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Bao G, Wang Z, Liu L, Zhang B, Song S, Wang D, Cheng S, Moon ES, Roesch F, Zhao J, Yu B, Zhu X. Targeting CXCR4/CXCL12 axis via [ 177Lu]Lu-DOTAGA.(SA.FAPi) 2 with CXCR4 antagonist in triple-negative breast cancer. Eur J Nucl Med Mol Imaging 2024; 51:2744-2757. [PMID: 38587644 PMCID: PMC11224082 DOI: 10.1007/s00259-024-06704-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Accepted: 03/16/2024] [Indexed: 04/09/2024]
Abstract
PURPOSE Radiopharmaceutical therapies targeting fibroblast activation protein (FAP) have shown promising efficacy against many tumor types. But radiopharmaceuticals alone in most cases are insufficient to completely eradicate tumor cells, which can partially be attributed to the protective interplay between tumor cells and cancer-associated fibroblasts (CAFs). The C-X-C chemokine receptor type 4/C-X-C motif chemokine 12 (CXCR4/CXCL12) interaction plays an important role in orchestrating tumor cells and CAFs. We hereby investigated the feasibility and efficacy of [177Lu]Lu-DOTAGA.(SA.FAPi)2, a FAP-targeting radiopharmaceutical, in combination with AMD3100, a CXCR4 antagonist, in a preclinical murine model of triple-negative breast cancer (TNBC). METHODS Public database was first interrogated to reveal the correlation between CAFs' scores and the prognosis of TNBC patients, as well as the expression levels of FAP and CXCR4 in normal tissues and tumors. In vitro therapeutic efficacy regarding cell proliferation, migration, and colony formation was assessed in BALB/3T3 fibroblasts and 4T1 murine breast cancer cells. In vivo therapeutic efficacy was longitudinally monitored using serial 18F-FDG, [18F]AlF-NOTA-FAPI-04, and [68Ga]Ga-DOTA-Pentixafor PET/CT scans and validated using tumor sections through immunohistochemical staining of Ki-67, α-SMA, CXCR4, and CXCL12. Intratumoral abundance of myeloid-derived suppressive cells (MDSCs) was analyzed using flow cytometry in accordance with the PET/CT schedules. Treatment toxicity was evaluated by examining major organs including heart, lung, liver, kidney, and spleen. RESULTS CAFs' scores negatively correlated with the survival of TNBC patients (p < 0.05). The expression of CXCR4 and FAP was both significantly higher in tumors than in normal tissues. The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 significantly suppressed cell proliferation, migration, and colony formation in cell culture, and exhibited synergistic effects in 4T1 tumor models along with a decreased number of MDSCs. PET/CT imaging revealed lowest tumor accumulation of 18F-FDG and [18F]AlF-NOTA-FAPI-04 on day 13 and day 14 after treatment started, both of which gradually increased at later time points. A similar trend was observed in the IHC staining of Ki-67, α-SMA, and CXCL12. CONCLUSION The combination of [177Lu]Lu-DOTAGA.(SA.FAPi)2 and AMD3100 is a feasible treatment against TNBC with minimal toxicity in main organs.
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Affiliation(s)
- Guangfa Bao
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Ziqiang Wang
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Luoxia Liu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Buchuan Zhang
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Shuang Song
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Dongdong Wang
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Siyuan Cheng
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Eu-Song Moon
- Department of Chemistry, Johannes Gutenberg University, 55131, Mainz, Germany
| | - Frank Roesch
- Department of Chemistry, Johannes Gutenberg University, 55131, Mainz, Germany
| | - Jun Zhao
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
- Department of Anatomy, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, 430030, Hubei Province, China
- Cell Architecture Research Center, Huazhong University of Science and Technology, Wuhan, Hubei Province, 430030, China
| | - Bo Yu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China
| | - Xiaohua Zhu
- Department of Nuclear Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1095 Jiefang Ave, Wuhan, 430030, China.
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Wang MJ, Xia Y, Gao QL. DNA Damage-driven Inflammatory Cytokines: Reprogramming of Tumor Immune Microenvironment and Application of Oncotherapy. Curr Med Sci 2024; 44:261-272. [PMID: 38561595 DOI: 10.1007/s11596-024-2859-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/29/2024] [Indexed: 04/04/2024]
Abstract
DNA damage occurs across tumorigenesis and tumor development. Tumor intrinsic DNA damage can not only increase the risk of mutations responsible for tumor generation but also initiate a cellular stress response to orchestrate the tumor immune microenvironment (TIME) and dominate tumor progression. Accumulating evidence documents that multiple signaling pathways, including cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) and ataxia telangiectasia-mutated protein/ataxia telangiectasia and Rad3-related protein (ATM/ATR), are activated downstream of DNA damage and they are associated with the secretion of diverse cytokines. These cytokines possess multifaced functions in the anti-tumor immune response. Thus, it is necessary to deeply interpret the complex TIME reshaped by damaged DNA and tumor-derived cytokines, critical for the development of effective tumor therapies. This manuscript comprehensively reviews the relationship between the DNA damage response and related cytokines in tumors and depicts the dual immunoregulatory roles of these cytokines. We also summarize clinical trials targeting signaling pathways and cytokines associated with DNA damage and provide future perspectives on emerging technologies.
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Affiliation(s)
- Meng-Jie Wang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China
| | - Yu Xia
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
| | - Qing-Lei Gao
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China.
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Anastasiadou DP, Quesnel A, Duran CL, Filippou PS, Karagiannis GS. An emerging paradigm of CXCL12 involvement in the metastatic cascade. Cytokine Growth Factor Rev 2024; 75:12-30. [PMID: 37949685 DOI: 10.1016/j.cytogfr.2023.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2023] [Accepted: 10/20/2023] [Indexed: 11/12/2023]
Abstract
The chemokine CXCL12, also known as stromal cell-derived factor 1 (SDF1), has emerged as a pivotal regulator in the intricate molecular networks driving cancer progression. As an influential factor in the tumor microenvironment, CXCL12 plays a multifaceted role that spans beyond its traditional role as a chemokine inducing invasion and metastasis. Indeed, CXCL12 has been assigned functions related to epithelial-to-mesenchymal transition, cancer cell stemness, angiogenesis, and immunosuppression, all of which are currently viewed as specialized biological programs contributing to the "metastatic cascade" among other cancer hallmarks. Its interaction with its cognate receptor, CXCR4, initiates a cascade of events that not only shapes the metastatic potential of tumor cells but also defines the niches within the secondary organs that support metastatic colonization. Given the profound implications of CXCL12 in the metastatic cascade, understanding its mechanistic underpinnings is of paramount importance for the targeted elimination of rate-limiting steps in the metastatic process. This review aims to provide a comprehensive overview of the current knowledge surrounding the role of CXCL12 in cancer metastasis, especially its molecular interactions rationalizing its potential as a therapeutic target.
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Affiliation(s)
- Dimitra P Anastasiadou
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA; Tumor Microenvironment & Metastasis Program, Albert Einstein Cancer Center, Bronx, NY, USA
| | - Agathe Quesnel
- School of Health & Life Sciences, Teesside University, Middlesbrough TS1 3BX, United Kingdom; National Horizons Centre, Teesside University, Darlington DL1 1HG, United Kingdom
| | - Camille L Duran
- Tumor Microenvironment & Metastasis Program, Albert Einstein Cancer Center, Bronx, NY, USA; Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA; Integrated Imaging Program for Cancer Research, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Panagiota S Filippou
- School of Health & Life Sciences, Teesside University, Middlesbrough TS1 3BX, United Kingdom; National Horizons Centre, Teesside University, Darlington DL1 1HG, United Kingdom
| | - George S Karagiannis
- Department of Microbiology & Immunology, Albert Einstein College of Medicine, Bronx, NY, USA; Tumor Microenvironment & Metastasis Program, Albert Einstein Cancer Center, Bronx, NY, USA; Integrated Imaging Program for Cancer Research, Albert Einstein College of Medicine, Bronx, NY, USA; Gruss-Lipper Biophotonics Center, Albert Einstein College of Medicine, Bronx, NY, USA; Cancer Dormancy and Tumor Microenvironment Institute, Albert Einstein College of Medicine, Bronx, NY, USA.
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Lu X, Wang X, Cheng H, Wang X, Liu C, Tan X. Anti-triple-negative breast cancer metastasis efficacy and molecular mechanism of the STING agonist for innate immune pathway. Ann Med 2023; 55:2210845. [PMID: 37162544 PMCID: PMC10173802 DOI: 10.1080/07853890.2023.2210845] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/11/2023] Open
Abstract
BACKGROUND With high recurrence and metastatic rates, triple-negative breast cancer (TNBC) has few therapy choices. The innate immune stimulator of interferon genes protein (STING) pathway has emerged as a critical foundation for improving anticancer immunotherapy. Although 2',3'-cGAMP has been shown to have therapeutic potential as a STING agonist in subcutaneous solid tumour treatments in mice, the effect of cGAMP in metastatic malignancies has received less attention. METHODS Bioluminescence imaging technology was applied to monitor TNBC tumour cell metastasis in living mice. Serum biochemical test and blood routine examination of mice were used to demonstrate cGAMP administration had no toxicity. The activation of DCs and CD8+ T cells was demonstrated by flow cytometry. The pharmacological mechanism of cGAMP for suppressing breast tumour metastasis was also explored. RESULTS cGAMP treatment substantially suppressed tumour development and metastasis without adverse effects. cGAMP activated the cGAS-STING-IRF3 pathway, which modified the tumour immune milieu to reverse the Epithelial-Mesenchymal Transition (EMT) and PI3K/AKT pathways and prevent tumour metastasis. It was postulated and proven that cGAMP had a pharmacological mechanism for reducing breast tumour metastasis. CONCLUSION The findings suggest that cGAMP could be useful in the immunotherapy of immune-insensitive metastatic breast cancer.
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Affiliation(s)
- Xing Lu
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiang Wang
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Hao Cheng
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiaoqing Wang
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Chang Liu
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
| | - Xiangshi Tan
- Department of Chemistry & Institutes of Biomedical Sciences, Fudan University, Shanghai, China
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Kassassir H, Papiewska-Pająk I, Kryczka J, Boncela J, Kowalska MA. Platelet-derived microparticles stimulate the invasiveness of colorectal cancer cells via the p38MAPK-MMP-2/MMP-9 axis. Cell Commun Signal 2023; 21:51. [PMID: 36882818 PMCID: PMC9990213 DOI: 10.1186/s12964-023-01066-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Accepted: 02/04/2023] [Indexed: 03/09/2023] Open
Abstract
BACKGROUND Metastasis is the main cause of death in patients with colorectal cancer (CRC). Apart from platelets, platelet-derived microparticles (PMPs) are also considered important factors that can modify the activity of cancer cells. PMPs are incorporated by cancer cells and can also serve as intracellular signalling vesicles. PMPs are believed to affect cancer cells by upregulating their invasiveness. To date, there is no evidence that such a mechanism occurs in colorectal cancer. It has been shown that platelets can stimulate metalloproteases (MMPs) expression and activity via the p38MAPK pathway in CRC cells, leading to their elevated migratory potential. This study aimed to investigate the impact of PMPs on the invasive potential of CRC cells of various phenotypes via the MMP-2, MMP-9 and p38MAPK axis. METHODS We used various CRC cell lines, including the epithelial-like HT29 and the mesenchymal-like SW480 and SW620. Confocal imaging was applied to study PMP incorporation into CRC cells. The presence of surface receptors on CRC cells after PMP uptake was evaluated by flow cytometry. Transwell and scratch wound-healing assays were used to evaluate cell migration. The level of C-X-C chemokine receptor type 4 (CXCR4), MMP-2, and MMP-9 and the phosphorylation of ERK1/2 and p38MAPK were measured by western blot. MMP activity was determined using gelatine-degradation assays, while MMP release was evaluated by ELISA. RESULTS We found that CRC cells could incorporate PMPs in a time-dependent manner. Moreover, PMPs could transfer platelet-specific integrins and stimulate the expression of integrins already present on tested cell lines. While mesenchymal-like cells expressed less CXCR4 than epithelial-like CRC cells, PMP uptake did not increase its intensity. No significant changes in CXCR4 level either on the surface or inside CRC cells were noticed. Levels of cellular and released MMP-2 and MMP-9 were elevated in all tested CRC cell lines after PMP uptake. PMPs increased the phosphorylation of p38MAPK but not that of ERK1/2. Inhibition of p38MAPK phosphorylation reduced the PMP-induced elevated level and release of MMP-2 and MMP-9 as well as MMP-dependent cell migration in all cell lines. CONCLUSIONS We conclude that PMPs can fuse into both epithelial-like and mesenchymal-like CRC cells and increase their invasive potential by inducing the expression and release of MMP-2 and MMP-9 via the p38MAPK pathway, whereas CXCR4-related cell motility or the ERK1/2 pathway appears to not be affected by PMPs. Video Abstract.
