB3 expression. We verified the effect of SERPINB3 on prognosis in gastric cancer specimens by immunohistochemistry. RESULTS In vitro experiments confirmed that SDF-1 upregulated the expression of SERPINB3 and promoted metastasis in gastric cancer cells. This phenomenon was reversed by knockdown of SERPINB3, a chemokine receptor 4 (CXCR4) antagonist, and an NF-kappaB inhibitor, which downregulated the expression of SERPINB3. In patients with gastric cancer, a significant positive correlation was observed between CXCR4 and SERPINB3 expression (r=0.222, P=0.029). Moreover, double positivity for SERPINB3 and CXCR4 was certified to be an independent prognostic factor (HR=3.332, P<0.001). CXCR4-positive patients who also expressed SERPINB3 were inclined to suffer from lymph node metastasis, confirming that SERPINB3 is a downstream molecule of CXCR4. CONCLUSIONS In vitro and pathological results showed that SDF-1/CXCR4 activated the NF-kappaB pathway and upregulated SERPINB3 to facilitate the migration and invasion of gastric cancer cells.
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Affiliation(s)
- Jing Gong
- Department of Geriatrics, The First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Yongxi Song
- Department of Surgical Oncology and General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Ling Xu
- Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Xiaofang Che
- Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Kezuo Hou
- Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Tianshu Guo
- Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Yu Cheng
- Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Yunpeng Liu
- Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
| | - Xiujuan Qu
- Department of Medical Oncology, Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Liaoning Province Clinical Research Center for Cancer, The First Hospital of China Medical University, Shenyang, Liaoning, P.R. China
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25
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Li J, Yan Y, Ang L, Li X, Liu C, Sun B, Lin X, Peng Z, Zhang X, Zhang Q, Wu H, Zhao M, Su C. Extracellular vesicles-derived OncomiRs mediate communication between cancer cells and cancer-associated hepatic stellate cells in hepatocellular carcinoma microenvironment. Carcinogenesis 2020; 41:223-234. [PMID: 31140556 DOI: 10.1093/carcin/bgz096] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 05/08/2019] [Accepted: 05/28/2019] [Indexed: 01/10/2023] Open
Abstract
Tumor microenvironment (TME) is a critical determinant for hepatocellular carcinoma (HCC). Hepatic stellate cells (HSCs) are main interstitial cells in TME and play a vital role in early intrahepatic invasion and metastasis of HCC. The potential mechanism on the interactions between HSCs and HCC cells remains unclear. In this study, the effects of extracellular vesicles (EVs)-derived OncomiRs that mediate communication between HCC cells and cancer-associated hepatic stellate cells (caHSCs) and remold TME were investigated. The results found that the HCC cells-released EVs contained more various OncomiRs, which could activate HSCs (LX2 cells) and transform them to caHSCs, the caHSCs in turn exerted promotion effects on HCC cells through HSCs-released EVs. To further simulate the effects of OncomiRs in EVs on construction of pro-metastatic TME, a group of OncomiRs, miR-21, miR-221 and miR-151 was transfected into HCC cells and LX2 cells. These microRNAs in the EVs from OncomiRs-enhanced cells were demonstrated to have oncogenic effects on HCC cells by upregulating the activities of protein kinase B (AKT)/extracellular signal-regulated kinase (ERK) signal pathways. Equivalent results were also found in HCC xenografted tumor models. The findings suggested that the OncomiR secretion and transference by cancer cells-released EVs can mediate the communication between HCC cells and HSCs. HCC cells and caHSCs, as well as their secreted EVs, jointly construct a pro-metastatic TME suitable for invasion and metastasis of cancer cells, all these TME components form a positive feedback loop to promote HCC progression and metastasis.
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Affiliation(s)
- Jiang Li
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Yan Yan
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Lin Ang
- Department of Pathology, The Second People's Hospital of Hefei, Hefei, Anhui Province, China
| | - Xiaoya Li
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Chunying Liu
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Bin Sun
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Xuejing Lin
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Zhangxiao Peng
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Xiaofeng Zhang
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Qin Zhang
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Hongping Wu
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
| | - Min Zhao
- Department of Pathology, The Second People's Hospital of Hefei, Hefei, Anhui Province, China
| | - Changqing Su
- Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital and National Center for Liver Cancer, Second Military Medical University, Shanghai, China
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26
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Zubair H, Khan MA, Anand S, Srivastava SK, Singh S, Singh AP. Modulation of the tumor microenvironment by natural agents: implications for cancer prevention and therapy. Semin Cancer Biol 2020; 80:237-255. [PMID: 32470379 PMCID: PMC7688484 DOI: 10.1016/j.semcancer.2020.05.009] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 05/10/2020] [Accepted: 05/14/2020] [Indexed: 02/07/2023]
Abstract
The development of cancer is not just the growth and proliferation of a single transformed cell, but its surrounding environment also coevolves with it. Indeed, successful cancer progression depends on the ability of the tumor cells to develop a supportive tumor microenvironment consisting of various types of stromal cells. The interactions between the tumor and stromal cells are bidirectional and mediated through a variety of growth factors, cytokines, metabolites, and other biomolecules secreted by these cells. Tumor-stromal crosstalk creates optimal conditions for the tumor growth, metastasis, evasion of immune surveillance, and therapy resistance, and its targeting is being explored for clinical management of cancer. Natural agents from plants and marine life have been at the forefront of traditional medicine. Numerous epidemiological studies have reported the health benefits imparted on the consumption of certain fruits, vegetables, and their derived products. Indeed, a significant majority of anti-cancer drugs in clinical use are either naturally occurring compounds or their derivatives. In this review, we describe fundamental cellular and non-cellular components of the tumor microenvironment and discuss the significance of natural compounds in their targeting. Existing literature provides hope that novel prevention and therapeutic approaches will emerge from ongoing scientific efforts leading to the reduced tumor burden and improve clinical outcomes in cancer patients.
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Affiliation(s)
- Haseeb Zubair
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Mohammad Aslam Khan
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Shashi Anand
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Sanjeev Kumar Srivastava
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA
| | - Seema Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA
| | - Ajay Pratap Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, USA; Mitchell Cancer Institute, University of South Alabama, Mobile, AL, USA; Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, USA.
