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Hu Y, Xu X, Zhong H, Ding C, Zhang S, Qin W, Zhang E, Shu D, Yu M, Naijipu Abuduaini, Yang X, Feng B, Li J. Integrated single cell and bulk RNA sequencing analyses reveal the impact of tryptophan metabolism on prognosis and immunotherapy in colon cancer. Sci Rep 2025; 15:12496. [PMID: 40216815 PMCID: PMC11992224 DOI: 10.1038/s41598-025-85893-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 01/07/2025] [Indexed: 04/14/2025] Open
Abstract
Tryptophan metabolism is intricately associated with the progression of colon cancer. This research endeavored to meticulously analyze tryptophan metabolic characteristics in colon cancer and forecast immunotherapy responses. This study analyzed colon cancer samples from a training cohort of 473 tumors and 41 normal tissues from TCGA, with validation in 902 cancer patients across multiple GEO datasets. Patients were stratified into subtypes through consistent clustering, and a tryptophan metabolic risk score model was constructed using the random forest algorithm. Based on these risk scores, patients were delineated into high and low-risk groups, and their clinicopathologic characteristics, immune cell infiltration, immune checkpoint expression, and signaling pathway disparities were examined. The Oncopredict algorithm facilitated the identification of sensitive chemotherapeutic agents, while the immune escape score was employed to evaluate the immunotherapy response across risk groups. Transcriptomic sequencing findings were corroborated by single-cell sequencing from Shanghai Ruijin Hospital. Two distinct subtypes of colon cancer patients emerged, exhibiting significant prognostic and immune cell infiltration differences. The high-risk group demonstrated a poorer prognosis (p < 0.001), advanced clinical stage (p < 0.001), and elevated immunosuppressive cell expression (p < 0.05). Additionally, three chemotherapeutic drugs showed efficacy in the high-risk cohort, displaying a heightened immune escape potential (p < 0.05) and diminished response to immunotherapy. Single-cell sequencing validated the overexpression of tryptophan-related genes in epithelial cells. In conclusion, tryptophan metabolism significantly influences the colon cancer immune microenvironment, with high-risk patients experiencing adverse prognoses and potentially reduced efficacy of immunotherapy.
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Affiliation(s)
- Yanyan Hu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Ximo Xu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Hao Zhong
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chengshen Ding
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Sen Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wei Qin
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Enkui Zhang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Duohuo Shu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Mengqin Yu
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Naijipu Abuduaini
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiao Yang
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Bo Feng
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Jianwen Li
- Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
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Li Y, Li C, Yao X, Lv J, Li W, Fu R, Chen M, Yang P, Dai Q, Wei W, Li Z. IDO1-mediated kynurenine production inhibits IGFBP5 signaling to promote 5-fluorouracil-induced senescence escape and chemoresistance in colorectal cancer. Am J Cancer Res 2024; 14:4551-4566. [PMID: 39417170 PMCID: PMC11477834 DOI: 10.62347/xtrc3347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 09/22/2024] [Indexed: 10/19/2024] Open
Abstract
Cellular senescence is an irreversible state of growth arrest, and induction of senescence is considered a potential therapeutic strategy against cancer. Indoleamine 2,3-dioxygenase 1 (IDO1), an enzyme catabolizing L-tryptophan into kynurenine, plays a key role in tumor immune tolerance. However, the roles of IDO1 in cellular senescence and chemoresistance remain elusive. Herein, we observed a significant elevation of IDO1 expression in colorectal cancer (CRC) tissues compared to non-neoplastic controls, based on both the GEPIA database and mouse model. Functionally, ectopic expression of IDO1 blunted 5-fluorouracil (5-FU)-induced cell senescence and rendered CRC cells more refractory towards 5-FU treatment, whereas IDO1 silencing resulted in opposing effects. Further studies demonstrated that IDO1 overexpression decreased the levels of senescent-related proteins, including p16, p21, p53, and cyclin D1. Mechanistically, the kynurenine released from IDO1-expressing CRC cells inhibited the IGFBP5/p53 signaling pathway, accounting for IDO1-mediated suppression of cell senescence and induction of chemoresistance. Collectively, these data revealed an unrecognized role of IDO1 in senescence escape and chemoresistance via releasing its catabolite kynurenine, implicating that therapeutically targeting IDO1 or IGFBP5/p53 signaling pathway holds great promise for CRC treatment.