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Affiliation(s)
- Hassan Kassassir
- Laboratory of Cellular Signaling, Institute of Medical Biology, Polish Academy of Science, Lodowa 106, Lodz, Poland.
| | - Izabela Papiewska-Pająk
- Laboratory of Cellular Signaling, Institute of Medical Biology, Polish Academy of Science, Lodowa 106, Lodz, Poland
| | - Jakub Kryczka
- Laboratory of Cellular Signaling, Institute of Medical Biology, Polish Academy of Science, Lodowa 106, Lodz, Poland
| | - Joanna Boncela
- Laboratory of Cellular Signaling, Institute of Medical Biology, Polish Academy of Science, Lodowa 106, Lodz, Poland
| | - M Anna Kowalska
- Laboratory of Cellular Signaling, Institute of Medical Biology, Polish Academy of Science, Lodowa 106, Lodz, Poland.,The Children's Hospital of Philadelphia, Philadelphia, PA, USA
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He H, Qin G, Bi S, Feng Z, Mao J, Guan X, Xue M, Wang Z, Wang X, Yu D, Huang F. Deep-Learning-Enhanced Diffusion Imaging Assay for Resolving Local-Density Effects on Membrane Receptors. Anal Chem 2023; 95:3300-3308. [PMID: 36716433 DOI: 10.1021/acs.analchem.2c04326] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
G-protein-coupled receptor (GPCR) density at the cell surface is thought to regulate receptor function. Spatially resolved measurements of local-density effects on GPCRs are needed but technically limited by density heterogeneity and mobility of membrane receptors. We now develop a deep-learning (DL)-enhanced diffusion imaging assay that can measure local-density effects on ligand-receptor interactions in the plasma membrane of live cells. In this method, the DL algorithm allows the transformation of 100 ms exposure images to density maps that report receptor numbers over any specified region with ∼95% accuracy by 1 s exposure images as ground truth. With the density maps, a diffusion assay is further established for spatially resolved measurements of receptor diffusion coefficient as well as to express relationships between receptor diffusivity and local density. By this assay, we scrutinize local-density effects on chemokine receptor CXCR4 interactions with various ligands, which reveals that an agonist prefers to act with CXCR4 at low density while an inverse agonist dominates at high density. This work suggests a new insight into density-dependent receptor regulation as well as provides an unprecedented assay that can be applicable to a wide variety of receptors in live cells.
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Affiliation(s)
- Hua He
- State Key Laboratory of Heavy Oil Processing and College of Chemistry and Chemical Engineering, China University of Petroleum (East China), Qingdao266580, China
| | - Guangyong Qin
- State Key Laboratory of Heavy Oil Processing and College of Chemistry and Chemical Engineering, China University of Petroleum (East China), Qingdao266580, China
| | - Simin Bi
- State Key Laboratory of Heavy Oil Processing and College of Chemistry and Chemical Engineering, China University of Petroleum (East China), Qingdao266580, China
| | - Zhenzhen Feng
- Technical Center of Qingdao Customs District, Qingdao266500, China
| | - Jian Mao
- State Key Laboratory of Heavy Oil Processing and College of Chemistry and Chemical Engineering, China University of Petroleum (East China), Qingdao266580, China
| | - Xin Guan
- State Key Laboratory of Heavy Oil Processing and College of Chemistry and Chemical Engineering, China University of Petroleum (East China), Qingdao266580, China
| | - Minmin Xue
- State Key Laboratory of Heavy Oil Processing and College of Chemistry and Chemical Engineering, China University of Petroleum (East China), Qingdao266580, China
| | - Zhirui Wang
- State Key Laboratory of Heavy Oil Processing and College of Chemistry and Chemical Engineering, China University of Petroleum (East China), Qingdao266580, China
| | - Xiaojuan Wang
- State Key Laboratory of Heavy Oil Processing and College of Chemistry and Chemical Engineering, China University of Petroleum (East China), Qingdao266580, China
| | - Daoyong Yu
- State Key Laboratory of Heavy Oil Processing and College of Chemistry and Chemical Engineering, China University of Petroleum (East China), Qingdao266580, China
| | - Fang Huang
- State Key Laboratory of Heavy Oil Processing and College of Chemistry and Chemical Engineering, China University of Petroleum (East China), Qingdao266580, China
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Systemic inflammation response index correlates with survival and predicts oncological outcome of resected pancreatic cancer following neoadjuvant chemotherapy. Pancreatology 2022; 22:987-993. [PMID: 36064516 DOI: 10.1016/j.pan.2022.08.009] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 07/25/2022] [Accepted: 08/14/2022] [Indexed: 12/11/2022]
Abstract
BACKGROUND The Systemic Inflammation Response Index (SIRI) has been used to predict the prognosis of various cancers. This study examined SIRI as a prognostic factor in the neoadjuvant setting and determined whether it changing after chemotherapy is related to patient prognosis. METHODS Patients who underwent pancreatic surgery following neoadjuvant chemotherapy for pancreatic cancer were retrospectively analyzed. To establish the cut-off values, SIRIpre-neoadjuvant, SIRIpost-neoadjuvant, and SIRIquotient (SIRIpost-neoadjuvant/SIRIpre-neoadjuvant) were calculated and significant SIRI values were statistically determined to examine their effects on survival rate. RESULTS The study included 160 patients. Values of SIRIpost-neoadjuvant ≥ 0.8710 and SIRIquotient <0.9516 affected prognosis (hazard ratio [HR], 1.948; 95% confidence interval [CI], 1.210-3.135; ∗∗P = 0.006; HR, 1.548; 95% CI, 1.041-2.302; ∗∗P = 0.031). Disease-free survival differed significantly at values of SIRIpost-neoadjuvant < 0.8710 and SIRIpost-neoadjuvant ≥ 0.8710 (P = 0.0303). Overall survival differed significantly between SIRIquotient <0.9516 and SIRIquotient ≥0.9516 (P = 0.0368). CONCLUSIONS SIRI can predict the survival of patients with pancreatic ductal adenocarcinoma after resection and neoadjuvant chemotherapy. Preoperative SIRI value was correlated with disease-free survival, while changes in SIRI values were correlated with overall survival.
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Marayati R, Julson JR, Bownes LV, Quinn CH, Hutchins SC, Williams AP, Markert HR, Beierle AM, Stewart JE, Hjelmeland AB, Mroczek-Musulman E, Beierle EA. Metastatic human hepatoblastoma cells exhibit enhanced tumorigenicity, invasiveness and a stem cell-like phenotype. J Pediatr Surg 2022; 57:1018-1025. [PMID: 35300860 PMCID: PMC9119922 DOI: 10.1016/j.jpedsurg.2022.01.063] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 01/31/2022] [Indexed: 10/19/2022]
Abstract
BACKGROUND/PURPOSE Metastatic hepatoblastoma continues to pose a significant treatment challenge, primarily because the precise mechanisms involved in metastasis are not fully understood, making cell lines and preclinical models that depict the progression of disease and metastasis-related biology paramount. We aimed to generate and characterize a metastatic hepatoblastoma cell line to create a model for investigation of the molecular mechanisms associated with metastasis. MATERIALS/METHODS Using a murine model of serial tail vein injections of the human hepatoblastoma HuH6 cell line, non-invasive bioluminescence imaging, and dissociation of metastatic pulmonary lesions, we successfully established and characterized the metastatic human hepatoblastoma cell line, HLM_3. RESULTS The HLM_3 cells exhibited enhanced tumorigenicity and invasiveness, both in vitro and in vivo compared to the parent HuH6 cell line. Moreover, HLM_3 metastatic hepatoblastoma cells exhibited a stem cell-like phenotype and were more resistant to the standard chemotherapeutic cisplatin. CONCLUSION This newly described metastatic hepatoblastoma cell line offers a novel tool to study mechanisms of tumor metastasis and evaluate new therapeutic strategies for metastatic hepatoblastoma.
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Affiliation(s)
- Raoud Marayati
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Janet R Julson
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Laura V Bownes
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Colin H Quinn
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Sara C Hutchins
- Division of Pediatric Hematology-Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Adele P Williams
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Hooper R Markert
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Andee M Beierle
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Jerry E Stewart
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Anita B Hjelmeland
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America
| | - Elizabeth Mroczek-Musulman
- Department of Pathology, The Children's Hospital of Alabama, Birmingham, AL 35233, United States of America
| | - Elizabeth A Beierle
- Division of Pediatric Surgery, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL 35233, United States of America.
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Karin N. Chemokines in the Landscape of Cancer Immunotherapy: How They and Their Receptors Can Be Used to Turn Cold Tumors into Hot Ones? Cancers (Basel) 2021; 13:6317. [PMID: 34944943 PMCID: PMC8699256 DOI: 10.3390/cancers13246317] [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: 11/25/2021] [Revised: 12/13/2021] [Accepted: 12/14/2021] [Indexed: 02/07/2023] Open
Abstract
Over the last decade, monoclonal antibodies to immune checkpoint inhibitors (ICI), also known as immune checkpoint blockers (ICB), have been the most successful approach for cancer therapy. Starting with mAb to cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors in metastatic melanoma and continuing with blockers of the interactions between program cell death 1 (PD-1) and its ligand program cell death ligand 1 (PDL-1) or program cell death ligand 2 (PDL-2), that have been approved for about 20 different indications. Yet for many cancers, ICI shows limited success. Several lines of evidence imply that the limited success in cancer immunotherapy is associated with attempts to treat patients with "cold tumors" that either lack effector T cells, or in which these cells are markedly suppressed by regulatory T cells (Tregs). Chemokines are a well-defined group of proteins that were so named due to their chemotactic properties. The current review focuses on key chemokines that not only attract leukocytes but also shape their biological properties. CXCR3 is a chemokine receptor with 3 ligands. We suggest using Ig-based fusion proteins of two of them: CXL9 and CXCL10, to enhance anti-tumor immunity and perhaps transform cold tumors into hot tumors. Potential differences between CXCL9 and CXCL10 regarding ICI are discussed. We also discuss the possibility of targeting the function or deleting a key subset of Tregs that are CCR8+ by monoclonal antibodies to CCR8. These cells are preferentially abundant in several tumors and are likely to be the key drivers in suppressing anti-cancer immune reactivity.
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Affiliation(s)
- Nathan Karin
- Department of Immunology, Faculty of Medicine, Technion, P.O. Box 9697, Haifa 31096, Israel
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Campbell CA, Burdick MD, Strieter RM. Systemic Fibrocyte Levels and Keloid Expression of the Chemoattractant CXCL12 Are Upregulated Compared With Patients With Normal Scar. Ann Plast Surg 2021; 87:150-155. [PMID: 34253698 DOI: 10.1097/sap.0000000000002929] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Fibrocytes are bone marrow mesenchymal precursors with a surface phenotype compatible with leukocytes, fibroblasts, and hematopoietic progenitors that have been shown to traffic to wound healing sites in response to described chemokine pathways. Keloids are focal fibrotic responses to cutaneous trauma characterized by disordered collagen, which may be associated with elevated systemic fibrocyte levels and/or wound bed chemokine expression. METHODS Blood specimens from patients with longstanding keloids and those who form grossly normal scars were assayed by fluorescence activated cell sorting analysis for fibrocytes (CD45+, Col I+). The expression of the fibrocyte chemotactic cell surface marker CXCR4, intracellular markers of fibroblast differentiation (pSMAD2/3), and plasma levels of the CXCR4 cognate CXCL12 were compared. Keloid specimens and grossly normal scars were excised, and local expression of CXCL12 was assayed. RESULTS Keloid-forming patients demonstrated a significantly greater number of circulating fibrocytes (17.4 × 105 cells/mL) than control patients (1.01 × 105 cells/mL, P = 0.004). The absolute number of fibrocytes expressing CXCR4 was significantly greater (P = 0.012) in keloid-forming patients. Systemic CXCL12 levels were insignificantly greater in keloid-forming patients than controls. Keloid specimens had significantly greater CXCL12 expression (529.3 pg/mL) than normal scar (undetectable). CONCLUSIONS Systemic fibrocyte levels and the CXCR4/CXCL12 biologic axis responsible for fibrocyte trafficking to areas of regional fibrosis were both upregulated in patients who form keloids compared with controls. Keloids persistently expressed CXLC12, which serves both as the main chemoattractant for fibrocytes and a downstream mediator for local inflammation, suggesting a role for this biologic axis in keloid formation and possibly recurrence.