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27
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Khan MA, Srivastava SK, Zubair H, Patel GK, Arora S, Khushman M, Carter JE, Gorman GS, Singh S, Singh AP. Co-targeting of CXCR4 and hedgehog pathways disrupts tumor-stromal crosstalk and improves chemotherapeutic efficacy in pancreatic cancer. J Biol Chem 2020; 295:8413-8424. [PMID: 32358063 DOI: 10.1074/jbc.ra119.011748] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 04/17/2020] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) remains a therapeutic challenge because of its intrinsic and extrinsic chemoresistance mechanisms. Here, we report that C-X-C motif chemokine receptor 4 (CXCR4) and hedgehog pathways cooperate in PC chemoresistance via bidirectional tumor-stromal crosstalk. We show that when PC cells are co-cultured with pancreatic stellate cells (PSCs) they are significantly more resistant to gemcitabine toxicity than those grown in monoculture. We also demonstrate that this co-culture-induced chemoresistance is abrogated by inhibition of the CXCR4 and hedgehog pathways. Similarly, the co-culture-induced altered expression of genes in PC cells associated with gemcitabine metabolism, antioxidant defense, and cancer stemness is also reversed upon CXCR4 and hedgehog inhibition. We have confirmed the functional impact of these genetic alterations by measuring gemcitabine metabolites, reactive oxygen species production, and sphere formation in vehicle- or gemcitabine-treated monocultures and co-cultured PC cells. Treatment of orthotopic pancreatic tumor-bearing mice with gemcitabine alone or in combination with a CXCR4 antagonist (AMD3100) or hedgehog inhibitor (GDC-0449) displays reduced tumor growth. Notably, we show that the triple combination treatment is the most effective, resulting in nearly complete suppression of tumor growth. Immunohistochemical analysis of Ki67 and cleaved caspase-3 confirm these findings from in vivo imaging and tumor measurements. Our findings provide preclinical and mechanistic evidence that a combination of gemcitabine treatment with targeted inhibition of both the CXCR4 and hedgehog pathways improves outcomes in a PC mouse model.
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Affiliation(s)
- Mohammad Aslam Khan
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Sanjeev Kumar Srivastava
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Haseeb Zubair
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Girijesh Kumar Patel
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Sumit Arora
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - Moh'd Khushman
- Department of Medical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama
| | - James Elliot Carter
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama
| | | | - Seema Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama.,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama
| | - Ajay Pratap Singh
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, Alabama .,Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, Alabama
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28
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Huang R, Huang Y, Zeng G, Li M, Jin Y. Ursodeoxycholic acid inhibits intimal hyperplasia, vascular smooth muscle cell excessive proliferation, migration via blocking miR-21/PTEN/AKT/mTOR signaling pathway. Cell Cycle 2020; 19:918-932. [PMID: 32202193 PMCID: PMC7217369 DOI: 10.1080/15384101.2020.1732514] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Excessive migration and proliferation of vascular smooth muscle cells (VSMCs) are critical cellular events that lead to intimal hyperplasia in atherosclerosis and restenosis. In this study, we investigated the protective effects of ursodeoxycholic acid (UDCA) on intimal hyperplasia and VSMC proliferation and migration, and the underlying mechanisms by which these events occur. A rat unilateral carotid artery was ligated to induce vascular injury and the microRNA (miRNA) expression profiles were determined using miRNA microarray analysis. We observed that UDCA significantly reduced the degree of intimal hyperplasia and induced miR-21 dysregulation. Restoration of miR-21 by agomir-miR-21 reversed the protective effects of UDCA on intimal hyperplasia and proliferation in vivo. In vitro, UDCA suppressed PDGF-BB-induced VSMC proliferation, invasion and migration in a dose-dependent manner, whereas the suppressive effect of UDCA was abrogated by overexpression of miR-21 in PDGF-BB-incubated VSMCs. Furthermore, we identified that miR-21 in VSMCs targeted the phosphatase and tensin homolog (PTEN), a tumor suppressor gene, negatively modulated the AKT/mTOR pathway. More importantly, we observed that that UDCA suppressed AKT/mTOR signaling pathway in the carotid artery injury model, whereas this pathway was reactivated by overexpression of miR-21. Taken together, our findings indicated that UDCA inhibited intimal hyperplasia and VSMCs excessive migration and proliferation via blocking miR-21/PTEN/AKT/mTOR signaling pathway, which suggests that UDCA may be a promising candidate for the therapy of atherosclerosis.
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Affiliation(s)
- Rong Huang
- Department of General Surgery, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yi Huang
- Department of General Surgery, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Guang Zeng
- Department of General Surgery, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengfan Li
- Department of General Surgery, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yongzhi Jin
- Department of General Surgery, Putuo Hospital Shanghai University of Traditional Chinese Medicine, Shanghai, China
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29
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Daniel SK, Seo YD, Pillarisetty VG. The CXCL12-CXCR4/CXCR7 axis as a mechanism of immune resistance in gastrointestinal malignancies. Semin Cancer Biol 2019; 65:176-188. [PMID: 31874281 DOI: 10.1016/j.semcancer.2019.12.007] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Revised: 12/03/2019] [Accepted: 12/11/2019] [Indexed: 02/07/2023]
Abstract
Single agent checkpoint inhibitor therapy has not been effective for most gastrointestinal solid tumors, but combination therapy with drugs targeting additional immunosuppressive pathways is being attempted. One such pathway, the CXCL12-CXCR4/CXCR7 chemokine axis, has attracted attention due to its effects on tumor cell survival and metastasis as well as immune cell migration. CXCL12 is a small protein that functions in normal hematopoietic stem cell homing in addition to repair of damaged tissue. Binding of CXCL12 to CXCR4 leads to activation of G protein signaling kinases such as P13K/mTOR and MEK/ERK while binding to CXCR7 leads to β-arrestin mediated signaling. While some gastric and colorectal carcinoma cells have been shown to make CXCL12, the primary source in pancreatic cancer and peritoneal metastases is cancer-associated fibroblasts. Binding of CXCL12 to CXCR4 and CXCR7 on tumor cells leads to anti-apoptotic signaling through Bcl-2 and survivin upregulation, as well as promotion of the epithelial-to-mesechymal transition through the Rho-ROCK pathway and alterations in cell adhesion molecules. High levels of CXCL12 seen in the bone marrow, liver, and spleen could partially explain why these are popular sites of metastases for many tumors. CXCL12 is a chemoattractant for lymphocytes at lower levels, but becomes chemorepellant at higher levels; it is unclear exactly what gradient exists in the tumor microenvironment and how this influences tumor-infiltrating lymphocytes. AMD3100 (Plerixafor or Mozobil) is a small molecule CXCR4 antagonist and is the most frequently used drug targeting the CXCL12-CXCR4/CXCR7 axis in clinical trials for gastrointestinal solid tumors currently. Other small molecules and monoclonal antibodies against CXCR4 are being trialed. Further understanding of the CXCL12- CXCR4/CXCR7 chemokine axis in the tumor microenvironment will allow more effective targeting of this pathway in combination immunotherapy.