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Affiliation(s)
- Yu Li
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Chao Li
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Xufeng Yao
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Junjie Lv
- Department of Oncology, The First Affiliated Hospital of Anhui Medical UniversityHefei 230022, Anhui, China
| | - Wenjun Li
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Rong Fu
- School of Basic Medical Sciences, Shanxi Medical UniversityTaiyuan 030001, Shanxi, China
| | - Mengyang Chen
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi UniversityTaiyuan 030006, Shanxi, China
| | - Peng Yang
- Institute of Biotechnology, Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Shanxi UniversityTaiyuan 030006, Shanxi, China
| | - Qian Dai
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
| | - Wei Wei
- Department of Oncology, The First Affiliated Hospital of Anhui Medical UniversityHefei 230022, Anhui, China
| | - Zongwei Li
- School of Life Science, Anhui Medical UniversityHefei 230032, Anhui, China
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Fu Q, Han M, Dai X, Lu R, Deng E, Shen X, Ou F, Pu Y, Xie X, Liu K, Gan Y, Li D. Therapeutic effect of three-dimensional hanging drop cultured human umbilical cord mesenchymal stem cells on osteoarthritis in rabbits. Stem Cell Res Ther 2024; 15:311. [PMID: 39294780 PMCID: PMC11411824 DOI: 10.1186/s13287-024-03905-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2024] [Accepted: 08/27/2024] [Indexed: 09/21/2024] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) have shown a positive effect on Osteoarthritis (OA), but the efficacy is still not significant in clinical. Conventional two-dimensional (2D) monolayer culture method is prone to cause MSCs undergoing replication senescence, which may affect the functions of MSCs. Three-dimensional (3D) culture strategy can sustain cell proliferative capacity and multi-differentiation potential. This study aimed to investigate the therapeutic potential of human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) cultured by 3D hanging drop method on OA. METHODS hUC-MSCs were isolated from umbilical cord and cultured by 3D hanging drop method for 48 h. Scanning electron microscopy (SEM) was used to observe gross morphology 2D and 3D hUC-MSCs. Transcriptome comparison of gene expression differences between 2D and 3D hUC-MSCs. GO enrichment analysis, KEGG pathway enrichment analysis and GSEA enrichment analysis were used to analyze the impact of 3D hanging drop culture on the biological functions of hUC-MSCs. Female New Zealand rabbits (n = 12) were divided into 4 groups: Normal group, Model group, 2D hUC-MSCs treatment group and 3D hUC-MSCs treatment group. After 8 weeks, the gross and histological appearance of the cartilage was evaluated by safranin O-fast green staining and Mankin scoring system. The expression of type I collagen and type II collagen was detected by immunohistochemistry. The levels of IL-6, IL-7, TNFα, TGFβ1 and IL-10 in the knee joint fluid were tested by ELISA. RESULTS 3D hanging drop culture changed cell morphology but did not affect phenotype. The MSCs transcriptome profiles showed that 3D hanging drop culture method enhanced cell-cell contact, improved cell responsiveness to external stimuli and immunomodulatory function. The animal experiment results showed that hUC-MSCs could promote cartilage regeneration compared with Model group. 3D hUC-MSCs treatment group had a higher histological score and significantly increased type II collagen secretion. In addition, 3D hUC-MSCs treatment group increased the expression of anti-inflammatory factors TGFβ1 and IL-10. CONCLUSION The above experimental results illustrated that 3D hanging drop culture method could enhance the therapeutic effect of hUC-MSCs, and showed a good clinical application prospect in the treatment of OA.