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Affiliation(s)
| | | | - Robert M Strieter
- Novartis Institutes for BioMedical Research, Cambridge, United Kingdom
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11
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Yarso KY, Bellynda M, Azmiardi A, Wasita B, Heriyanto DS, Astuti I, Hakimi M, Aryandono T. Chemotherapy Negates the Effect of SDF1 mRNA to Distant Metastasis and Poor Overall Survival in Breast Cancer Patients. Asian Pac J Cancer Prev 2021; 22:757-766. [PMID: 33773539 PMCID: PMC8286657 DOI: 10.31557/apjcp.2021.22.3.757] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Indexed: 01/06/2023] Open
Abstract
OBJECTIVE Investigate the effect of SDF1a, nuclear, and cytoplasmic CXCR4 breast cancer tissue on metastasis and overall survival in patients with complete-chemotherapy and no-chemotherapy. METHODS Cohort ambidirectional design was employed with survival analysis that followed the patient's diagnosis until obtaining the outcome, distant metastasis, or death. We analyzed samples in three groups (all-patient, no-chemotherapy, and complete-chemotherapy groups). Breast cancer cell nuclear and cytoplasm expressions of CXCR4 protein were examined using immunohistochemistry. Amplification of mRNA SDF1a of breast cancer tissue was examined using rtPCR on 131 samples from the same initial paraffin block. RESULTS In the distant metastasis and Overall Survival (OS) analysis, there was no correlation between cytoplasmic and nuclear CXCR4 in all-patient, no-chemotherapy, and complete-chemotherapy groups. SDF1a was significantly correlated to shorter distant metastasis and poor OS in the all-patient (p=0.004 and p=0.04, respectively) and no-chemotherapy group (p=0.008 and p=0.026, respectively). However, in the complete-chemotherapy group, SDF1a was not correlated to either metastasis (p=0.527) or OS (p=0.993), advanced stage demonstrated a strong association on shorter distant metastatic in no-chemotherapy (p=0.021) and complete-chemotherapy group (p=0.004) and also poor OS in both groups (p=0.006 and p=0.002, respectively). The hormone receptor showed a protective effect on the no-chemotherapy group's OS (p= 0.019). Meanwhile, not undergoing chemotherapy was associated with poor OS in the all-patient group (p= 0.011). CONCLUSION SDF1a mRNA amplification has a significant correlation with the occurrence of metastasis and OS in all-patient and no-chemotherapy group. Undergoing chemotherapy negates the effect of SDF1a for distant metastasis and OS.
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Affiliation(s)
- Kristanto Yuli Yarso
- Department of Surgery, Oncology Division, Medical Faculty, Sebelas Maret University, Indonesia
| | - Monica Bellynda
- Department of Surgery, Medical Faculty, Sebelas Maret University, Indonesia
| | - Akhmad Azmiardi
- Department of Public Health, Faculty of Public Health, Veteran Bangun Nusantara Sukoharjo University, Indonesia
| | - Brian Wasita
- Department of Anatomical Pathology, Medical Faculty, Sebelas Maret University, Indonesia
| | - Didik Setyo Heriyanto
- Department of Anatomical Pathology, Medical Faculty, Gadjah Mada University, Indonesia
| | - Indwiani Astuti
- Department of Pharmacology and Therapy, Medical Faculty, Gadjah Mada University, Indonesia
| | - Mohammad Hakimi
- Department of Obstetrics and Gynecology, Medical Faculty, Gadjah Mada University, Indonesia
| | - Teguh Aryandono
- Department of Surgery, Oncology Division, Medical Faculty, Gadjah Mada University, Indonesia
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12
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Lu G, Qiu Y, Su X. Targeting CXCL12-CXCR4 Signaling Enhances Immune Checkpoint Blockade Therapy Against Triple Negative Breast Cancer. Eur J Pharm Sci 2021; 157:105606. [PMID: 33131745 DOI: 10.1016/j.ejps.2020.105606] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Revised: 06/21/2020] [Accepted: 10/16/2020] [Indexed: 12/18/2022]
Abstract
Insufficient T cell infiltration in triple-negative breast cancer (TNBC) has limited its response rate to immune checkpoint blockade (ICB) therapies and motivated the development of immunostimulatory approaches to enhance the ICB therapy. CXCR4 is a chemokine receptor highly upregulated both on cell surface and cytoplasm in tumor tissues. Activating CXCR4 has been associated with increased immunosuppression in the tumor microenvironment. Here, we developed a CXCR4-targeted liposomal formulation (Liposomal-AMD3100) to enhance therapeutic efficacy of AMD3100, a CXCR4 antagonist. Particularly, AMD3100 is not only encapsulated into the liposome but coated on the surface of the formulation to serve as a targeting moiety and a dual blocker capable of inhibiting CXCR4 activation extracellularly and intracellularly. The Liposomal-AMD3100 remodeled both immune and stromal microenvironment more efficiently compared with free AMD3100, indicating better pharmacodynamic profile of AMD3100 achieved by liposomal formulation. The combination of anti-PD-L1 with Liposomal-AMD3100 formulation exhibited an increased antitumor effect and prolonged survival time compared with monotherapies in a murine TNBC model (4T1). This work proves that immune activation via liposomal delivery of CXCR4 inhibitors has a great potential to expand ICB therapies to originally ICB-insensitive cancer types.
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Affiliation(s)
- Guowen Lu
- Department of Thyroid and breast mininally invasive surgery, Ningbo Yinzhou People's Hospital, No.251 Baizhang East Road, 315000 Ningbo, Zhejiang, P.R. China.
| | - Yier Qiu
- Department of Thyroid and breast mininally invasive surgery, Ningbo Yinzhou People's Hospital, No.251 Baizhang East Road, 315000 Ningbo, Zhejiang, P.R. China
| | - Xiaobao Su
- Department of Thyroid and breast mininally invasive surgery, Ningbo Yinzhou People's Hospital, No.251 Baizhang East Road, 315000 Ningbo, Zhejiang, P.R. China
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13
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“Star” miR-34a and CXCR4 antagonist based nanoplex for binary cooperative migration treatment against metastatic breast cancer. J Control Release 2020; 326:615-627. [DOI: 10.1016/j.jconrel.2020.07.029] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Revised: 07/15/2020] [Accepted: 07/17/2020] [Indexed: 01/14/2023]
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14
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Jäger B, Klatt D, Plappert L, Golpon H, Lienenklaus S, Barbosa PD, Schambach A, Prasse A. CXCR4/MIF axis amplifies tumor growth and epithelial-mesenchymal interaction in non-small cell lung cancer. Cell Signal 2020; 73:109672. [DOI: 10.1016/j.cellsig.2020.109672] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Revised: 05/11/2020] [Accepted: 05/12/2020] [Indexed: 12/20/2022]
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15
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Identification of Matrine as a Novel Regulator of the CXCR4 Signaling Axis in Tumor Cells. Int J Mol Sci 2020; 21:ijms21134731. [PMID: 32630806 PMCID: PMC7370290 DOI: 10.3390/ijms21134731] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 06/29/2020] [Accepted: 06/30/2020] [Indexed: 12/22/2022] Open
Abstract
Matrine, a quinolizidine alkaloid, is commonly employed for treating various viral and inflammatory disorders. Here, we have evaluated matrine for its activity on C-X-C chemokine receptor type 4 (CXCR4) and matrix metalloproteinases (MMP-9/2) expression, and its potential to affect tumor metastasis and invasion. The effects of matrine on CXCR4, MMP-9/2, and nuclear factor κB (NF-κB) activation in lung (A549), prostate (DU145), and pancreas (MIA PaCa-2) cells were investigated by diverse techniques. The expression level of CXCR4 and MMP-9/2 was analyzed by western blot analysis and reverse transcription polymerase chain reaction. NF-κB activation was also evaluated by western blot analysis, electrophoretic mobility shift assay as well as immunocytochemical experiments. Furthermore, we monitored cell invasion and metastasis activities by wound healing and Boyden chamber assays. We noted that matrine induced a down-regulation of CXCR4 and MMP-9/2 at both protein and mRNA levels. In addition, matrine negatively regulated human epidermal growth factor receptor 2 (HER2) and C-X-C Motif Chemokine Ligand 12 (CXCL12)-induced CXCR4 expression. Moreover, NF-κB suppression by matrine led to inhibition of metastatic potential of tumor cells. Our results suggest that matrine can block the cancer metastasis through the negative regulation of CXCR4 and MMP-9/2 and consequently it can be considered as a potential candidate for cancer therapy.
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16
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Chao CC, Lee CW, Chang TM, Chen PC, Liu JF. CXCL1/CXCR2 Paracrine Axis Contributes to Lung Metastasis in Osteosarcoma. Cancers (Basel) 2020; 12:cancers12020459. [PMID: 32079335 PMCID: PMC7072404 DOI: 10.3390/cancers12020459] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 02/10/2020] [Accepted: 02/13/2020] [Indexed: 12/17/2022] Open
Abstract
Osteosarcoma, the most common of all bone malignancies, has a high likelihood of lung metastasis. Up until now, the molecular mechanisms involved in osteosarcomas with lung metastases are not clearly understood. Recent observations have shown that the chemokine CXCL1 and its receptor CXCR2 assist with the homing of neutrophils into the tumor microenvironment. Here, we show that the CXCL1/CXCR2 paracrine axis is crucial for lung metastasis in osteosarcoma. In an in vivo lung metastasis model of osteosarcoma, lung blood vessels expressed CXCL1 and osteosarcoma cells expressed the CXCR2 receptor. CXCR2 expression was higher in osteosarcoma cell lines than in normal osteoblast cells. Immunohistochemistry staining of clinical osteosarcoma specimens revealed positive correlations between CXCR2 expression and pathology stage and also vascular cell adhesion molecule 1 (VCAM-1) expression. High levels of CXCL1 secreted by human pulmonary artery endothelial cells (HPAECs) promoted osteosarcoma cell mobility, which was mediated by the upregulation of VCAM-1 expression. When HPAECs-conditioned media was incubated in osteosarcoma cells, we observed that the CXCR2 receptor and FAK/PI3K/Akt/NF-κB signaling cascade were required for VCAM-1 expression. Our findings illustrate a molecular mechanism of lung metastasis in osteosarcoma and indicate that CXCL1/CXCR2 is worth targeting in treatment schemas.
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Affiliation(s)
- Chia-Chia Chao
- Department of Respiratory Therapy, Fu Jen Catholic University, New Taipei City 24205, Taiwan;
| | - Chiang-Wen Lee
- Department of Orthopaedic Surgery, Chang Gung Memorial Hospital, Puzi City, Chiayi County 61363, Taiwan;
- Department of Nursing, Division of Basic Medical Sciences, and Chronic Diseases and Health Promotion Research Center, Chang Gung University of Science and Technology, Puzi City, Chiayi County 61363, Taiwan
- Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Guishan Dist., Taoyuan City 33303, Taiwan
| | - Tsung-Ming Chang
- School of Medicine, Institute of Physiology, National Yang-Ming University, Taipei City 11221, Taiwan;
| | - Po-Chun Chen
- Translational medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei City 11101, Taiwan;
- Department of Biotechnology, College of Medical and Health Science, Asia University, Taichung 41354, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
| | - Ju-Fang Liu
- Translational medicine Center, Shin-Kong Wu Ho-Su Memorial Hospital, Taipei City 11101, Taiwan;
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung 40402, Taiwan
- School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence: or ; Tel.: +(886)-2-2833-2211 (ext. 9420)
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de Sena M. Pinheiro P, Rodrigues DA, do Couto Maia R, Thota S, Fraga CA. The Use of Conformational Restriction in Medicinal Chemistry. Curr Top Med Chem 2019; 19:1712-1733. [DOI: 10.2174/1568026619666190712205025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 05/01/2019] [Accepted: 05/05/2019] [Indexed: 12/13/2022]
Abstract
During the early preclinical phase, from hit identification and optimization to a lead compound,
several medicinal chemistry strategies can be used to improve potency and/or selectivity. The
conformational restriction is one of these approaches. It consists of introducing some specific structural
constraints in a lead candidate to reduce the overall number of possible conformations in order to favor
the adoption of a bioactive conformation and, as a consequence, molecular recognition by the target receptor.