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Affiliation(s)
- Sara K Daniel
- University of Washington, Dept. of Surgery, Seattle, WA, USA
| | - Y David Seo
- University of Washington, Dept. of Surgery, Seattle, WA, USA
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30
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Tharp D, Nandana S. How Prostate Cancer Cells Use Strategy Instead of Brute Force to Achieve Metastasis. Cancers (Basel) 2019; 11:cancers11121928. [PMID: 31817000 PMCID: PMC6966655 DOI: 10.3390/cancers11121928] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2019] [Revised: 11/25/2019] [Accepted: 11/27/2019] [Indexed: 12/26/2022] Open
Abstract
Akin to many other cancers, metastasis is the predominant cause of lethality in prostate cancer (PCa). Research in the past decade or so has revealed that although metastatic manifestation is a multi-step and complex process that is orchestrated by distinct cellular and molecular mechanisms, the process in itself is an extremely inefficient one. It is now becoming increasingly evident that PCa cells employ a plethora of strategies to make the most of this inefficient process. These strategies include priming the metastatic sites ahead of colonization, devising ways to metastasize to specific organs, outsmarting the host defense surveillance, lying in a dormant state at the metastatic site for prolonged periods, and widespread reprogramming of the gene expression to suit their needs. Based on established, recent, and evolving lines of research, this review is an attempt to understand PCa metastasis from the perspective of military combat, wherein strategic maneuvering instead of brute force often plays a decisive role in the outcome.
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31
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Mousavi A. CXCL12/CXCR4 signal transduction in diseases and its molecular approaches in targeted-therapy. Immunol Lett 2019; 217:91-115. [PMID: 31747563 DOI: 10.1016/j.imlet.2019.11.007] [Citation(s) in RCA: 100] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 11/01/2019] [Accepted: 11/15/2019] [Indexed: 02/08/2023]
Abstract
Chemokines are small molecules called "chemotactic cytokines" and regulate many processes like leukocyte trafficking, homing of immune cells, maturation, cytoskeletal rearrangement, physiology, migration during development, and host immune responses. These proteins bind to their corresponding 7-membrane G-protein-coupled receptors. Chemokines and their receptors are anti-inflammatory factors in autoimmune conditions, so consider as potential targets for neutralization in such diseases. They also express by cancer cells and function as angiogenic factors, and/or survival/growth factors that enhance tumor angiogenesis and development. Among chemokines, the CXCL12/CXCR4 axis has significantly been studied in numerous cancers and autoimmune diseases. CXCL12 is a homeostatic chemokine, which is acts as an anti-inflammatory chemokine during autoimmune inflammatory responses. In cancer cells, CXCL12 acts as an angiogenic, proliferative agent and regulates tumor cell apoptosis as well. CXCR4 has a role in leukocyte chemotaxis in inflammatory situations in numerous autoimmune diseases, as well as the high levels of CXCR4, observed in different types of human cancers. These findings suggest CXCL12/CXCR4 as a potential therapeutic target for therapy of autoimmune diseases and open a new approach to targeted-therapy of cancers by neutralizing CXCL12 and CXCR4. In this paper, we reviewed the current understanding of the role of the CXCL12/CXCR4 axis in disease pathology and cancer biology, and discuss its therapeutic implications in cancer and diseases.
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32
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Lafaro KJ, Melstrom LG. The Paradoxical Web of Pancreatic Cancer Tumor Microenvironment. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:44-57. [PMID: 30558722 DOI: 10.1016/j.ajpath.2018.09.009] [Citation(s) in RCA: 67] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 08/28/2018] [Accepted: 09/25/2018] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is increasing in incidence and is projected to become the second leading cause of cancer death in the United States. Despite significant advances in understanding the disease, there has been minimal increase in PDAC patient survival. PDAC tumors are unique in the fact that there is significant desmoplasia. This generates a large stromal compartment composed of immune cells, inflammatory cells, growth factors, extracellular matrix, and fibroblasts, comprising the tumor microenvironment (TME), which may represent anywhere from 15% to 85% of the tumor. It has become evident that the TME, including both the stroma and extracellular component, plays an important role in tumor progression and chemoresistance of PDAC. This review will discuss the multiple components of the TME, their specific impact on tumorigenesis, and the multiple therapeutic targets.
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Affiliation(s)
- Kelly J Lafaro
- Department of Surgery, City of Hope National Medical Center, Duarte, California
| | - Laleh G Melstrom
- Department of Surgery, City of Hope National Medical Center, Duarte, California.
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Geismann C, Schäfer H, Gundlach JP, Hauser C, Egberts JH, Schneider G, Arlt A. NF-κB Dependent Chemokine Signaling in Pancreatic Cancer. Cancers (Basel) 2019; 11:cancers11101445. [PMID: 31561620 PMCID: PMC6826905 DOI: 10.3390/cancers11101445] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 09/12/2019] [Accepted: 09/24/2019] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is one of the carcinomas with the worst prognoses, as shown by its five-year survival rate of 9%. Although there have been new therapeutic innovations, the effectiveness of these therapies is still limited, resulting in pancreatic ductal adenocarcinoma (PDAC) becoming the second leading cause of cancer-related death in 2020 in the US. In addition to tumor cell intrinsic resistance mechanisms, this disease exhibits a complex stroma consisting of fibroblasts, immune cells, neuronal and vascular cells, along with extracellular matrix, all conferring therapeutic resistance by several mechanisms. The NF-κB pathway is involved in both the tumor cell-intrinsic and microenvironment-mediated therapeutic resistance by regulating the transcription of a plethora of target genes. These genes are involved in nearly all scenarios described as the hallmarks of cancer. In addition to classical regulators of apoptosis, NF-κB regulates the expression of chemokines and their receptors, both in the tumor cells and in cells of the microenvironment. These chemokines mediate autocrine and paracrine loops among tumor cells but also cross-signaling between tumor cells and the stroma. In this review, we will focus on NF-κB-mediated chemokine signaling, with an emphasis on therapy resistance in pancreatic cancer.
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Affiliation(s)
- Claudia Geismann
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany.
| | - Heiner Schäfer
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany.
- Institute of Experimental Cancer Research, UKSH Campus Kiel, 24105 Kiel, Germany.
| | | | | | | | - Günter Schneider
- Technische Universität München, Klinikum rechts der Isar, II. Medizinische Klinik, 81675 Munich, Germany.
| | - Alexander Arlt
- Laboratory of Molecular Gastroenterology & Hepatology, Department of Internal Medicine I, UKSH-Campus Kiel, 24105 Kiel, Germany.
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CXCL12 and Its Isoforms: Different Roles in Pancreatic Cancer? JOURNAL OF ONCOLOGY 2019; 2019:9681698. [PMID: 31275385 PMCID: PMC6582792 DOI: 10.1155/2019/9681698] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Accepted: 05/09/2019] [Indexed: 12/11/2022]
Abstract
CXCL12 is a chemokine that acts through CXCR4 and ACKR3 receptors and plays a physiological role in embryogenesis and haematopoiesis. It has an important role also in tumor development, since it is released by stromal cells of tumor microenvironment and alters the behavior of cancer cells. Many studies investigated the roles of CXCL12 in order to understand if it has an anti- or protumor role. In particular, it seems to promote tumor invasion, proliferation, angiogenesis, epithelial to mesenchymal transition (EMT), and metastasis in pancreatic cancer. Nevertheless, some evidence shows opposite functions; therefore research on CXCL12 is still ongoing. These discrepancies could be due to the presence of at least six CXCL12 splicing isoforms, each with different roles. Interestingly, three out of six variants have the highest levels of expression in the pancreas. Here, we report the current knowledge about the functions of this chemokine and then focus on pancreatic cancer. Moreover, we discuss the methods applied in recent studies in order to understand if they took into account the existence of the CXCL12 isoforms.