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Affiliation(s)
- Qiang Fu
- Chongqing Perfect Cell Biotechnology Co. LTD, Chongqing, 400700, P.R. China
| | - Mei Han
- Chongqing Perfect Cell Biotechnology Co. LTD, Chongqing, 400700, P.R. China
| | - Xiaoyu Dai
- Chongqing Perfect Cell Biotechnology Co. LTD, Chongqing, 400700, P.R. China
| | - Ruian Lu
- Chongqing Perfect Cell Biotechnology Co. LTD, Chongqing, 400700, P.R. China
| | - Enjie Deng
- Chongqing Perfect Cell Biotechnology Co. LTD, Chongqing, 400700, P.R. China
| | - Xuemei Shen
- Chongqing Perfect Cell Biotechnology Co. LTD, Chongqing, 400700, P.R. China
| | - Feng Ou
- Chongqing Perfect Cell Biotechnology Co. LTD, Chongqing, 400700, P.R. China
| | - Yongguang Pu
- Chongqing Perfect Cell Biotechnology Co. LTD, Chongqing, 400700, P.R. China
| | - Xueqin Xie
- Chongqing Perfect Cell Biotechnology Co. LTD, Chongqing, 400700, P.R. China
| | - Kang Liu
- Chongqing Perfect Cell Biotechnology Co. LTD, Chongqing, 400700, P.R. China
| | - Yuanshan Gan
- Chongqing Perfect Cell Biotechnology Co. LTD, Chongqing, 400700, P.R. China
| | - Dong Li
- Stem Cell and Regenerative Medicine Research Center, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, P.R. China.
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Welz L, Harris DM, Kim NM, Alsaadi AI, Wu Q, Oumari M, Taubenheim J, Volk V, Credido G, Koncina E, Mukherjee PK, Tran F, Sievers LK, Pavlidis P, Powell N, Rieder F, Letellier E, Waschina S, Kaleta C, Feuerhake F, Verstockt B, McReynolds MR, Rosenstiel P, Schreiber S, Aden K. A metabolic constraint in the kynurenine pathway drives mucosal inflammation in IBD. MEDRXIV : THE PREPRINT SERVER FOR HEALTH SCIENCES 2024:2024.08.08.24311598. [PMID: 39211892 PMCID: PMC11361206 DOI: 10.1101/2024.08.08.24311598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Inflammatory bowel disease (IBD) is associated with perturbed metabolism of the essential amino acid tryptophan (Trp). Whether increased degradation of Trp directly fuels mucosal inflammation or acts as a compensatory attempt to restore cellular energy levels via de-novo nicotinamide adenine dinucleotide (NAD + ) synthesis is not understood. Employing a systems medicine approach on longitudinal IBD therapy intervention cohorts and targeted screening in preclinical IBD models, we discover that steady increases in Trp levels upon therapy success coincide with a rewiring of metabolic processes within the kynurenine pathway (KP). In detail, we identify that Trp catabolism in IBD is metabolically constrained at the level of quinolinate phosphorybosyltransferase (QPRT), leading to accumulation of quinolinic acid (Quin) and a decrease of NAD + . We further demonstrate that Trp degradation along the KP occurs locally in the inflamed intestinal mucosa and critically depends on janus kinase / signal transducers and activators of transcription (JAK/STAT) signalling. Subsequently, knockdown of QPRT in-vitro induces NAD + depletion and a pro-inflammatory state, which can largely be rescued by bypassing QPRT via other NAD + precursors. We hence propose a model of impaired de-novo NAD + synthesis from Trp in IBD. These findings point towards the replenishment of NAD + precursors as a novel therapeutic pathway in IBD.
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Dai Z, Deng KL, Wang XM, Yang DX, Tang CL, Zhou YP. Bidirectional effects of the tryptophan metabolite indole-3-acetaldehyde on colorectal cancer. World J Gastrointest Oncol 2024; 16:2697-2715. [PMID: 38994159 PMCID: PMC11236226 DOI: 10.4251/wjgo.v16.i6.2697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 02/13/2024] [Accepted: 03/25/2024] [Indexed: 06/14/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) has a high incidence and mortality. Recent studies have shown that indole derivatives involved in gut microbiota metabolism can impact the tumorigenesis, progression, and metastasis of CRC. AIM To investigate the effect of indole-3-acetaldehyde (IAAD) on CRC. METHODS The effect of IAAD was evaluated in a syngeneic mouse model of CRC and CRC cell lines (HCT116 and DLD-1). Cell proliferation was assessed by Ki-67 fluorescence staining and cytotoxicity tests. Cell apoptosis was analysed by flow cytometry after staining with Annexin V-fluorescein isothiocyanate and propidium iodide. Invasiveness was investigated using the transwell assay. Western blotting and real-time fluorescence quantitative polymerase chain reaction were performed to evaluate the expression of epithelial-mesenchymal transition related genes and aryl hydrocarbon receptor (AhR) downstream genes. The PharmMapper, SEA, and SWISS databases were used to screen for potential target proteins of IAAD, and the core proteins were identified through the String database. RESULTS IAAD reduced tumorigenesis in a syngeneic mouse model. In CRC cell lines HCT116 and DLD1, IAAD exhibited cytotoxicity starting at 24 h of treatment, while it reduced Ki67 expression in the nucleus. The results of flow cytometry showed that IAAD induced apoptosis in HCT116 cells but had no effect on DLD1 cells, which may be related to the activation of AhR. IAAD can also increase the invasiveness and epithelial-mesenchymal transition of HCT116 and DLD1 cells. At low concentrations (< 12.5 μmol/L), IAAD only exhibited cytotoxic effects without promoting cell invasion. In addition, predictions based on online databases, protein-protein interaction analysis, and molecular docking showed that IAAD can bind to matrix metalloproteinase-9 (MMP9), angiotensin converting enzyme (ACE), poly(ADP-ribose) polymerase-1 (PARP1), matrix metalloproteinase-2 (MMP2), and myeloperoxidase (MPO). CONCLUSION Indole-3-aldehyde can induce cell apoptosis and inhibit cell proliferation to prevent the occurrence of CRC; however, at high concentrations (≥ 25 μmol/L), it can also promote epithelial-mesenchymal transition and invasion in CRC cells. IAAD activates AhR and directly binds MMP9, ACE, PARP1, MMP2, and MPO, which partly reveals why it has a bidirectional effect.
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Affiliation(s)
- Ze Dai
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Kai-Li Deng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xiao-Mei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Dong-Xue Yang
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
- Ningbo Key Laboratory of Translational Medicine Research on Gastroenterology and Hepatology, Ningbo Key Laboratory, Ningbo 315020, Zhejiang Province, China
| | - Chun-Lan Tang
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Yu-Ping Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
- Ningbo Key Laboratory of Translational Medicine Research on Gastroenterology and Hepatology, Ningbo Key Laboratory, Ningbo 315020, Zhejiang Province, China
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Dai Z, Deng KL, Wang XM, Yang DX, Tang CL, Zhou YP. Bidirectional effects of the tryptophan metabolite indole-3-acetaldehyde on colorectal cancer. World J Gastrointest Oncol 2024; 16:2685-2703. [DOI: 10.4251/wjgo.v16.i6.2685] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 02/13/2024] [Accepted: 03/25/2024] [Indexed: 06/13/2024] Open
Abstract
BACKGROUND Colorectal cancer (CRC) has a high incidence and mortality. Recent studies have shown that indole derivatives involved in gut microbiota metabolism can impact the tumorigenesis, progression, and metastasis of CRC.
AIM To investigate the effect of indole-3-acetaldehyde (IAAD) on CRC.
METHODS The effect of IAAD was evaluated in a syngeneic mouse model of CRC and CRC cell lines (HCT116 and DLD-1). Cell proliferation was assessed by Ki-67 fluorescence staining and cytotoxicity tests. Cell apoptosis was analysed by flow cytometry after staining with Annexin V-fluorescein isothiocyanate and propidium iodide. Invasiveness was investigated using the transwell assay. Western blotting and real-time fluorescence quantitative polymerase chain reaction were performed to evaluate the expression of epithelial-mesenchymal transition related genes and aryl hydrocarbon receptor (AhR) downstream genes. The PharmMapper, SEA, and SWISS databases were used to screen for potential target proteins of IAAD, and the core proteins were identified through the String database.
RESULTS IAAD reduced tumorigenesis in a syngeneic mouse model. In CRC cell lines HCT116 and DLD1, IAAD exhibited cytotoxicity starting at 24 h of treatment, while it reduced Ki67 expression in the nucleus. The results of flow cytometry showed that IAAD induced apoptosis in HCT116 cells but had no effect on DLD1 cells, which may be related to the activation of AhR. IAAD can also increase the invasiveness and epithelial-mesenchymal transition of HCT116 and DLD1 cells. At low concentrations (< 12.5 μmol/L), IAAD only exhibited cytotoxic effects without promoting cell invasion. In addition, predictions based on online databases, protein-protein interaction analysis, and molecular docking showed that IAAD can bind to matrix metalloproteinase-9 (MMP9), angiotensin converting enzyme (ACE), poly(ADP-ribose) polymerase-1 (PARP1), matrix metalloproteinase-2 (MMP2), and myeloperoxidase (MPO).