In this work, we focused on the application of the conformational restriction strategy in the last
five years for the optimization of hits and/or leads of several important classes of therapeutic targets in
the drug discovery field. Thus, we recognize the importance of several kinase inhibitors to the current
landscape of drug development for cancer therapy and the use of G-protein Coupled Receptor (GPCR)
modulators. Several other targets are also highlighted, such as the class of epigenetic drugs. Therefore,
the possibility of exploiting conformational restriction as a tool to increase the potency and selectivity
and promote changes in the intrinsic activity of some ligands intended to act on many different targets
makes this strategy of structural modification valuable for the discovery of novel drug candidates.
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Affiliation(s)
- Pedro de Sena M. Pinheiro
- Laboratorio de Avaliacao e Síntese de Substancias Bioativas (LASSBio), Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902, Rio de Janeiro, RJ, Brazil
| | - Daniel A. Rodrigues
- Laboratorio de Avaliacao e Síntese de Substancias Bioativas (LASSBio), Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902, Rio de Janeiro, RJ, Brazil
| | - Rodolfo do Couto Maia
- Laboratorio de Avaliacao e Síntese de Substancias Bioativas (LASSBio), Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902, Rio de Janeiro, RJ, Brazil
| | - Sreekanth Thota
- Laboratorio de Avaliacao e Síntese de Substancias Bioativas (LASSBio), Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902, Rio de Janeiro, RJ, Brazil
| | - Carlos A.M. Fraga
- Laboratorio de Avaliacao e Síntese de Substancias Bioativas (LASSBio), Instituto de Ciencias Biomedicas, Universidade Federal do Rio de Janeiro, PO Box 68023, 21941-902, Rio de Janeiro, RJ, Brazil
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18
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Liu Y, Ren CC, Yang L, Xu YM, Chen YN. Role of CXCL12-CXCR4 axis in ovarian cancer metastasis and CXCL12-CXCR4 blockade with AMD3100 suppresses tumor cell migration and invasion in vitro. J Cell Physiol 2018; 234:3897-3909. [PMID: 30191987 DOI: 10.1002/jcp.27163] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2018] [Accepted: 07/10/2018] [Indexed: 12/14/2022]
Abstract
Ovarian cancer (OC) is a lethal gynecologic tumor, which brings its mortality to the head. CXCL12 and its receptor chemokine receptor 4 ( CXCR4) have been found to be highly expressed in OC and contribute to the disease progression by affecting tumor cell proliferation and invasion. Here, in this study, we aim to explore whether the blockade of CXCL12-CXCR4 axis with AMD3100 (a selective CXCR4 antagonist) has effects on the progression of OC. On the basis of the gene expression omnibus database of OC gene expression chips, the OC differentially expressed genes were screened by microarray analysis. OC (nonmetastatic and metastatic) and normal ovarian tissues were collected to determine the expressions of CXCL12 and CXCR4. A series of AMD3100, shRNA against CXCR4, and pCNS-CXCR4 were introduced to treat CAOV3 cells with the highest CXCR4 was assessed. Cell viability, apoptosis, migration, and invasion were all evaluated. The microarray analysis screened out the differential expression of CXCL12-CXCR4 in OC. CXCL12 and CXCR4 expressions were increased in OC tissues, particularly in the metastatic OC tissues. Downregulation of CXCR4 by AMD3100 or shRNA was observed to have a critical role in inhibiting cell proliferation, migration, and invasion of the CAOV3 OC cell line while promoting cell apoptosis. Overexpressed CXCR4 brought significantly promoting effects on the proliferation and invasiveness of OC cells. These results reinforce that the blockade of CXCL12-CXCR4 axis with AMD3100 inhibits the growth of OC cells. The antitumor role of the inhibition of CXCL12-CXCR4 axis offers a preclinical validation of CXCL12-CXCR4 axis as a therapeutic target in OC.
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Affiliation(s)
- Yan Liu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Chen-Chen Ren
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Li Yang
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yi-Ming Xu
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan-Nan Chen
- Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China
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19
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Karin N, Razon H. Chemokines beyond chemo-attraction: CXCL10 and its significant role in cancer and autoimmunity. Cytokine 2018; 109:24-28. [DOI: 10.1016/j.cyto.2018.02.012] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2017] [Revised: 01/25/2018] [Accepted: 02/06/2018] [Indexed: 01/07/2023]
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20
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Ballestero Fêo H, Montoya Flórez L, Yamatogi RS, Prado Duzanski A, Araújo JP, Oliveira RA, Rocha NS. Does the tumour microenvironment alter tumorigenesis and clinical response in transmissible venereal tumour in dogs? Vet Comp Oncol 2018; 16:370-378. [DOI: 10.1111/vco.12388] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2017] [Revised: 12/20/2017] [Accepted: 01/04/2018] [Indexed: 12/22/2022]
Affiliation(s)
- H. Ballestero Fêo
- Department of Veterinary Clinics, Faculty of Veterinary Medicine; UNESP; Botucatu Brazil
| | - L. Montoya Flórez
- Department of Veterinary Clinics, Faculty of Veterinary Medicine; UNESP; Botucatu Brazil
- Veterinary Pathology Research Group, Faculty of Agricultural Sciences; Universidad de Caldas; Manizales Colombia
- Universidad Pedagógica y Tecnológica de Colombia; Boyacá Colombia
| | - R. S. Yamatogi
- Department of Veterinary; Federal University of Viçosa; Viçosa Brazil
| | - A. Prado Duzanski
- Department of Veterinary Clinics, Faculty of Veterinary Medicine; UNESP; Botucatu Brazil
- Department of Pathology, Botucatu Medical School; UNESP; Botucatu Brazil
| | - J. P. Araújo
- Institute of Biosciences, Department of Microbiology and Immunology, Laboratory of Virology; UNESP; Botucatu Brazil
| | - R. A. Oliveira
- Department of Biostatistics, Biosciences Institute - IB; UNESP; Botucatu Brazil
| | - N. S. Rocha
- Department of Veterinary Clinics, Faculty of Veterinary Medicine; UNESP; Botucatu Brazil
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21
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Mukherjee D, Lu H, Yu L, He C, Lahiri SK, Li T, Zhao J. Krüppel-like factor 8 activates the transcription of C-X-C cytokine receptor type 4 to promote breast cancer cell invasion, transendothelial migration and metastasis. Oncotarget 2018; 7:23552-68. [PMID: 26993780 PMCID: PMC5029647 DOI: 10.18632/oncotarget.8083] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2015] [Accepted: 02/25/2016] [Indexed: 02/04/2023] Open
Abstract
Krüppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels, as determined by quantitative real-time PCR and immunoblotting. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of the cells towards the ligand CXCL12. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced CXCR4 expression associated with decreased cell migration, invasion and TEM towards CXCL12. Histological and database mining analyses of independent cohorts of patient tissue microarrays revealed a correlation of aberrant co-elevation of KLF8 and CXCR4 with metastatic potential. Promoter analysis indicated that KLF8 directly binds and activates the human CXCR4 gene promoter. Interestingly, a CXCR4-dependent activation of focal adhesion kinase (FAK), a known upregulator of KLF8, was highly induced by CXCL12 treatment in KLF8-overexpressing, but not KLF8 deficient cells. This activation of FAK in turn induced a further increase in KLF8 expression. Xenograft studies showed that overexpression of CXCR4, but not a dominant-negative mutant of it, in the MDA-MB-231 cells prevented the invasive growth of primary tumor and lung metastasis from inhibition by knockdown of KLF8. These results collectively suggest a critical role for a previously unidentified feed-forward signaling wheel made of KLF8, CXCR4 and FAK in promoting breast cancer metastasis and shed new light on potentially more effective anti-cancer strategies.
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Affiliation(s)
- Debarati Mukherjee
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA
| | - Heng Lu
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA
| | - Lin Yu
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA
| | - Chunjiang He
- School of Basic Medical Sciences, Wuhan University, Wuhan, China
| | - Satadru K Lahiri
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA
| | - Tianshu Li
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA.,Current address: Cleveland Clinic, Cleveland, OH, USA
| | - Jihe Zhao
- Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA
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Feng Q, Guo P, Wang J, Zhang X, Yang HC, Feng JG. High expression of SDF-1 and VEGF is associated with poor prognosis in patients with synovial sarcomas. Exp Ther Med 2018; 15:2597-2603. [PMID: 29456663 DOI: 10.3892/etm.2018.5684] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Accepted: 03/17/2017] [Indexed: 01/18/2023] Open
Abstract
Stromal cell-derived factor-1 (SDF-1) predicts poor clinical outcomes of certain types of cancer. Furthermore, vascular endothelial growth factor (VEGF) promotes the growth and metastasis of solid tumors. The aim of the present study was to examine the expression of SDF-1 and VEGF in patients with synovial sarcoma and to determine their expression is correlated with unfavorable outcomes. Levels of SDF-1 and VEGF proteins were evaluated in 54 patients with synovial sarcoma using immunohistochemical and immunofluorescence staining. Potential associations between the expression of SDF-1 and VEGF and various clinical parameters were analyzed using Pearson's χ2 test and the Spearman-rho test. Additionally, univariate and multivariate Cox regression analyses were used to identify potential prognostic factors, and the Kaplan-Meier method was used to analyze the overall survival rates of patients. Low SDF-1 and VEGF expression was detected in 20.4% (11/54) and 22.2% (12/54) of patients with synovial sarcoma; moderate expression was detected in 35.2% (19/54) and 37.0% (20/54) of patients and high expression was detected in 44.4% (24 of 54) and 40.7% (22 of 54) of patients, respectively. Levels of SDF-1 and VEGF proteins were significantly associated with histological grade (P<0.05), metastasis (P<0.05) and American Joint Committee on Cancer staging (P<0.05). In addition, levels of SDF-1 and VEGF expression were positively correlated with each other (P<0.001). Univariate analysis also indicated that VEGF expression was associated with shorter overall survival rates in (P<0.05), whereas multivariate analysis demonstrated that SDF-1 expression was associated with shorter patient survival rates (P<0.05). Finally, both SDF-1 and VEGF expression were associated with various characteristics of synovial sarcoma. Therefore, SDF-1 expression may be a potential independent prognostic indicator in patients with synovial sarcomas.
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Affiliation(s)
- Qi Feng
- Department of Orthopedics, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Peng Guo
- Department of Orthopedics, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Jin Wang
- Department of Orthopedics, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Xiaoyu Zhang
- Department of Orthopedics, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Hui-Chai Yang
- Department of Pathology, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
| | - Jian-Gang Feng
- Department of Orthopedics, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China
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23
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Ham SL, Thakuri PS, Plaster M, Li J, Luker KE, Luker GD, Tavana H. Three-dimensional tumor model mimics stromal - breast cancer cells signaling. Oncotarget 2017; 9:249-267. [PMID: 29416611 PMCID: PMC5787462 DOI: 10.18632/oncotarget.22922] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Accepted: 11/09/2017] [Indexed: 12/11/2022] Open
Abstract
Tumor stroma is a major contributor to the biological aggressiveness of cancer cells. Cancer cells induce activation of normal fibroblasts to carcinoma-associated fibroblasts (CAFs), which promote survival, proliferation, metastasis, and drug resistance of cancer cells. A better understanding of these interactions could lead to new, targeted therapies for cancers with limited treatment options, such as triple negative breast cancer (TNBC). To overcome limitations of standard monolayer cell cultures and xenograft models that lack tumor complexity and/or human stroma, we have developed a high throughput tumor spheroid technology utilizing a polymeric aqueous two-phase system to conveniently model interactions of CAFs and TNBC cells and quantify effects on signaling and drug resistance of cancer cells. We focused on signaling by chemokine CXCL12, a hallmark molecule secreted by CAFs, and receptor CXCR4, a driver of tumor progression and metastasis in TNBC. Using three-dimensional stromal-TNBC cells cultures, we demonstrate that CXCL12 – CXCR4 signaling significantly increases growth of TNBC cells and drug resistance through activation of mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) pathways. Despite resistance to standard chemotherapy, upregulation of MAPK and PI3K signaling sensitizes TNBC cells in co-culture spheroids to specific inhibitors of these kinase pathways. Furthermore, disrupting CXCL12 – CXCR4 signaling diminishes drug resistance of TNBC cells in co-culture spheroid models. This work illustrates the capability to identify mechanisms of drug resistance and overcome them using our engineered model of tumor-stromal interactions.