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Clinicopathological significance and prognostic role of chemokine receptor CXCR4 expression in pancreatic ductal adenocarcinoma, a meta-analysis and literature review. Int J Surg 2019; 65:32-38. [DOI: 10.1016/j.ijsu.2019.03.009] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 02/12/2019] [Accepted: 03/11/2019] [Indexed: 12/18/2022]
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Khan S, Setua S, Kumari S, Dan N, Massey A, Hafeez BB, Yallapu MM, Stiles ZE, Alabkaa A, Yue J, Ganju A, Behrman S, Jaggi M, Chauhan SC. Superparamagnetic iron oxide nanoparticles of curcumin enhance gemcitabine therapeutic response in pancreatic cancer. Biomaterials 2019; 208:83-97. [PMID: 30999154 DOI: 10.1016/j.biomaterials.2019.04.005] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Revised: 03/08/2019] [Accepted: 04/05/2019] [Indexed: 01/14/2023]
Abstract
Pancreatic cancer is a complex disease accounting for fibrotic tumors and an aggressive phenotype. Gemcitabine (GEM) is used as a standard therapy, which develops chemoresistance leading to poor patient outcome. We have recently developed a superparamagnetic iron oxide nanoparticle (SPION) formulation of curcumin (SP-CUR), which is a nontoxic, bioactive anti-inflammatory/anti-cancer agent for its enhanced delivery in tumors. In this study, we demonstrate that SP-CUR effectively delivers bioactive curcumin to pancreatic tumors, simultaneously enhances GEM uptake and its efficacy. Mechanistic revelations suggest that SP-CUR targets tumor microenvironment via suppression of sonic hedgehog (SHH) pathway and an oncogenic CXCR4/CXCL12 signaling axis that inhibits bidirectional tumor-stromal cells interaction. Increased GEM uptake was observed due to upregulation of the human nucleoside transporter genes (DCK, hCNT) and blocking ribonucleotide reductase subunits (RRM1/RRM2). Additionally, co-treatment of SP-CUR and GEM targets cancer stem cells by regulating pluripotency maintaining stemness factors (Nanog, Sox2, c-Myc and Oct-4), and restricting tumor sphere formation. In an orthotopic mouse model, an enhanced accumulation of SP-CUR was found in pancreas, which potentiated GEM to reduce tumor growth and metastasis. Analysis of tumor tissues suggest that the treatment inhibits tumor stroma (α-SMA, Desmin and Hyluronic Acid) and induces changes in cell stiffness, as measured via Atomic Force Microscopy. This was accompanied by alteration of key cellular proteins of SHH signaling such as SHH, Gli-1, Gli-2, Sufu, and NFĸB-65 as indicated by Immunoblotting and Immunohistochemistry. These results suggest that SP-CUR has a great potential for future clinical use in the management of pancreatic cancer.
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Affiliation(s)
- Sheema Khan
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Saini Setua
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Sonam Kumari
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Nirnoy Dan
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Andrew Massey
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Bilal Bin Hafeez
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Murali M Yallapu
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Zachary Edwar Stiles
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Anas Alabkaa
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Junming Yue
- Department of Pathology, University of Tennessee Health Science Center, Memphis, USA
| | - Aditya Ganju
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Stephen Behrman
- Department of Surgery, University of Tennessee Health Science Center, Memphis, USA
| | - Meena Jaggi
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA
| | - Subhash C Chauhan
- Department of Pharmaceutical Sciences and Center for Cancer Research, University of Tennessee Health Science Center, Memphis, USA.
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37
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Cai K, Na W, Guo M, Xu R, Wang X, Qin Y, Wu Y, Jiang J, Huang H. Targeting the cross-talk between the hedgehog and NF-κB signaling pathways in multiple myeloma. Leuk Lymphoma 2019; 60:772-781. [PMID: 30644322 DOI: 10.1080/10428194.2018.1493727] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Multiple myeloma (MM) is an incurable plasma cell malignancy. Aberrant activation of the Hedgehog (Hh) and NF-κB signaling pathways is observed in MM and plays a pivotal role in the development of MM by promoting myeloma cell growth, survival, and drug resistance. In this study, we found that the Sonic Hh (SHh) ligand in the bone marrow microenvironment is responsible for the enhancement of NF-κB activity in MM cell lines NCI-H929 and U266. Notably, we discovered that Hh signaling regulates NF-κB through its classical pathway (SHh/PTCH1/SMO/GLI1) in MM cells. Meanwhile, non-classical pathway by SMO recruitment of TRAF6 to ubiquitination is also involved in it. Moreover, the SMO inhibitor cyclopamine enhances the cytotoxic effects of bortezomib in MM cell lines. Our study reveals the cross-talk between Hh members and the NF-κB pathway in the myeloma cells and provides a theoretical basis for combined utilization of Hh members and proteasome inhibition in MM.
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Affiliation(s)
- Ke Cai
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Wenxiu Na
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Mengjie Guo
- b School of Medicine and Life Sciences , Nanjing University of Chinese Medicine , Nanjing , 210023 , P.R. China
| | - Ruirong Xu
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Xinfeng Wang
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Yi Qin
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Yan Wu
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Jie Jiang
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
| | - Hongming Huang
- a Department of Hematology , The Affiliated Hospital of Nantong University , Nantong , Jiangsu , 226001 , P.R. China
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Ahmmed B, Kampo S, Khan M, Faqeer A, Kumar SP, Yulin L, Liu JW, Yan Q. Rg3 inhibits gemcitabine-induced lung cancer cell invasiveness through ROS-dependent, NF-κB- and HIF-1α-mediated downregulation of PTX3. J Cell Physiol 2019; 234:10680-10697. [PMID: 30628067 DOI: 10.1002/jcp.27731] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Accepted: 10/22/2018] [Indexed: 12/14/2022]
Abstract
PTX3, a member of the long pentraxin subfamily, associated with innate immunity is indispensable for resistance to some cancer. Gemcitabine, an analog of cytosine arabinoside, has shown restrained benefits because of profound chemoresistance. The PTX3 expression on GEM in human lung cancer cells have not yet been clarified; the present study aimed to show reactive oxygen species (ROS) mediatory PTX3 expression through distinct mechanisms. Whereas ginsenoside Rg3 is a herbal medicine with strong antitumor activity. Furthermore, we tested the hypothesis; Rg3 abrogates GEM-induced production of ROS-mediated activation of Akt and extracellular signal-regulated kinase (ERK) pathways and inhibits nuclear piling-up of nuclear factor kappa B (NF-κB) and HIF-1α. On the basis of time and dose-dependent manner, our data demonstrated that GEM-induced PTX3 expression was dependent on ROS generation as it was abrogated by pretreatment of lung cancer cells with the free radical scavenger N-acetyl-l-cysteine. Our data demonstrated that PTX3 upregulation by GEM correlated with the time-dependent escalation of NF-κB and HIF-1α in the nucleus resulted from phosphorylation-induced degradation of IκBα, whereas HIF-1α upregulation was NF-κB-dependent. Increase in ROS expression in lung cancer cells on GEM treatment preceded the nuclear accumulation of NF-κB and HIF-1α and suppression of ROS diminished these effects. ERK1/2 and Akt activation mediated the effect of ROS on NF-κB and HIF-1α and their pharmacological inhibition suppressed GEM-induced PTX3. Our study findings reinforced the role regarding PTX3 signaling in GEM-induced resistance and pointed toward an unintended and undesired effect of chemotherapy and to get an active regimen; the synergy was associated with NF-κB downregulation in lung cancer.