CONCLUSION Indole-3-aldehyde can induce cell apoptosis and inhibit cell proliferation to prevent the occurrence of CRC; however, at high concentrations (≥ 25 μmol/L), it can also promote epithelial-mesenchymal transition and invasion in CRC cells. IAAD activates AhR and directly binds MMP9, ACE, PARP1, MMP2, and MPO, which partly reveals why it has a bidirectional effect.
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Affiliation(s)
- Ze Dai
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Kai-Li Deng
- School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, Guangdong Province, China
| | - Xiao-Mei Wang
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Dong-Xue Yang
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
- Ningbo Key Laboratory of Translational Medicine Research on Gastroenterology and Hepatology, Ningbo Key Laboratory, Ningbo 315020, Zhejiang Province, China
| | - Chun-Lan Tang
- Health Science Center, Ningbo University, Ningbo 315211, Zhejiang Province, China
| | - Yu-Ping Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Ningbo University, Ningbo 315020, Zhejiang Province, China
- Institute of Digestive Disease of Ningbo University, Ningbo University, Ningbo 315020, Zhejiang Province, China
- Ningbo Key Laboratory of Translational Medicine Research on Gastroenterology and Hepatology, Ningbo Key Laboratory, Ningbo 315020, Zhejiang Province, China
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Di Russo S, Liberati FR, Riva A, Di Fonzo F, Macone A, Giardina G, Arese M, Rinaldo S, Cutruzzolà F, Paone A. Beyond the barrier: the immune-inspired pathways of tumor extravasation. Cell Commun Signal 2024; 22:104. [PMID: 38331871 PMCID: PMC10851599 DOI: 10.1186/s12964-023-01429-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 12/08/2023] [Indexed: 02/10/2024] Open
Abstract
Extravasation is a fundamental step in the metastatic journey, where cancer cells exit the bloodstream and breach the endothelial cell barrier to infiltrate target tissues. The tactics cancer cells employ are sophisticated, closely reflecting those used by the immune system for tissue surveillance. Remarkably, tumor cells have been observed to form distinct associations or clusters with immune cells where neutrophils stand out as particularly crucial partners. These interactions are not accidental; they are critical for cancer cells to exploit the immune functions of neutrophils and successfully extravasate. In another strategy, tumor cells mimic the behavior and characteristics of immune cells. They release a suite of inflammatory mediators, which under normal circumstances, guide the processes of endothelium reshaping and facilitate the entry and movement of immune cells within tissues. In this review, we offer a new perspective on the tactics employed by cancer cells to extravasate and infiltrate target tissues. We delve into the myriad mechanisms that tumor cells borrow, adapt, and refine from the immune playbook. Video Abstract.
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Affiliation(s)
- Sara Di Russo
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti P.Le A. Moro 5, Rome, 00185, Italy
| | - Francesca Romana Liberati
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti P.Le A. Moro 5, Rome, 00185, Italy
| | - Agnese Riva
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti P.Le A. Moro 5, Rome, 00185, Italy
| | - Federica Di Fonzo
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti P.Le A. Moro 5, Rome, 00185, Italy
| | - Alberto Macone
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti P.Le A. Moro 5, Rome, 00185, Italy
| | - Giorgio Giardina
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti P.Le A. Moro 5, Rome, 00185, Italy
| | - Marzia Arese
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti P.Le A. Moro 5, Rome, 00185, Italy
| | - Serena Rinaldo
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti P.Le A. Moro 5, Rome, 00185, Italy
| | - Francesca Cutruzzolà
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti P.Le A. Moro 5, Rome, 00185, Italy
| | - Alessio Paone
- Department of Biochemical Sciences "Alessandro Rossi Fanelli", Sapienza University of Rome, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti P.Le A. Moro 5, Rome, 00185, Italy.