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Affiliation(s)
- Stephanie Lemmo Ham
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325, USA
| | - Pradip Shahi Thakuri
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325, USA
| | - Madison Plaster
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325, USA
| | - Jun Li
- Department of Mathematical Sciences, Kent State University, Kent, OH 44242, USA
| | - Kathryn E Luker
- Department of Radiology, Microbiology and Immunology, Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Gary D Luker
- Department of Radiology, Microbiology and Immunology, Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA
| | - Hossein Tavana
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325, USA
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24
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Abstract
Distant metastasis during the advanced stage of malignant tumor progression can cause considerable morbidity in cancer patients. Bone is known to be one of the most common sites of distant metastasis in patients with breast cancer (BC). BC metastases in bone are associated with excessive skeletal complications. These complications can be fatal and reduce quality of life of patients. It is important to understand the metastatic process of BC to bone to improve quality of life and design new therapeutic methods. At present, the molecular mechanisms leading to the BC metastasis to bone are not fully understood. Studying the molecular basis of BC metastasis to bone might improve our insight into this complex process. In addition, it can provide novel approaches for designing advanced and effective targeted therapies. The present article aimed to review the published papers on the molecular basis of the metastatic process of BC to bone, focusing on involved genes and signaling networks. Furthermore, we propose potential therapeutic targets that may be more effective for the inhibition and treatment of BC metastasis to bone.
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25
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Nazari A, Khorramdelazad H, Hassanshahi G. Biological/pathological functions of the CXCL12/CXCR4/CXCR7 axes in the pathogenesis of bladder cancer. Int J Clin Oncol 2017; 22:991-1000. [PMID: 29022185 DOI: 10.1007/s10147-017-1187-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2017] [Accepted: 08/21/2017] [Indexed: 12/14/2022]
Abstract
CXC chemokine ligand 12 (CXCL12) is an important member of the CXC subfamily of chemokines, and has been extensively studied in various human body organs and systems, both in physiological and clinical states. Ligation of CXCL12 to CXCR4 and CXCR7 as its receptors on peripheral immune cells gives rise to pleiotropic activities. CXCL12 itself is a highly effective chemoattractant which conservatively attracts lymphocytes and monocytes, whereas there exists no evidence to show attraction for neutrophils. CXCL12 regulates inflammation, neo-vascularization, metastasis, and tumor growth, phenomena which are all pivotally involved in cancer development and further metastasis. Generation and secretion of CXCL12 by stromal cells facilitate attraction of cancer cells, acting through its cognate receptor, CXCR4, which is expressed by both hematopoietic and non-hematopoietic tumor cells. CXCR4 stimulates tumor progression by different mechanisms and is required for metastatic spread to organs where CXCL12 is expressed, thereby allowing tumor cells to access cellular niches, such as the marrow, which favor tumor cell survival and proliferation. It has also been demonstrated that CXCL12 binds to another seven-transmembrane G-protein receptor or G-protein-coupled receptor, namely CXCR7. These studies indicated critical roles for CXCR4 and CXCR7 mediation of tumor metastasis in several types of cancers, suggesting their contributions as biomarkers of tumor behavior as well as potential therapeutic targets. Furthermore, CXCL12 itself has the capability to stimulate survival and growth of neoplastic cells in a paracrine fashion. CXCL12 is a supportive chemokine for tumor neovascularization via attracting endothelial cells to the tumor microenvironment. It has been suggested that elevated protein and mRNA levels of CXCL12/CXCR4/CXCR7 are associated with human bladder cancer (BC). Taken together, mounting evidence suggests a role for CXCR4, CXCR7, and their ligand CXCL12 during the genesis of BC and its further development. However, a better understanding is still required before exploring CXCL12/CXCR4/CXCR7 targeting in the clinic.
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Affiliation(s)
- Alireza Nazari
- Department of Surgery, School of Medicine, Rafsanjan University of Medical Science, Rafsanjan, Iran.,Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Hossein Khorramdelazad
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Gholamhossein Hassanshahi
- Molecular Medicine Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran. .,Department of Immunology, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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26
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Halakou F, Kilic ES, Cukuroglu E, Keskin O, Gursoy A. Enriching Traditional Protein-protein Interaction Networks with Alternative Conformations of Proteins. Sci Rep 2017; 7:7180. [PMID: 28775330 PMCID: PMC5543104 DOI: 10.1038/s41598-017-07351-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2017] [Accepted: 06/27/2017] [Indexed: 12/19/2022] Open
Abstract
Traditional Protein-Protein Interaction (PPI) networks, which use a node and edge representation, lack some valuable information about the mechanistic details of biological processes. Mapping protein structures to these PPI networks not only provides structural details of each interaction but also helps us to find the mutual exclusive interactions. Yet it is not a comprehensive representation as it neglects the conformational changes of proteins which may lead to different interactions, functions, and downstream signalling. In this study, we proposed a new representation for structural PPI networks inspecting the alternative conformations of proteins. We performed a large-scale study by creating breast cancer metastasis network and equipped it with different conformers of proteins. Our results showed that although 88% of proteins in our network has at least two structures in Protein Data Bank (PDB), only 22% of them have alternative conformations and the remaining proteins have different regions saved in PDB. However, using even this small set of alternative conformations we observed a considerable increase in our protein docking predictions. Our protein-protein interaction predictions increased from 54% to 76% using the alternative conformations. We also showed the benefits of investigating structural data and alternative conformations of proteins through three case studies.
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Affiliation(s)
- Farideh Halakou
- Department of Computer Engineering, Koc University, Istanbul, 34450, Turkey
| | - Emel Sen Kilic
- Department of Chemical and Biological Engineering, Koc University, Istanbul, 34450, Turkey.,Microbiology, Immunology and Cell Biology Department, West Virginia University, Morgantown, 26505, WV, USA
| | - Engin Cukuroglu
- Computational Sciences and Engineering, Graduate School of Sciences and Engineering, Koc University, Istanbul, 34450, Turkey
| | - Ozlem Keskin
- Department of Chemical and Biological Engineering, Koc University, Istanbul, 34450, Turkey
| | - Attila Gursoy
- Department of Computer Engineering, Koc University, Istanbul, 34450, Turkey.
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27
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Zhang F, Xiang S, Cao Y, Li M, Ma Q, Liang H, Li H, Ye Y, Zhang Y, Jiang L, Hu Y, Zhou J, Wang X, Zhang Y, Nie L, Liang X, Gong W, Liu Y. EIF3D promotes gallbladder cancer development by stabilizing GRK2 kinase and activating PI3K-AKT signaling pathway. Cell Death Dis 2017; 8:e2868. [PMID: 28594409 PMCID: PMC5520919 DOI: 10.1038/cddis.2017.263] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2017] [Revised: 05/07/2017] [Accepted: 05/08/2017] [Indexed: 02/05/2023]
Abstract
Recent evidence suggests that dysregulated eIF3d expression may be critical in various genetic disorders as well as cancer. In this study, we observed that EIF3d levels increased in gallbladder cancer (GBC) samples compared with non-tumor tissue. High eIF3d levels were associated with advanced tumor stage and metastasis and were correlated with poor prognosis in 92 patients with GBC. Depletion of EIF3d in GBC cell lines inhibited cell proliferation, colony formation and metastasis and induced apoptosis and cell cycle arrest in vitro and in vivo. In contrast, ectopic expression of eIF3d had the opposite effects. Moreover, in this study, we revealed that a novel non-translational factor function of eIF3d mediated its protumoral effects. In details, eIF3d stabilizes GRK2 protein by blocking ubiquitin-mediated degradation, consequently activates PI3K/Akt signaling, and promotes GBC cell proliferation and migration. In conclusion, eIF3d promotes GBC progression mainly via eIF3d-GRK2-AKT axis and it may be used as a prognostic factor. The therapeutic targeting of eIF3d-GRK2 axis may be a potential treatment approach for GBC.
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Affiliation(s)
- Fei Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Shanshan Xiang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yang Cao
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Maolan Li
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Qiang Ma
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Haibin Liang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Huaifeng Li
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yuanyuan Ye
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yijian Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Lin Jiang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yunping Hu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Jian Zhou
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Xuefeng Wang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yong Zhang
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Lei Nie
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xiao Liang
- Department of General Surgery, Sir Runrun Shaw Hospital Affiliated to Zhejiang University, Hangzhou, China
| | - Wei Gong
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Shanghai Research Center of Biliary Tract Disease, Shanghai, China
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28
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Abstract
Cancer stem cells (CSCs), with their self-renewal ability and multilineage differentiation potential, are a critical subpopulation of tumor cells that can drive tumor initiation, growth, and resistance to therapy. Like embryonic and adult stem cells, CSCs express markers that are not expressed in normal somatic cells and are thus thought to contribute towards a 'stemness' phenotype. This review summarizes the current knowledge of stemness-related markers in human cancers, with a particular focus on important transcription factors, protein surface markers and signaling pathways.
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Affiliation(s)
- Wenxiu Zhao
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
| | - Yvonne Li
- Dana Farber cancer Institute and Harvard Medical School, Boston, Massachusetts 02115
| | - Xun Zhang
- Neuroendocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114
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29
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Yang QL, Zhang LY, Wang HF, Li Y, Wang YY, Chen TT, Dai MF, Wu HH, Chen SL, Wang WR, Wu Q, Chen CJ, Zhou CZ. The N-terminal polypeptide derived from viral macrophage inflammatory protein II reverses breast cancer epithelial-to-mesenchymal transition via a PDGFRα-dependent mechanism. Oncotarget 2017; 8:37448-37463. [PMID: 28415580 PMCID: PMC5514921 DOI: 10.18632/oncotarget.16394] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Accepted: 03/01/2017] [Indexed: 01/22/2023] Open
Abstract
NT21MP, a 21-residue peptide derived from the viral macrophage inflammatory protein II, competed effectively with the natural ligand of CXC chemokine receptor 4 (CXCR4), stromal cell-derived factor 1-alpha, to induce apoptosis and inhibit growth in breast cancer. Its role in tumor epithelial-to-mesenchymal transition (EMT) regulation remains unknown. In this study, we evaluated the reversal of EMT upon NT21MP treatment and examined its role in the inhibition of EMT in breast cancer. The parental cells of breast cancer (SKBR-3 and MCF-7) and paclitaxel-resistant (SKBR-3 PR and MCF-7 PR) cells were studied in vitro and in combined immunodeficient mice. The mice injected with SKBR-3 PR cells were treated with NT21MP through the tail vein or intraperitoneally with paclitaxel or saline. Sections from tumors were evaluated for tumor weight and EMT markers based on Western blot. In vitro, the effects of NT21MP, CXCR4 and PDGFRα on tumor EMT were assessed by relative quantitative real-time reverse transcription-polymerase chain reaction, western blot and biological activity in breast cancer cell lines expressing high or low levels of CXCR4. Our results illustrated that NT21MP could reverse the phenotype of EMT in paclitaxel-resistant cells. Furthermore, we found that NT21MP governed PR-mediated EMT partly due to controlling platelet-derived growth factors A and B (PDGFA and PDGFB) and their receptor (PDGFRα). More importantly, NT21MP down-regulated AKT and ERK1/2 activity, which were activated by PDGFRα, and eventually reversed the EMT. Together, these results indicated that CXCR4 overexpression drives acquired paclitaxel resistance, partly by activating the PDGFA and PDGFB/PDGFRα autocrine signaling loops that activate AKT and ERK1/2. Inhibition of the oncogenic EMT process by targeting CXCR4/PDGFRα-mediated pathways using NT21MP may provide a novel therapeutic approach towards breast cancer.
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Affiliation(s)
- Qing-Ling Yang
- Hefei National Laboratory for Physical Sciences at Microscale and the Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 233030, China
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Bengbu, Anhui 233030, China
| | - Ling-Yu Zhang
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Hai-Feng Wang
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Yu Li
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Yue-Yue Wang
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Tian-Tian Chen
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Meng-Fen Dai
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Hai-Hua Wu
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233000, China
| | - Su-Lian Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Bengbu, Anhui 233030, China
| | - Wen-Rui Wang
- Department of Biotechnology, Bengbu Medical College, Bengbu, Anhui 233030, China
| | - Qiong Wu
- Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China
| | - Chang-Jie Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Bengbu, Anhui 233030, China
| | - Cong-Zhao Zhou
- Hefei National Laboratory for Physical Sciences at Microscale and the Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 233030, China
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30
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Phosphatidylcholine-specific phospholipase C inhibition down- regulates CXCR4 expression and interferes with proliferation, invasion and glycolysis in glioma cells. PLoS One 2017; 12:e0176108. [PMID: 28423060 PMCID: PMC5397108 DOI: 10.1371/journal.pone.0176108] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 04/05/2017] [Indexed: 02/07/2023] Open
Abstract
Background The chemokine receptor CXCR4 plays a crucial role in tumors, including glioblastoma multiforme (GBM), the most aggressive glioma. Phosphatidylcholine-specific phospholipase C (PC-PLC), a catabolic enzyme of PC metabolism, is involved in several aspects of cancer biology and its inhibition down-modulates the expression of growth factor membrane receptors interfering with their signaling pathways. In the present work we investigated the possible interplay between CXCR4 and PC-PLC in GBM cells. Methods Confocal microscopy, immunoprecipitation, western blot analyses, and the evaluation of migration and invasion potential were performed on U87MG cells after PC-PLC inhibition with the xanthate D609. The intracellular metabolome was investigated by magnetic resonance spectroscopy; lactate levels and lactate dehydrogenase (LDH) activity were analyzed by colorimetric assay. Results Our studies demonstrated that CXCR4 and PC-PLC co-localize and are associated on U87MG cell membrane. D609 reduced CXCR4 expression, cell proliferation and invasion, interfering with AKT and EGFR activation and expression. Metabolic analyses showed a decrease in intracellular lactate concentration together with a decrement in LDH activity. Conclusions Our data suggest that inhibition of PC-PLC could represent a new molecular approach in glioma biology not only for its ability in modulating cell metabolism, glioma growth and motility, but also for its inhibitory effect on crucial molecules involved in cancer progression.