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Affiliation(s)
- Bulbul Ahmmed
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China
| | - Sylvanus Kampo
- Department of Anesthesiology, First Affiliated Hospital of Dalian Medical University, Dalian, China
| | - Muhammad Khan
- Department of Zoology, University of Punjab, Quaid-e-Azam Campus, Lahore, Pakistan
| | - Abdullah Faqeer
- Department of Biochemistry and Molecular Biology, Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China
| | | | - Li Yulin
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China
| | - Ji Wei Liu
- Department of Oncology, The First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, China
| | - Qiu Yan
- Department of Biochemistry and Molecular Biology, Liaoning Provincial Core Lab of Glycobiology and Glycoengineering, Dalian Medical University, Dalian, China
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39
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Mu W, Wang Z, Zöller M. Ping-Pong-Tumor and Host in Pancreatic Cancer Progression. Front Oncol 2019; 9:1359. [PMID: 31921628 PMCID: PMC6927459 DOI: 10.3389/fonc.2019.01359] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 11/18/2019] [Indexed: 12/12/2022] Open
Abstract
Metastasis is the main cause of high pancreatic cancer (PaCa) mortality and trials dampening PaCa mortality rates are not satisfying. Tumor progression is driven by the crosstalk between tumor cells, predominantly cancer-initiating cells (CIC), and surrounding cells and tissues as well as distant organs, where tumor-derived extracellular vesicles (TEX) are of major importance. A strong stroma reaction, recruitment of immunosuppressive leukocytes, perineural invasion, and early spread toward the peritoneal cavity, liver, and lung are shared with several epithelial cell-derived cancer, but are most prominent in PaCa. Here, we report on the state of knowledge on the PaCIC markers Tspan8, alpha6beta4, CD44v6, CXCR4, LRP5/6, LRG5, claudin7, EpCAM, and CD133, which all, but at different steps, are engaged in the metastatic cascade, frequently via PaCIC-TEX. This includes the contribution of PaCIC markers to TEX biogenesis, targeting, and uptake. We then discuss PaCa-selective features, where feedback loops between stromal elements and tumor cells, including distorted transcription, signal transduction, and metabolic shifts, establish vicious circles. For the latter particularly pancreatic stellate cells (PSC) are responsible, furnishing PaCa to cope with poor angiogenesis-promoted hypoxia by metabolic shifts and direct nutrient transfer via vesicles. Furthermore, nerves including Schwann cells deliver a large range of tumor cell attracting factors and Schwann cells additionally support PaCa cell survival by signaling receptor binding. PSC, tumor-associated macrophages, and components of the dysplastic stroma contribute to perineural invasion with signaling pathway activation including the cholinergic system. Last, PaCa aggressiveness is strongly assisted by the immune system. Although rich in immune cells, only immunosuppressive cells and factors are recovered in proximity to tumor cells and hamper effector immune cells entering the tumor stroma. Besides a paucity of immunostimulatory factors and receptors, immunosuppressive cytokines, myeloid-derived suppressor cells, regulatory T-cells, and M2 macrophages as well as PSC actively inhibit effector cell activation. This accounts for NK cells of the non-adaptive and cytotoxic T-cells of the adaptive immune system. We anticipate further deciphering the molecular background of these recently unraveled intermingled phenomena may turn most lethal PaCa into a curatively treatable disease.
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Affiliation(s)
- Wei Mu
- School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Wei Mu
| | - Zhe Wang
- Department of Oncology, The First Affiliated Hospital of Guangdong, Pharmaceutical University, Guangzhou, China
| | - Margot Zöller
- Department of Oncology, The First Affiliated Hospital of Guangdong, Pharmaceutical University, Guangzhou, China
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40
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Abstract
Pancreatic cancer is a devastating disease with poor prognosis in the modern era. Inflammatory processes have emerged as key mediators of pancreatic cancer development and progression. Recently, studies have been carried out to investigate the underlying mechanisms that contribute to tumorigenesis induced by inflammation. In this review, the role of inflammation in the initiation and progression of pancreatic cancer is discussed.
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Affiliation(s)
- Kamleshsingh Shadhu
- Pancreas Center of The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
- Pancreas Institute of Nanjing Medical University, Nanjing, P.R. China
- School of International Education of Nanjing Medical University, Nanjing, P.R. China
| | - Chunhua Xi
- Pancreas Center of The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
- Pancreas Institute of Nanjing Medical University, Nanjing, P.R. China
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41
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Chu GCY, Chung LWK, Gururajan M, Hsieh CL, Josson S, Nandana S, Sung SY, Wang R, Wu JB, Zhau HE. Regulatory signaling network in the tumor microenvironment of prostate cancer bone and visceral organ metastases and the development of novel therapeutics. Asian J Urol 2018; 6:65-81. [PMID: 30775250 PMCID: PMC6363607 DOI: 10.1016/j.ajur.2018.11.003] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 10/13/2018] [Accepted: 10/18/2018] [Indexed: 12/26/2022] Open
Abstract
This article describes cell signaling network of metastatic prostate cancer (PCa) to bone and visceral organs in the context of tumor microenvironment and for the development of novel therapeutics. The article focuses on our recent progress in the understanding of: 1) The plasticity and dynamics of tumor–stroma interaction; 2) The significance of epigenetic reprogramming in conferring cancer growth, invasion and metastasis; 3) New insights on altered junctional communication affecting PCa bone and brain metastases; 4) Novel strategies to overcome therapeutic resistance to hormonal antagonists and chemotherapy; 5) Genetic-based therapy to co-target tumor and bone stroma; 6) PCa-bone-immune cell interaction and TBX2-WNTprotein signaling in bone metastasis; 7) The roles of monoamine oxidase and reactive oxygen species in PCa growth and bone metastasis; and 8) Characterization of imprinting cluster of microRNA, in tumor–stroma interaction. This article provides new approaches and insights of PCa metastases with emphasis on basic science and potential for clinical translation. This article referenced the details of the various approaches and discoveries described herein in peer-reviewed publications. We dedicate this article in our fond memory of Dr. Donald S. Coffey who taught us the spirit of sharing and the importance of focusing basic science discoveries toward translational medicine.