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Pichler R, Siska PJ, Tymoszuk P, Martowicz A, Untergasser G, Mayr R, Weber F, Seeber A, Kocher F, Barth DA, Pichler M, Thurnher M. A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma. Front Immunol 2023; 14:1095195. [PMID: 37006314 PMCID: PMC10060976 DOI: 10.3389/fimmu.2023.1095195] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 02/28/2023] [Indexed: 03/18/2023] Open
Abstract
Renal cell carcinoma (RCC) is frequently infiltrated by immune cells, a process which is governed by chemokines. CD8+ T cells in the RCC tumor microenvironment (TME) may be exhausted which most likely influence therapy response and survival. The aim of this study was to evaluate chemokine-driven T cell recruitment, T cell exhaustion in the RCC TME, as well as metabolic processes leading to their functional anergy in RCC. Eight publicly available bulk RCC transcriptome collectives (n=1819) and a single cell RNAseq dataset (n=12) were analyzed. Immunodeconvolution, semi-supervised clustering, gene set variation analysis and Monte Carlo-based modeling of metabolic reaction activity were employed. Among 28 chemokine genes available, CXCL9/10/11/CXCR3, CXCL13/CXCR5 and XCL1/XCR1 mRNA expression were significantly increased in RCC compared to normal kidney tissue and also strongly associated with tumor-infiltrating effector memory and central memory CD8+ T cells in all investigated collectives. M1 TAMs, T cells, NK cells as well as tumor cells were identified as the major sources of these chemokines, whereas T cells, B cells and dendritic cells were found to predominantly express the cognate receptors. The cluster of RCCs characterized by high chemokine expression and high CD8+ T cell infiltration displayed a strong activation of IFN/JAK/STAT signaling with elevated expression of multiple T cell exhaustion-associated transcripts. Chemokinehigh RCCs were characterized by metabolic reprogramming, in particular by downregulated OXPHOS and increased IDO1-mediated tryptophan degradation. None of the investigated chemokine genes was significantly associated with survival or response to immunotherapy. We propose a chemokine network that mediates CD8+ T cell recruitment and identify T cell exhaustion, altered energy metabolism and high IDO1 activity as key mechanisms of their suppression. Concomitant targeting of exhaustion pathways and metabolism may pose an effective approach to RCC therapy.
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Affiliation(s)
- Renate Pichler
- Department of Urology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
- *Correspondence: Renate Pichler,
| | - Peter J. Siska
- Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
| | | | - Agnieszka Martowicz
- Department of Internal Medicine V (Hematology and Oncology), Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
- Tyrolean Cancer Research Institute (TKFI), Medical University of Innsbruck, Innsbruck, Austria
| | - Gerold Untergasser
- Department of Internal Medicine V (Hematology and Oncology), Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
- Tyrolean Cancer Research Institute (TKFI), Medical University of Innsbruck, Innsbruck, Austria
| | - Roman Mayr
- Department of Urology, Caritas St. Josef Medical Centre, University of Regensburg, Regensburg, Germany
| | - Florian Weber
- Department of Pathology, University of Regensburg, Regensburg, Germany
| | - Andreas Seeber
- Department of Internal Medicine V (Hematology and Oncology), Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
| | - Florian Kocher
- Department of Internal Medicine V (Hematology and Oncology), Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
| | - Dominik A. Barth
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Research Unit for Non-Coding RNAs and Genome Editing, Medical University of Graz, Graz, Austria
| | - Martin Pichler
- Division of Oncology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Research Unit for Non-Coding RNAs and Genome Editing, Medical University of Graz, Graz, Austria
| | - Martin Thurnher
- Immunotherapy Unit, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria
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9
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Ding P, Gao Y, Wang J, Xiang H, Zhang C, Wang L, Ji G, Wu T. Progress and challenges of multidrug resistance proteins in diseases. Am J Cancer Res 2022; 12:4483-4501. [PMID: 36381332 PMCID: PMC9641395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 10/09/2022] [Indexed: 06/16/2023] Open
Abstract
Chemotherapy remains the first choice for patients with advanced cancers when other treatments are ineffective. Multidrug resistance (MDR) is an unavoidable factor that negatively affects the effectiveness of cancer chemotherapy drugs. Researchers are trying to reduce MDR, improve the effectiveness of chemotherapeutic drugs, and alleviate patient suffering to positively contribute to disease treatment. MDR also occurs in inflammation and genetic disorders, which increases the difficulty of clinically beneficial treatments. The ATP-binding cassette (ABC) is an active transporter that plays an important role in the barrier and secretory functions of many normal cells. As the C subfamily in the ABC family, multidrug resistance proteins (MRPs/ABCCs) export a variety of antitumour drugs and are expressed in a variety of cancers. The present review summarises the role of MRPs in cancer and other diseases and recent research progress of MRP inhibitors to better examine the mechanism and function of MRPs, and establish a good relationship with clinical treatment.