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31
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Yang Q, Wu H, Wang H, Li Y, Zhang L, Zhu L, Wang W, Zhou J, Fu Y, Chen S, Wu Q, Chen C, Zhou C. N-terminal polypeptide derived from vMIP-II exerts its antitumor activity by inhibiting the CXCR4 pathway in human glioma. Int J Oncol 2017; 50:1160-1174. [PMID: 28350074 PMCID: PMC5363877 DOI: 10.3892/ijo.2017.3906] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/15/2016] [Accepted: 02/28/2017] [Indexed: 11/06/2022] Open
Abstract
Emerging evidence demonstrates that the stromal derived factor-1 (SDF-1α)/CXCR4 axis is associated with tumor aggressiveness and metastasis, including glioma, the most common brain cancer. In the present study, we demonstrated that a novel designed peptide NT21MP of viral macrophage inflammatory protein II, targeting CXCR4 inhibits SDF-1α-induced activation in glioma. The effects of NT21MP on CXCR4 expression, cell survival and migration were assessed on the human glioma cell line U251 and SHG-44 exposed to SDF-1α, by western blotting, MTT assay, flow cytometry and transwell migration assay. Our results illustrated that NT21MP inhibited SDF-1α induced proliferation, migration and invasion by upregulated pro-apoptotic genes (Bak1 and caspase-3) and downregulated Bcl-2/Bax as well as cell cycle regulators (cyclin D1 and CDK4) to arrest cell cycle in G0/G1 phase and promote apoptosis. By RT-qPCR and immunofluorescence we found that CXCR4 was highly expressed in SHG-44 cells. Our results from wound healing and transwell invasion assays indicated silencing of CXCR4 significantly inhibited the SDF-1α‑induced migration and invasion; similarly, flow cytometry showed that treatment with si-CXCR4 affected cell cycle and induced cell apoptosis in SHG-44. However, these effects were significantly weakened by NT21MP. In conclusion, the present study indicates that NT21MP plays a regulatory role in the SDF-1α/CXCR4 axis and further manages the invasion, migration, apoptosis and cell cycle of glioma cells. Thus, NT21MP might represent a novel therapeutic approach against glioma.
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Affiliation(s)
- Qingling Yang
- Hefei National Laboratory for Physical Sciences at Microscale and the Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, P.R. China
| | - Haihua Wu
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Haifeng Wang
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Yu Li
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Lingyu Zhang
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Lihua Zhu
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Wenrui Wang
- Department of Biotechnology, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Jihong Zhou
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Yingxiao Fu
- Department of Bioscience, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Sulian Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Qiong Wu
- Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Changjie Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Bengbu, Anhui 233030, P.R. China
| | - Congzhao Zhou
- Hefei National Laboratory for Physical Sciences at Microscale and the Innovation Center for Cell Signaling Network, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui 230026, P.R. China
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32
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Goto Y, Aoyama M, Sekiya T, Kakita H, Waguri-Nagaya Y, Miyazawa K, Asai K, Goto S. CXCR4 + CD45 - Cells are Niche Forming for Osteoclastogenesis via the SDF-1, CXCL7, and CX3CL1 Signaling Pathways in Bone Marrow. Stem Cells 2016; 34:2733-2743. [PMID: 27339271 DOI: 10.1002/stem.2440] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 05/19/2016] [Accepted: 05/30/2016] [Indexed: 01/16/2023]
Abstract
Bone homeostasis comprises the balance between bone-forming osteoblasts and bone-resorbing osteoclasts (OCs), with an acceleration of osteoclastic bone resorption leading to osteoporosis. OCs can be generated from bone marrow cells (BMCs) under the tightly regulated local bone environment. However, it remained difficult to identify the critical cells responsible for providing an osteoclastogenesis niche. In this study, we used a fluorescence-activated cell sorting technique to determine the cell populations important for forming an appropriate microenvironment for osteoclastogenesis and to verify the associated interactions between osteoclast precursor cells and non-OCs. We isolated and removed a small cell population specific for osteoclastogenesis (CXCR4+ CD45- ) from mouse BMCs and cultured the remaining cells with receptor activator of nuclear factor-kappa B ligand (RANKL) and macrophage-colony stimulating factor. The resulting cultures showed significantly less large osteoclast formation. Quantitative RT-PCR analysis revealed that these CXCR4+ CD45- cells expressed low levels of RANK and RANKL, but high levels of critical chemokines including stromal cell derived factor 1 (SDF-1), chemokine (C-X-C motif) ligand 7 (CXCL7), and chemokine (C-X3-C motif) ligand 1 (CX3CL1). Furthermore, an SDF-1-specific antibody strongly suppressed OC formation in RAW264.7 cells and antibodies against SDF-1, CXCL7, and CX3CL1 suppressed OC formation in BMCs. These results suggest that isolated CXCR4+ CD45- cells support an appropriate microenvironment for osteoclastogenesis with a direct effect on the cells expressing SDF-1, CXCL7, and CX3CL1 receptors. The regulation of CXCR4+ CD45- cell function might therefore inform therapeutic strategies for diseases involving loss of bone homeostasis. Stem Cells 2016;34:2733-2743.
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Affiliation(s)
- Yoh Goto
- Department of Orthodontics, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan.,Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Mineyoshi Aoyama
- Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Pathobiology, Nagoya City University Graduate School of Pharmaceutical Sciences, Nagoya, Japan
| | - Takeo Sekiya
- Department of Orthodontics, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan.,Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Hiroki Kakita
- Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.,Department of Perinatal and Neonatal Medicine, Aichi Medical University, Nagakute, Japan
| | - Yuko Waguri-Nagaya
- Department of Joint Surgery for Rheumatic Diseases, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Ken Miyazawa
- Department of Orthodontics, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan
| | - Kiyofumi Asai
- Department of Molecular Neurobiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan
| | - Shigemi Goto
- Department of Orthodontics, School of Dentistry, Aichi-Gakuin University, Nagoya, Japan
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33
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Shaked Y. Balancing efficacy of and host immune responses to cancer therapy: the yin and yang effects. Nat Rev Clin Oncol 2016; 13:611-26. [PMID: 27118493 DOI: 10.1038/nrclinonc.2016.57] [Citation(s) in RCA: 89] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Local and systemic treatments for cancer include surgery, radiation, chemotherapy, hormonal therapy, molecularly targeted therapies, antiangiogenic therapy, and immunotherapy. Many of these therapies can be curative in patients with early stage disease, but much less frequently is this the case when they are used to treat advanced-stage metastatic disease. In the latter setting, innate and/or acquired resistance are among the reasons for reduced responsiveness or nonresponsiveness to therapy, or for tumour relapse after an initial response. Most studies of resistance or reduced responsiveness focus on 'driver' genetic (or epigenetic) changes in the tumour-cell population. Several studies have highlighted the contribution of therapy-induced physiological changes in host tissues and cells that can reduce or even nullify the desired antitumour effects of therapy. These unwanted host effects can promote tumour-cell proliferation (repopulation) and even malignant aggressiveness. These effects occur as a result of systemic release of numerous cytokines, and mobilization of various host accessory cells, which can invade the treated tumour microenvironment. In short, the desired tumour-targeting effects of therapy (the 'yin') can be offset by a reactive host response (the 'yang'); proactively preventing or actively suppressing the latter represents a possible new approach to improving the efficacy of both local and systemic cancer therapies.
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Affiliation(s)
- Yuval Shaked
- Department of Cell Biology and Cancer Science, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, 1 Efron St. Bat Galim, Haifa 31096, Israel
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Smolkova B, Mego M, Horvathova Kajabova V, Cierna Z, Danihel L, Sedlackova T, Minarik G, Zmetakova I, Krivulcik T, Gronesova P, Karaba M, Benca J, Pindak D, Mardiak J, Reuben JM, Fridrichova I. Expression of SOCS1 and CXCL12 Proteins in Primary Breast Cancer Are Associated with Presence of Circulating Tumor Cells in Peripheral Blood. Transl Oncol 2016; 9:184-90. [PMID: 27267835 PMCID: PMC4856862 DOI: 10.1016/j.tranon.2016.03.004] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2015] [Accepted: 03/16/2016] [Indexed: 12/13/2022] Open
Abstract
Circulating tumor cells (CTCs) are independent prognostic factors in the primary and metastatic breast cancer patients and play crucial role in hematogenous tumor dissemination. The aim of this study was to correlate the presence of CTCs in peripheral blood with the expression of proteins in tumor tissue that have a putative role in regulation of cell growth and metastatic potential. This prospective study included 203 primary breast cancer patients treated by definitive surgery. CTCs were detected by quantitative real-time PCR for the expression of epithelial (CK19) or epithelial-to-mesenchymal transition–inducing transcription factor genes (TWIST1, SNAIL1, SLUG, and ZEB1). Expression of APC, ADAM23, CXCL12, E-cadherin, RASSF1, SYK, TIMP3, BRMS1, and SOCS1 proteins in primary breast tumor tissue was evaluated by immunohistochemistry. CTCs with epithelial markers were found in 17 (9.2%) patients. Their occurrence was associated with inhibition of SOCS1 expression (odds ratio [OR] = 0.07; 95% confidence interval [CI], 0.03-0.13; P < .001). CTCs with positive epithelial-to-mesenchymal transition markers were detected in 30 (15.8%) patients; however, no association with analyzed protein expressions was found. Overall, CTCs were detected in 44 (22.9%) patients. Presence of any CTC marker was significantly associated with positive CXCL12 expression (OR = 3.08; 95% CI, 1.15-8.26; P = .025) and lack of SOCS1 expression (OR = 0.10; 95% CI, 0.04-0.25; P < .001) in patient’s tumor tissues. As both CXCL12 and SOCS1 proteins are involved in cytokine signaling, our results provide support for the hypothesis that aberrant signaling cross talk between cytokine and chemokine responses could have an important role in hematogenous dissemination of tumor cells in breast cancer.
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Affiliation(s)
- Bozena Smolkova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava, Slovakia.
| | - Michal Mego
- 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Klenova 1, Bratislava, Slovakia.
| | - Viera Horvathova Kajabova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava, Slovakia.
| | - Zuzana Cierna
- Institute of Pathological Anatomy, Faculty of Medicine, Comenius University, University Hospital, Sasinkova 4, Bratislava, Slovakia.
| | - Ludovit Danihel
- Institute of Pathological Anatomy, Faculty of Medicine, Comenius University, University Hospital, Sasinkova 4, Bratislava, Slovakia; Pathological-Anatomical Workplace, Health Care Surveillance Authority, Sasinkova 4, Bratislava, Slovakia.
| | - Tatiana Sedlackova
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
| | - Gabriel Minarik
- Institute of Molecular Biomedicine, Faculty of Medicine, Comenius University, Bratislava, Slovakia.
| | - Iveta Zmetakova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava, Slovakia.
| | - Tomas Krivulcik
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava, Slovakia.
| | - Paulina Gronesova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava, Slovakia.
| | - Marian Karaba
- Department of Surgical Oncology, National Cancer Institute, Klenova 1, Bratislava, Slovakia.
| | - Juraj Benca
- Department of Surgical Oncology, National Cancer Institute, Klenova 1, Bratislava, Slovakia.
| | - Daniel Pindak
- Department of Surgical Oncology, National Cancer Institute, Klenova 1, Bratislava, Slovakia.
| | - Jozef Mardiak
- 2nd Department of Oncology, Faculty of Medicine, Comenius University, National Cancer Institute, Klenova 1, Bratislava, Slovakia.
| | - James M Reuben
- Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Ivana Fridrichova
- Department of Genetics, Cancer Research Institute, Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, Bratislava, Slovakia.