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Affiliation(s)
- Gina Chia-Yi Chu
- Uro-Oncology Research, Department of Medicine and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Leland W K Chung
- Uro-Oncology Research, Department of Medicine and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Murali Gururajan
- Uro-Oncology Research, Department of Medicine and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Bristol-Myer Squibb Company, Princeton, NJ, USA
| | - Chia-Ling Hsieh
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Sajni Josson
- Uro-Oncology Research, Department of Medicine and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Oncoveda Cancer Research Center, Genesis Biotechnology Group, Hamilton, NJ, USA
| | - Srinivas Nandana
- Uro-Oncology Research, Department of Medicine and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Texas Tech University Health Sciences Center, Department of Cell Biology and Biochemistry, Lubbock, TX, USA
| | - Shian-Ying Sung
- Department of Urology, Emory University School of Medicine, Atlanta, GA, USA
| | - Ruoxiang Wang
- Uro-Oncology Research, Department of Medicine and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Jason Boyang Wu
- Uro-Oncology Research, Department of Medicine and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.,Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA
| | - Haiyen E Zhau
- Uro-Oncology Research, Department of Medicine and Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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42
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Lee NH, Nikfarjam M, He H. Functions of the CXC ligand family in the pancreatic tumor microenvironment. Pancreatology 2018; 18:705-716. [PMID: 30078614 DOI: 10.1016/j.pan.2018.07.011] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/06/2018] [Accepted: 07/30/2018] [Indexed: 02/06/2023]
Abstract
Therapeutic resistance is the major contributor to the poor prognosis of and low survival from pancreatic cancer (PC). Cancer progression is a complex process reliant on interactions between the tumor and the tumor microenvironment (TME). Members of the CXCL family of chemokines are present in the pancreatic TME and seem to play a vital role in regulating PC progression. As pancreatic tumors interact with the TME and with PC stem cells (CSCs), determining the roles of specific members of the CXCL family is vital to the development of improved therapies. This review highlights the roles of selected CXCLs in the interactions between pancreatic tumor and its stroma, and in CSC phenotypes, which can be used to identify potential treatment targets.
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Affiliation(s)
- Nien-Hung Lee
- Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
| | - Mehrdad Nikfarjam
- Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria, Australia
| | - Hong He
- Department of Surgery, University of Melbourne, Austin Health, Melbourne, Victoria, Australia.
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43
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Wang K, Baldwin GS, Nikfarjam M, He H. p21-activated kinase signalling in pancreatic cancer: New insights into tumour biology and immune modulation. World J Gastroenterol 2018; 24:3709-3723. [PMID: 30197477 PMCID: PMC6127653 DOI: 10.3748/wjg.v24.i33.3709] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 06/22/2018] [Accepted: 06/27/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most aggressive and lethal malignancies worldwide, with a very poor prognosis and a five-year survival rate less than 8%. This dismal outcome is largely due to delayed diagnosis, early distant dissemination and resistance to conventional chemo-therapies. Kras mutation is a well-defined hallmark of pancreatic cancer, with over 95% of cases harbouring Kras mutations that give rise to constitutively active forms of Kras. As important down-stream effectors of Kras, p21-activated kinases (PAKs) are involved in regulating cell proliferation, apoptosis, invasion/migration and chemo-resistance. Immunotherapy is now emerging as a promising treatment modality in the era of personalized anti-cancer therapeutics. In this review, basic knowledge of PAK structure and regulation is briefly summarised and the pivotal role of PAKs in Kras-driven pancreatic cancer is highlighted in terms of tumour biology and chemo-resistance. Finally, the involvement of PAKs in immune modulation in the tumour microenvironment is discussed and the potential advantages of targeting PAKs are explored.
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Affiliation(s)
- Kai Wang
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Graham S Baldwin
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Mehrdad Nikfarjam
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
| | - Hong He
- Department of Surgery, University of Melbourne, Melbourne 3084, Australia
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44
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Fu L, Zhu P, Qi S, Li C, Zhao K. MicroRNA-92a antagonism attenuates lipopolysaccharide (LPS)-induced pulmonary inflammation and injury in mice through suppressing the PTEN/AKT/NF-κB signaling pathway. Biomed Pharmacother 2018; 107:703-711. [PMID: 30138892 DOI: 10.1016/j.biopha.2018.08.040] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Revised: 08/10/2018] [Accepted: 08/10/2018] [Indexed: 12/12/2022] Open
Abstract
Overwhelming lung inflammation is a key feature of acute lung injury (ALI). MicroRNAs (miRNAs) have been implicated in the regulation diverse cellular processes including the inflammatory response. However, little is known about their functions and molecular involvement in regulating the inflammatory process in ALI. Herein, we established a lipopolysaccharide (LPS)-induced ALI mouse model and used miRNA microarray analysis to investigate and compare the miRNA expression profiles in mouse lung tissues. We found that miR-92a was markedly upregulated in the lung tissues of ALI mice compared with that in normal lung tissues. This upregulation of miR-92a in LPS-induced ALI mice was further confirmed in lung tissues, splenocytes and bronchoalveolar lavage fluid (BALF) by quantitative real-time PCR. Inhibition of miR-92a by injection with antagomir-92a markedly reduced LPS-induced pathological changes associated with lung inflammation, and reduces lung wet/dry ratio (W/D ratio), and Evans blue dye extravasation (an indicator of lung epithelial permeability). Moreover, inhibition of miR-92a ameliorated the inflammatory response by reducing the repression of proinflammatory cytokines including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 in lung tissues. In addition, we identified that miR-92a inhibited the phosphatase and tensin homolog on chromosome ten (PTEN) by binding to its 3'-UTR in RAW264.7 murine macrophage cells. Western blot analysis demonstrated that inhibition of miR-92a may ameliorate inflammatory response through blocking PTEN/AKT/NF-κB signaling pathway in ALI mice. Collectively, these results have revealed a significant role of miR-92a in the lung inflammatory response associated with ALI in mice, and suggest that miR-92a may have potential as a prognostic indicator and novel therapeutic target for the treatment of ALI in future.