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Alam F, Al-Hilal TA, Park J, Choi JU, Mahmud F, Jeong JH, Kim IS, Kim SY, Hwang SR, Byun Y. Multi-stage inhibition in breast cancer metastasis by orally active triple conjugate, LHTD4 (low molecular weight heparin-taurocholate-tetrameric deoxycholate). Biomaterials 2016; 86:56-67. [DOI: 10.1016/j.biomaterials.2016.01.058] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2015] [Revised: 01/27/2016] [Accepted: 01/27/2016] [Indexed: 12/29/2022]
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C. M. Okuyama N, Cezar dos Santos F, Paiva Trugilo K, Brajão de Oliveira K. Involvement of CXCL12 Pathway in HPV-related Diseases. AIMS MEDICAL SCIENCE 2016. [DOI: 10.3934/medsci.2016.4.417] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Yang Y, Pang D, Hu C, Lv Y, He T, An Y, Tang Z, Deng Z. Nestin Positive Bone Marrow Derived Cells Responded to Injury Mobilize into Peripheral Circulation and Participate in Skin Defect Healing. PLoS One 2015; 10:e0143368. [PMID: 26633897 PMCID: PMC4669078 DOI: 10.1371/journal.pone.0143368] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2015] [Accepted: 11/02/2015] [Indexed: 12/13/2022] Open
Abstract
Exogenously infused mesenchymal stem cells (MSCs) are thought to migrate to injury site through peripheral blood stream and participate in tissue repair. However, whether and how endogenous bone marrow MSCs mobilized to circulating and targeted to tissue injury has raised some controversy, and related studies were restricted by the difficulty of MSCs identifying in vivo. Nestin, a kind of intermediate filament protein initially identified in neuroepithelial stem cells, was recently reported as a credible criteria for MSCs in bone marrow. In this study, we used a green fluorescent protein (GFP) labeled bone marrow replacement model to trace the nestin positive bone marrow derived cells (BMDCs) of skin defected-mice. We found that after skin injured, numbers of nestin+ cells in peripheral blood and bone marrow both increased. A remarkable concentration of nestin+ BMDCs around skin wound was detected, while few of these cells could be observed in uninjured skin or other organs. This recruitment effect could not be promoted by granulocyte colony-stimulating factor (G-CSF), suggests a different mobilization mechanism from ones G-CSF takes effect on hematopoietic cells. Our results proposed nestin+ BMDCs as mobilized candidates in skin injury repair, which provide a new insight of endogenous MSCs therapy.
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Affiliation(s)
- Yi Yang
- State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Oral Prosthodontics, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Danlin Pang
- State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
- Xiangya Stomatology Hospital, Central South University, Changsha, Hunan, China
| | - Chenghu Hu
- State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
- Xi’an Institute of Tissue Engineering & Regenerative Medicine, Shaanxi, China
| | - Yajie Lv
- Department of Dermatology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shannxi, China
| | - Tao He
- State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Yulin An
- State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
| | - Zhangui Tang
- Xiangya Stomatology Hospital, Central South University, Changsha, Hunan, China
- * E-mail: (ZD)’ (ZT)
| | - Zhihong Deng
- State Key Laboratory of Military Stomatology, Center for Tissue Engineering, School of Stomatology, Fourth Military Medical University, Xi’an, Shaanxi, China
- Department of Otolaryngology, Xijing Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China
- * E-mail: (ZD)’ (ZT)
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38
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Tsai MF, Chang TH, Wu SG, Yang HY, Hsu YC, Yang PC, Shih JY. EGFR-L858R mutant enhances lung adenocarcinoma cell invasive ability and promotes malignant pleural effusion formation through activation of the CXCL12-CXCR4 pathway. Sci Rep 2015; 5:13574. [PMID: 26338423 PMCID: PMC4559673 DOI: 10.1038/srep13574] [Citation(s) in RCA: 52] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 07/30/2015] [Indexed: 12/13/2022] Open
Abstract
Malignant pleural effusion (MPE) is a common clinical problem in non-small cell lung carcinoma (NSCLC) patients; however, the underlying mechanisms are still largely unknown. Recent studies indicate that the frequency of the L858R mutant form of the epidermal growth factor receptor (EGFR-L858R) is higher in lung adenocarcinoma with MPE than in surgically resected specimens, suggesting that lung adenocarcinoma cells harboring this mutation tend to invade the adjacent pleural cavity. The purpose of this study was to clarify the relationship between the EGFR-L858R mutation and cancer cell invasion ability and to investigate the molecular mechanisms involved in the formation of MPE. We found that expression of EGFR-L858R in lung cancer cells resulted in up-regulation of the CXCR4 in association with increased cancer cell invasive ability and MPE formation. Ectopic expression of EGFR-L858R in lung cancer cells acted through activation of ERK signaling pathways to induce the expression of CXCR4. We also indicated that Inhibition of CXCR4 with small interfering RNA, neutralizing antibody, or receptor antagonist significantly suppressed the EGFR-L858R–dependent cell invasion. These results suggest that targeting the production of CXCR4 and blocking the CXCL12-CXCR4 pathway might be effective strategies for treating NSCLCs harboring a specific type of EGFR mutation.
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Affiliation(s)
- Meng-Feng Tsai
- Department of Molecular Biotechnology, College of Biotechnology and Bioresources, Dayeh University, Changhua 51591, Taiwan
| | - Tzu-Hua Chang
- Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei 10002, Taiwan
| | - Shang-Gin Wu
- Department of Internal Medicine, National Taiwan University Hospital, Yun-Lin Branch, Yunlin 64041, Taiwan
| | - Hsiao-Yin Yang
- Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei 10002, Taiwan
| | - Yi-Chiung Hsu
- Institute of Statistical Science, Academia Sinica, Taipei 11529, Taiwan
| | - Pan-Chyr Yang
- Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei 10002, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
| | - Jin-Yuan Shih
- Department of Internal Medicine, National Taiwan University Hospital, and College of Medicine, National Taiwan University, Taipei 10002, Taiwan.,Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei 10002, Taiwan
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Abstract
Central and sympathetic nervous systems govern functional activities of many organs. Solid tumors like organs are also innervated by sympathetic nerve fibers. Neurotransmitters released from sympathetic nerve fibers can modulate biological behaviors of tumor cells. Multiple physiologic processes of tumor development may be dominated by central and sympathetic nervous systems as well. Recent studies suggest that dysfunction of central and sympathetic nervous systems and disorder of the hormone network induced by psychological stress may influence malignant progression of cancer by inhibiting the functions of immune system, regulating metabolic reprogramming of tumor cells, and inducing interactions between tumor and stromal cells. Over-release of inflammatory cytokines by tumors may aggravate emotional disorder, triggering the vicious cycles in tumor microenvironment and host macroenvironment. It is reasonable to hypothesize that cancer progression may be controlled by central and sympathetic nervous systems. In this review, we will focus on the recent information about the impacts of central and sympathetic nervous systems on tumor invasion and metastasis.
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40
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Fazilaty H, Mehdipour P. Genetics of breast cancer bone metastasis: a sequential multistep pattern. Clin Exp Metastasis 2014; 31:595-612. [PMID: 24493024 DOI: 10.1007/s10585-014-9642-9] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Accepted: 01/26/2014] [Indexed: 02/05/2023]
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41
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Chakraborty PK, Zhang Y, Coomes AS, Kim WJ, Stupay R, Lynch LD, Atkinson T, Kim JI, Nie Z, Daaka Y. G protein-coupled receptor kinase GRK5 phosphorylates moesin and regulates metastasis in prostate cancer. Cancer Res 2014; 74:3489-500. [PMID: 24755472 DOI: 10.1158/0008-5472.can-13-2708] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
G protein-coupled receptor kinases (GRK) regulate diverse cellular functions ranging from metabolism to growth and locomotion. Here, we report an important contributory role for GRK5 in human prostate cancer. Inhibition of GRK5 kinase activity attenuated the migration and invasion of prostate cancer cells and, concordantly, increased cell attachment and focal adhesion formation. Mass spectrometric analysis of the phosphoproteome revealed the cytoskeletal-membrane attachment protein moesin as a putative GRK5 substrate. GRK5 regulated the subcellular distribution of moesin and colocalized with moesin at the cell periphery. We identified amino acid T66 of moesin as a principal GRK5 phosphorylation site and showed that enforcing the expression of a T66-mutated moesin reduced cell spreading. In a xenograft model of human prostate cancer, GRK5 silencing reduced tumor growth, invasion, and metastasis. Taken together, our results established GRK5 as a key contributor to the growth and metastasis of prostate cancer.
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Affiliation(s)
- Prabir Kumar Chakraborty
- Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida
| | - Yushan Zhang
- Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida
| | - Alexandra S Coomes
- Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida
| | - Wan-Ju Kim
- Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida
| | - Rachel Stupay
- Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida
| | - Lauren D Lynch
- Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida
| | - Tamieka Atkinson
- Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida
| | - Jae I Kim
- Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida
| | - Zhongzhen Nie
- Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida
| | - Yehia Daaka
- Authors' Affiliation: Department of Anatomy and Cell Biology, University of Florida College of Medicine, Gainesville, Florida
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42
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Guo P, You JO, Yang J, Jia D, Moses MA, Auguste DT. Inhibiting metastatic breast cancer cell migration via the synergy of targeted, pH-triggered siRNA delivery and chemokine axis blockade. Mol Pharm 2014; 11:755-65. [PMID: 24467226 PMCID: PMC3993942 DOI: 10.1021/mp4004699] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Because breast cancer patient survival inversely correlates with metastasis, we engineered vehicles to inhibit both the C-X-C chemokine receptor type 4 (CXCR4) and lipocalin-2 (Lcn2) mediated migratory pathways. pH-responsive liposomes were designed to protect and trigger the release of Lcn2 siRNA. Liposomes were modified with anti-CXCR4 antibodies to target metastatic breast cancer (MBC) cells and block migration along the CXCR4-CXCL12 axis. This synergistic approach--coupling the CXCR4 axis blockade with Lcn2 silencing--significantly reduced migration in triple-negative human breast cancer cells (88% for MDA-MB-436 and 92% for MDA-MB-231). The results suggested that drug delivery vehicles engineered to attack multiple migratory pathways may effectively slow progression of MBC.
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Affiliation(s)
- Peng Guo
- Department of Biomedical Engineering, The City College of New York , 160 Convent Avenue, New York, New York 10031, United States
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43
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Yang Q, Zhang F, Ding Y, Huang J, Chen S, Wu Q, Wang Z, Wang Z, Chen C. Antitumour activity of the recombination polypeptide GST-NT21MP is mediated by inhibition of CXCR4 pathway in breast cancer. Br J Cancer 2014; 110:1288-97. [PMID: 24448360 PMCID: PMC3950870 DOI: 10.1038/bjc.2014.1] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2013] [Revised: 12/09/2013] [Accepted: 12/19/2013] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND CXC chemokine receptor 4 (CXCR4) and its ligand stromal cell-derived factor-1α (SDF-1α, also known as CXCL12) have important roles in promoting tumour growth and metastasis. Therefore, targeting CXCR4 could be a promising strategy for treatment of human cancer. METHODS To achieve this goal, we developed a highly purified recombination polypeptide (GST-NT21MP), which is a synthetic 21-mer peptide antagonist of CXCR4 (NT21MP) derived from the viral macrophage inflammatory protein II by fermentation technology, affinity chromatography and fast protein liquid chromatography. In this study, we used multiple methods such as MTT assay, FACS, invasion assay, RT-PCR and western blot to explore the efficacy and mechanism by which GST-NT21MP inhibits cell growth, migration and invasion of breast cancer in vitro and in vivo. RESULTS We found that blockade of CXCR4 pathway by GST-NT21MP decreased SDF-1-induced cell growth, adhesion and migration capacities in breast cancer cells. Moreover, GST-NT21MP significantly retarded pulmonary metastasis in vivo. Furthermore, GST-NT21MP-mediated antitumour activity was found to be associated with reduced phosphorylated Src, Akt, FAK and ERK1/2 as well as decreased Bcl-2. CONCLUSIONS Our results suggest that GST-NT21MP could be a potential anticancer agent for the treatment of breast cancer.
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Affiliation(s)
- Q Yang
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Anhui 233030, China
| | - F Zhang
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Anhui 233000, China
| | - Y Ding
- Branch of Tumour of the Center Hospital of Bengbu, Anhui 233000, China
| | - J Huang
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Anhui 233000, China
| | - S Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Anhui 233030, China
| | - Q Wu
- Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, China
| | - Z Wang
- Clinical Testing and Diagnose Experimental Center of Bengbu Medical College, Anhui 233000, China
| | - Z Wang
- 1] Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA [2] Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215123, China
| | - C Chen
- Department of Biochemistry and Molecular Biology, Bengbu Medical College, Anhui 233030, China
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Epstein RJ. The unpluggable in pursuit of the undruggable: tackling the dark matter of the cancer therapeutics universe. Front Oncol 2013; 3:304. [PMID: 24377088 PMCID: PMC3859984 DOI: 10.3389/fonc.2013.00304] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 11/29/2013] [Indexed: 01/19/2023] Open
Abstract
The notion that targeted drugs can unplug gain-of-function tumor pathways has revitalized pharmaceutical research, but the survival benefits of this strategy have so far proven modest. A weakness of oncogene-blocking approaches is that they do not address the problem of cancer progression as selected by the recessive phenotypes of genetic instability and apoptotic resistance which in turn arise from loss-of-function – i.e., undruggable – defects of caretaker (e.g., BRCA, MLH1) or gatekeeper (e.g., TP53, PTEN) suppressor genes. Genetic instability ensures that rapid cell kill is balanced by rapid selection for apoptotic resistance and hence for metastasis, casting doubt on the assumption that cytotoxicity (“response”) remains the best way to identify survival-enhancing drugs. In the absence of gene therapy, it is proposed here that caretaker-defective (high-instability) tumors may be best treated with low-lethality drugs inducing replicative (RAS-RAF-ERK) arrest or dormancy, causing “stable disease” rather than tumorilytic remission. Gatekeeper-defective (death-resistant) tumors, on the other hand, may be best managed by combining survival (PI3K-AKT-mTOR) pathway blockade with metronomic or sequential pro-apoptotic drugs.
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Affiliation(s)
- Richard J Epstein
- Laboratory of Genome Evolution & Informatics, The Kinghorn Cancer Centre, and Clinical Informatics & Research Centre, Department of Oncology, St Vincent's Hospital, UNSW Clinical School , Sydney, NSW , Australia
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45
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Targeting tumor micro-environment for design and development of novel anti-angiogenic agents arresting tumor growth. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2013; 113:333-54. [PMID: 24139944 DOI: 10.1016/j.pbiomolbio.2013.10.001] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2013] [Revised: 10/05/2013] [Accepted: 10/08/2013] [Indexed: 12/12/2022]
Abstract
Angiogenesis: a process of generation of new blood vessels has been proved to be necessary for sustained tumor growth and cancer progression. Inhibiting angiogenesis pathway has long been remained a significant hope for the development of novel, effective and target orientated antitumor agents arresting the tumor proliferation and metastasis. The process of neoangiogenesis as a biological process is regulated by several pro- and anti-angiogenic factors, especially vascular endothelial growth factor, fibroblast growth factor, epidermal growth factor, hypoxia inducible factor 1 and transforming growth factor. Every endothelial cell destined for vessel formation is equipped with receptors for these angiogenic peptides. Moreover, numerous other angiogenic cytokines such as platelet derived growth factor (PGDF), placenta growth factor (PGF), nerve growth factor (NGF), stem-cell factor (SCF), and interleukins-2, 4, 6 etc. These molecular players performs critical role in regulating the angiogenic switch. Couple of decade's research in molecular aspects of tumor biology has unraveled numerous structural and functional mysteries of these angiogenic peptides. In present article, a detailed update on the functional and structural peculiarities of the various angiogenic peptides is described focusing on structural opportunities made available that has potential to be used to modulate function of these angiogenic peptides in developing therapeutic agents targeting neoplastic angiogenesis. The data may be useful in the mainstream of developing novel anticancer agents targeting tumor angiogenesis. We also discuss major therapeutic agents that are currently used in angiogenesis associated therapies as well as those are subject of active research or are in clinical trials.
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Cojoc M, Peitzsch C, Trautmann F, Polishchuk L, Telegeev GD, Dubrovska A. Emerging targets in cancer management: role of the CXCL12/CXCR4 axis. Onco Targets Ther 2013; 6:1347-61. [PMID: 24124379 PMCID: PMC3794844 DOI: 10.2147/ott.s36109] [Citation(s) in RCA: 121] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The chemokine CXCL12 (SDF-1) and its cell surface receptor CXCR4 were first identified as regulators of lymphocyte trafficking to the bone marrow. Soon after, the CXCL12/CXCR4 axis was proposed to regulate the trafficking of breast cancer cells to sites of metastasis. More recently, it was established that CXCR4 plays a central role in cancer cell proliferation, invasion, and dissemination in the majority of malignant diseases. The stem cell concept of cancer has revolutionized the understanding of tumorigenesis and cancer treatment. A growing body of evidence indicates that a subset of cancer cells, referred to as cancer stem cells (CSCs), plays a critical role in tumor initiation, metastatic colonization, and resistance to therapy. Although the signals generated by the metastatic niche that regulate CSCs are not yet fully understood, accumulating evidence suggests a key role of the CXCL12/CXCR4 axis. In this review we focus on physiological functions of the CXCL12/CXCR4 signaling pathway and its role in cancer and CSCs, and we discuss the potential for targeting this pathway in cancer management.
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Affiliation(s)
- Monica Cojoc
- OncoRay National Center for Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, Dresden University of Technology, Dresden, Germany
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Ramakrishnan M, Mathur SR, Mukhopadhyay A. Fusion-derived epithelial cancer cells express hematopoietic markers and contribute to stem cell and migratory phenotype in ovarian carcinoma. Cancer Res 2013; 73:5360-70. [PMID: 23856249 DOI: 10.1158/0008-5472.can-13-0896] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
For a long time, the external milieu of cancer cells was considered to be of secondary importance when compared with its intrinsic properties. That has changed now as the microenvironment is considered to be a major contributing factor toward the progression of tumor. In this study, we show that in human and mouse epithelial ovarian carcinoma and mouse lung carcinoma, the interaction between tumor-infiltrating hematopoietic cells and epithelial cancer cells results in their fusion. Intriguingly, even after the fusion event, cancer cells retain the expression of the pan-hematopoietic marker (CD45) and various markers of hematopoietic lineage, including those of hematopoietic stem cells, indicating that the hematopoietic genome is not completely reprogrammed. This observation may have implications on the bone marrow contribution to the cancer stem cell population. Interestingly, it was seen that in both cancer models, the expression of chemokine receptor CXCR4 was largely contributed to by the fused compartment of cancer cells. We hypothesize that the superior migratory potential gained by the cancer cells due to the fusion helps in its dissemination to various secondary organs upon activation of the CXCR4/CXCL12 axis. We are the first to report the presence of a hemato-epithelial cancer compartment, which contributes to stem cell markers and CXCR4 in epithelial carcinoma. This finding has repercussions on CXCR4-based therapeutics and opens new avenues in discovering novel molecular targets against fusion and metastasis.
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Affiliation(s)
- Mallika Ramakrishnan
- Stem Cell Biology Laboratory, National Institute of Immunology, All India Institute of Medical Sciences, New Delhi, India
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48
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Wu Q, Hou X, Xia J, Qian X, Miele L, Sarkar FH, Wang Z. Emerging roles of PDGF-D in EMT progression during tumorigenesis. Cancer Treat Rev 2012; 39:640-6. [PMID: 23261166 DOI: 10.1016/j.ctrv.2012.11.006] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2012] [Revised: 11/22/2012] [Accepted: 11/24/2012] [Indexed: 12/12/2022]
Abstract
Platelet-derived growth factor-D (PDGF-D) signaling pathway has been reported to be involved in regulating various cellular processes, such as cell growth, apoptotic cell death, migration, invasion, angiogenesis and metastasis. Recently, multiple studies have shown that PDGF-D plays a critical role in governing epithelial-to-mesenchymal transition (EMT), although the underlying mechanism of PDGF-D-mediated acquisition of EMT is largely unclear. Therefore, this mini review will discuss recent advances in our understanding of the role of PDGF-D in the acquisition of EMT during tumorigenesis. Furthermore, we will summarize the function of chemical inhibitors and natural compounds that are known to inactivate PDGF-D signaling pathway, which leads to the reversal of EMT. In summary, inactivation of PDGF-D could be a novel strategy for achieving better treatment outcome of patients inflicted with cancers.
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Affiliation(s)
- Qiong Wu
- Department of Medical Oncology, First Affiliated Hospital of Bengbu Medical College, Bengbu 233004, Anhui, PR China.
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Improved outcome of high-risk early HER2 positive breast cancer with high CXCL13-CXCR5 messenger RNA expression. Clin Breast Cancer 2012; 12:183-93. [PMID: 22607768 DOI: 10.1016/j.clbc.2012.03.006] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2011] [Revised: 02/02/2012] [Accepted: 03/16/2012] [Indexed: 02/06/2023]
Abstract
UNLABELLED The CXCL13-CXCR5 is a chemokine axis that is activated in some breast cancers. A total of 321 tissue blocks from a group of patients who received adjuvant, dose-dense chemotherapy for high-risk early breast cancer were examined. Activation of this axis was found to be associated with determinants of poor prognosis but also with improved outcome in the human epidermal growth factor receptor 2 overexpressing subpopulation. BACKGROUND Chemokines are important in cell migration and are thought to play a key role in metastasis. We explored the prognostic significance of C-X-C ligand-motif (CXCL) 12, CXCL13, and receptor (CXCR) 5 on disease-free survival (DFS) and overall survival (OS) in early breast cancer. METHODS A total of 595 patients with high risk, [corrected] early breast cancer were treated in a 2-arm trial (HE10/97) with dose-dense sequential epirubicin followed by cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) with or without paclitaxel. RNA was extracted from 321 formalin-fixed paraffin-embedded primary tumor tissue samples and quantitative reverse-transcriptase polymerase chain reaction was used to assess messenger RNA (mRNA) expression of CXCL12, CXCL13, and CXCR5; estrogen receptor; progesterone receptor (PgR); microtubule-associated protein tau and human epidermal growth factor receptor 2 (HER2). RESULTS CXCL13 and CXCR5 were found to be negatively associated with estrogen receptor and microtubule-associated protein tau mRNA expression and with dense lymphocytic infiltration, and were positively associated with nuclear grade. Only CXCL13 was positively associated with HER2. Multivariate analysis revealed an association between high CXCL13 mRNA expression and improved DFS (hazard ratio [HR] 0.48 [95% CI, 0.25-0.90]; Wald, P = .023) but not OS; whereas high CXCL12 expression was significantly associated with increased OS (HR 0.53 [95% CI, 0.33-0.85]; Wald, P = .009). In the HER2 mRNA overexpressing subgroup, high CXCL13 mRNA expression was associated with improved DFS (P < .001), whereas high CXCR5 was associated with increased DFS and OS (P = .004 and P = .049, respectively). CONCLUSIONS The CXCL13-CXCR5 axis is associated with classic determinants of poor prognosis, such as high grade, hormone receptor negativity, and axillary node involvement. Interestingly, this chemokine axis seems to be strongly associated with improved outcome in patients with HER2(+) disease.
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Guo P, You JO, Yang J, Moses MA, Auguste DT. Using breast cancer cell CXCR4 surface expression to predict liposome binding and cytotoxicity. Biomaterials 2012; 33:8104-10. [PMID: 22884683 DOI: 10.1016/j.biomaterials.2012.07.043] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2012] [Accepted: 07/21/2012] [Indexed: 01/13/2023]
Abstract
The primary cause of mortality in breast cancer is tumor aggressiveness, characterized by metastases to regional lymph nodes, bone marrow, lung, and liver. C-X-C chemokine receptor type 4 (CXCR4) has been shown to mobilize breast cancer cells along chemokine gradients. Quantification of CXCR4 surface expression may predict the efficacy of anti-CXCR4 labeled liposomal therapeutics to target and kill breast cancer cells. We evaluated gene and surface receptor expression of CXCR4 on breast cancer cell lines distinguished as having low and high invasiveness, MDA-MB-175VII and HCC1500, respectively. CXCR4 surface expression did not correlate with invasiveness. MDA-MB-175VII exhibited more binding to anti-CXCR4 labeled liposomes relative to HCC1500. Increased binding correlated with greater cell death relative to IgG labeled liposomes. Quantitative cell characterization may be used to select targeted therapeutics with enhanced efficacy and minimal side effects.
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Affiliation(s)
- Peng Guo
- School of Engineering and Applied Sciences, Harvard University, 29 Oxford St., Cambridge, MA 02138, USA
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