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Affiliation(s)
- Liming Fu
- Department of Emergency, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471009, Henan, China.
| | - Ping Zhu
- Department of Emergency, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471009, Henan, China
| | - Sanli Qi
- Department of Emergency, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471009, Henan, China
| | - Chunyan Li
- Department of Emergency, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471009, Henan, China
| | - Kunfang Zhao
- Department of Emergency, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, 471009, Henan, China
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45
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Deshmukh SK, Tyagi N, Khan MA, Srivastava SK, Al-Ghadhban A, Dugger K, Carter JE, Singh S, Singh AP. Gemcitabine treatment promotes immunosuppressive microenvironment in pancreatic tumors by supporting the infiltration, growth, and polarization of macrophages. Sci Rep 2018; 8:12000. [PMID: 30097594 PMCID: PMC6086900 DOI: 10.1038/s41598-018-30437-2] [Citation(s) in RCA: 44] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Accepted: 07/30/2018] [Indexed: 02/08/2023] Open
Abstract
Chemotherapy-induced immunosuppression poses an additional challenge to its limited efficacy in pancreatic cancer (PC). Here we investigated the effect of gemcitabine on macrophages, which are the first line of immune-defense mechanisms. We observed an increased presence of macrophages in orthotopic human pancreatic tumor xenografts from mice treated with gemcitabine as compared to those from vehicle only-treated mice. Conditioned media from gemcitabine-treated PC cells (Gem-CM) promoted growth, migration and invasion of RAW264.7 macrophage. In addition, Gem-CM also induced upregulation of M2-polarized macrophage markers, arginase-1 and TGF-β1. Cytokine profiling of gemcitabine-treated PC cells identified IL-8 as the most differentially-expressed cytokine. Incubation of Gem-CM with IL-8 neutralizing antibody diminished its ability to induce growth, migration and invasion of RAW264.7 macrophages, but did not abrogate their M2 polarization. Together, our findings identify IL-8 as an important mediator in the gemcitabine-induced infiltration of macrophages within the pancreatic tumor microenvironment and suggest the requirement of additional mechanism(s) for macrophage polarization.
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Affiliation(s)
- Sachin Kumar Deshmukh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA
| | - Nikhil Tyagi
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA
| | - Mohammad Aslam Khan
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA
| | - Sanjeev Kumar Srivastava
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA.,Division of Cell Biology and Genetics, Tatva Biosciences, Coastal Innovation Hub, 600 Clinic Drive, 3rd Floor, Mobile, AL, 36688, USA
| | - Ahmed Al-Ghadhban
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA
| | - Kari Dugger
- Department of Clinical and Diagnostic Sciences, University of Alabama at Birmingham, Birmingham, AL, 35294, USA
| | - James Elliot Carter
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL, 36617, USA
| | - Seema Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA. .,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA.
| | - Ajay Pratap Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL, 36604, USA. .,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL, 36688, USA.
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Xie Y, Wang Y, Li J, Hang Y, Jaramillo L, Wehrkamp CJ, Phillippi MA, Mohr AM, Chen Y, Talmon GA, Mott JL, Oupický D. Cholangiocarcinoma therapy with nanoparticles that combine downregulation of MicroRNA-210 with inhibition of cancer cell invasiveness. Am J Cancer Res 2018; 8:4305-4320. [PMID: 30214622 PMCID: PMC6134930 DOI: 10.7150/thno.26506] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Accepted: 07/04/2018] [Indexed: 12/19/2022] Open
Abstract
Cholangiocarcinoma (CCA) is the second most common primary liver malignancy with extremely poor therapeutic outcome due to high drug resistance, widespread metastasis and lack of effective treatment options. CCA progression and metastasis are regulated by multiple biological factors including multiple miRNAs and chemokine receptor CXCR4. The goal of this study was to test if nanotherapeutic blockade of CXCR4 by polymeric CXCR4 antagonist (PCX) combined with inhibition of hypoxia-inducible miR-210 cooperatively enhances therapeutic efficacy in CCA through reducing invasiveness, inducing cell killing, and reversing drug resistance. Methods: We first tested the activity of PCX to inhibit migration of CCA cells. We then prepared PCX/anti-miRNA nanoparticles and analyzed their miRNA delivery efficacy and anticancer activity in vitro. Finally, in vivo biodistribution assay and anticancer activity study were performed in CCA tumor-bearing mice. Results: Our results show that PCX had a broad inhibitory effect on cell migration, effectively delivered anti-miR-210, and downregulated miR-210 expression in CCA cells. Combination PCX/anti-miR-210 nanoparticles showed cytotoxic activity towards CCA cells and reduced the number of cancer stem-like cells. The nanoparticles reversed hypoxia-induced drug resistance and sensitized CCA cells to standard gemcitabine and cisplatin combination treatment. Systemic intravenous treatment with the nanoparticles in a CCA xenograft model resulted in prominent combined antitumor activity. Conclusion: Our findings support PCX-based nanoparticles as a promising delivery platform of therapeutic miRNA in combination CCA therapies.
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Gu J, Saiyin H, Fu D, Li J. Stroma - A Double-Edged Sword in Pancreatic Cancer: A Lesson From Targeting Stroma in Pancreatic Cancer With Hedgehog Signaling Inhibitors. Pancreas 2018; 47:382-389. [PMID: 29521941 DOI: 10.1097/mpa.0000000000001023] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Pancreatic cancer is a uniformly lethal malignancy with an abundant dense desmoplastic stroma. Because of its dense stroma, conventional drugs were considered to not penetrate this physical barrier, and this caused a systemic drug resistance. Thus, abolishing this barrier with targeted agents is considered to improve the efficiency of chemotherapeutic treatment. The Hedgehog (Hh) signaling pathway is a critical regulator of pancreas development and plays diversified roles in pancreatic cancer stroma and neoplastic cells. Increasing Hh expression in neoplastic cells added desmoplastic stroma accumulation in orthotopic tumors, and Hh inhibitors that target the stroma have an ability to prolong the overall survival of Pdx-1-Cre/KrasG12D/p53R172H mice models via deleting the stromal components and increasing vascularity in pancreatic tumor. However, the failure of translation from bench to bedside indicate the complexity of the relationship between Hh signaling and desmoplastic stroma, and more insights into the complex relationships between Hh signaling pathway and stroma, even tumor cells, might help redesign Hh-targeted therapy. In this review, we discuss the possible mechanism of translation of Hh inhibitor in the clinic from pathology to molecular mechanism.
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Savona MR, Pollyea DA, Stock W, Oehler VG, Schroeder MA, Lancet J, McCloskey J, Kantarjian HM, Ma WW, Shaik MN, Laird AD, Zeremski M, O'Connell A, Chan G, Cortes JE. Phase Ib Study of Glasdegib, a Hedgehog Pathway Inhibitor, in Combination with Standard Chemotherapy in Patients with AML or High-Risk MDS. Clin Cancer Res 2018; 24:2294-2303. [PMID: 29463550 DOI: 10.1158/1078-0432.ccr-17-2824] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Revised: 01/16/2018] [Accepted: 02/16/2018] [Indexed: 11/16/2022]
Abstract
Purpose: This open-label, multicenter, dose-finding, phase Ib study (NCT01546038) evaluated the safety, pharmacokinetics, pharmacodynamics, and clinical activity of the novel Hedgehog pathway Smoothened inhibitor glasdegib (PF-04449913) in patients (N = 52) with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS).Experimental Design: Glasdegib 100 or 200 mg was administered orally, once daily in 28-day cycles, in combination with low-dose cytarabine (arm A) or decitabine (arm B) to newly diagnosed patients considered not suitable for standard induction chemotherapy, and in combination with cytarabine/daunorubicin (arm C) to fit patients. The study followed a standard 3+3 dose-escalation design. The primary endpoint was dose-limiting toxicity (DLT). Ten additional patients were enrolled in expansion cohorts of arms A (n = 23) and C (n = 22) to confirm the recommended phase II dose (RP2D).Results: No DLTs were observed in arms A and B; 1 DLT (grade 4 neuropathy) occurred in arm C. The most common treatment-related nonhematologic adverse events were mostly grades 1 and 2 in all arms. Muscle spasms, dysgeusia, and alopecia were generally mild. Overall, 16 patients (31%) achieved a complete remission (CR)/CR with incomplete blood count recovery. Note that 100 mg daily was selected as the RP2D for glasdegib in combination with standard chemotherapies in the absence of an estimated MTD in this setting.Conclusions: Treatment with glasdegib in combination with standard chemotherapy was generally well-tolerated and consistent with prior findings, warranting further evaluation of glasdegib-based combinations in patients with AML or high-risk MDS. Clin Cancer Res; 24(10); 2294-303. ©2018 AACR.
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Affiliation(s)
- Michael R Savona
- Department of Medicine, Vanderbilt University Medical Center, Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.
| | - Daniel A Pollyea
- Division of Hematology, University of Colorado School of Medicine, Aurora, Colorado
| | | | | | - Mark A Schroeder
- Division of Oncology, Washington University School of Medicine, St Louis, Missouri
| | - Jeffrey Lancet
- Department of Malignant Hematology, Lee Moffitt Cancer Center, Tampa, Florida
| | - James McCloskey
- John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey
| | - Hagop M Kantarjian
- Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, Texas
| | | | | | | | | | | | | | - Jorge E Cortes
- Department of Leukemia, University of Texas, MD Anderson Cancer Center, Houston, Texas.
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The Function of SDF-1-CXCR4 Axis in SP Cells-Mediated Protective Role for Renal Ischemia/Reperfusion Injury by SHH/GLI1-ABCG2 Pathway. Shock 2018; 47:251-259. [PMID: 27454381 DOI: 10.1097/shk.0000000000000694] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Renal ischemia-reperfusion (I/R) injury ranks as the primary cause of acute renal injury with severe morbidity and mortality. Side population (SP) cells have recently drawn increasing attention due to their critical role in injury repair and regeneration. Unfortunately, the underlying mechanism involved in renal I/R remains poorly elucidated. Here, pronounced increases of stromal cell-derived factor-1 (SDF-1) and its receptor CXC chemokine receptor 4 (CXCR4) were substantiated in I/R kidneys from C57BL/6 mice subjected to clamp the bilateral renal pedicles to mimic renal ischemia. Similar up-regulation of them was also determined in SP cells upon simulated ischemia/reperfusion (SI/R). In contrast to non-SP cells, SP cells exhibited higher viability, apoptosis resistance, chemotaxis, and paracrine actions following SI/R treatment, and these were further enhanced after SDF-1 stimulation. Interestingly, blocking CXCR4 signaling with AMD3100 notably ameliorated the above effects. Mechanism analysis corroborated that SDF-1/CXCR4 further induced the expression of ATP-binding cassette transporter ABCG2, an essential element for SP-mediated kidney regeneration after renal I/R injury. Moreover, AMD3100 pretreatment strikingly attenuated ABCG2 elevation in SP cells. Additionally, sonic hedgehog (SHH)-Gli 1 signaling was involved in SDF-1/CXCR4-mediated ABCG2 expression. When SP cells pretreated with AMD3100 were intravenously injected into I/R mice, SP cell-mediated decreases in blood urea nitrogen, serum creatinine, and histological score of kidney were noticeably attenuated, indicating that blocking CXCR4 pathway mitigated the therapeutic function of SP cells in renal I/R injury. Together, this research suggests that SDF-1/CXCR4 axis might act, via Shh-Gli1-ABCG2 signaling, as a positive regulator of SP cell-based therapies for renal I/R by Shh-Gli 1-ABCG2 signaling.
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50
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Deshmukh SK, Srivastava SK, Tyagi N, Ahmad A, Singh AP, Ghadhban AAL, Dyess DL, Carter JE, Dugger K, Singh S. Emerging evidence for the role of differential tumor microenvironment in breast cancer racial disparity: a closer look at the surroundings. Carcinogenesis 2017; 38:757-765. [PMID: 28430867 DOI: 10.1093/carcin/bgx037] [Citation(s) in RCA: 51] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Accepted: 03/28/2017] [Indexed: 12/24/2022] Open
Abstract
Although increased awareness leading to early detection and prevention, as well as advancements in treatment strategies, have resulted in superior clinical outcomes, African American women with breast cancer continue to have greater mortality rates, compared to Caucasian American counterparts. Moreover, African American women are more likely to have breast cancer at a younger age and be diagnosed with aggressive tumor sub-types. Such racial disparities can be attributed to socioeconomic differences, but it is increasingly being recognized that these disparities may indeed be due to certain genetic and other non-genetic biological differences. Tumor microenvironment, which provides a favorable niche for the growth of tumor cells, is comprised of several types of stromal cells and the various proteins secreted as a consequence of bi-directional tumor-stromal cross-talk. Emerging evidence suggests inherent biological differences in the tumor microenvironment of breast cancer patients from different racial backgrounds. Tumor microenvironment components, affected by the genetic make-up of the tumor cells as well as other non-tumor-associated factors, may also render patients more susceptible to the development of aggressive tumors and faster progression of disease resulting in early onset, thus adversely affecting patients' survival. This review provides an overview of breast cancer racial disparity and discusses the existence of race-associated differential tumor microenvironment and its underlying genetic and non-genetic causal factors. A better understanding of these aspects would help further research on effective cancer management and improved approaches for reducing the racial disparities gaps in breast cancer patients.
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Affiliation(s)
- Sachin Kumar Deshmukh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
| | - Sanjeev K Srivastava
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.,Division of Cell Biology and Genetics, Tatva Biosciences, Coastal Innovation Hub, 600 Clinic Drive, 3rd Floor, Mobile, AL 36688, USA
| | - Nikhil Tyagi
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
| | - Aamir Ahmad
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
| | - Ajay P Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
| | - Ahmed A L Ghadhban
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
| | - Donna L Dyess
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA
| | - James E Carter
- Department of Pathology, College of Medicine, University of South Alabama, Mobile, AL 36617, USA
| | - Kari Dugger
- Department of Clinical and Diagnostic Sciences, University of Alabama at Birmingham, Birmingham, AL 35294, USA
| | - Seema Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.,Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA
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