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Affiliation(s)
- Peilun Ding
- Department of Hepatology, Longhua Hospital, Shanghai University of Traditional Chinese MedicineShanghai 200032, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Ying Gao
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Junmin Wang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Hongjiao Xiang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Caiyun Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
| | - Lei Wang
- Department of Hepatology, Longhua Hospital, Shanghai University of Traditional Chinese MedicineShanghai 200032, China
| | - Guang Ji
- Institute of Digestive Disease, Longhua Hospital, Shanghai University of Traditional Chinese MedicineShanghai 200032, China
| | - Tao Wu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese MedicineShanghai 201203, China
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10
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Perez-Castro L, Venkateswaran N, Garcia R, Hao YH, Lafita-Navarro MC, Kim J, Segal D, Saponzik E, Chang BJ, Fiolka R, Danuser G, Xu L, Brabletz T, Conacci-Sorrell M. The AHR target gene scinderin activates the WNT pathway by facilitating the nuclear translocation of β-catenin. J Cell Sci 2022; 135:jcs260028. [PMID: 36148682 PMCID: PMC10658791 DOI: 10.1242/jcs.260028] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 09/12/2022] [Indexed: 01/12/2023] Open
Abstract
The ligand-activated transcription factor aryl hydrocarbon receptor (AHR) regulates cellular detoxification, proliferation and immune evasion in a range of cell types and tissues, including cancer cells. In this study, we used RNA-sequencing to identify the signature of the AHR target genes regulated by the pollutant 2,3,7,8-tetrachlorodibenzodioxin (TCDD) and the endogenous ligand kynurenine (Kyn), a tryptophan-derived metabolite. This approach identified a signature of six genes (CYP1A1, ALDH1A3, ABCG2, ADGRF1 and SCIN) as commonly activated by endogenous or exogenous ligands of AHR in multiple colon cancer cell lines. Among these, the actin-severing protein scinderin (SCIN) was necessary for cell proliferation; SCIN downregulation limited cell proliferation and its expression increased it. SCIN expression was elevated in a subset of colon cancer patient samples, which also contained elevated β-catenin levels. Remarkably, SCIN expression promoted nuclear translocation of β-catenin and activates the WNT pathway. Our study identifies a new mechanism for adhesion-mediated signaling in which SCIN, likely via its ability to alter the actin cytoskeleton, facilitates the nuclear translocation of β-catenin. This article has an associated First Person interview with the first authors of the paper.
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Affiliation(s)
- Lizbeth Perez-Castro
- Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | | | - Roy Garcia
- Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Yi-Heng Hao
- Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - M. C. Lafita-Navarro
- Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Jiwoong Kim
- Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Dagan Segal
- Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Etai Saponzik
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Bo-Jui Chang
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Reto Fiolka
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Gaudenz Danuser
- Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Lin Xu
- Quantitative Biomedical Research Center, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Department of Pediatrics, Division of Hematology/Oncology, UT Southwestern Medical Center, Dallas, TX 75390, USA
| | - Thomas Brabletz
- Nikolaus-Fiebiger Center for Molecular Medicine, University Erlangen-Nurnberg, Erlangen 91054, Germany
| | - Maralice Conacci-Sorrell
- Department of Cell Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX 75390, USA
- Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
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11
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Huldani H, Jasim SA, Sergeenva KN, Bokov DO, Abdelbasset WK, Turakulov R, Al-Gazally ME, Ahmadzadeh B, Jawhar ZH, Siahmansouri H. Mechanisms of cancer stem cells drug resistance and the pivotal role of HMGA2. Pathol Res Pract 2022; 234:153906. [PMID: 35468338 DOI: 10.1016/j.prp.2022.153906] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/02/2022] [Accepted: 04/15/2022] [Indexed: 11/24/2022]
Abstract
Nowadays, the focus of researchers is on perceiving the heterogeneity observed in a tumor. The researchers studied the role of a specific subset of cancer cells with high resistance to traditional treatments, recurrence, and unregulated metastasis. This small population of tumor cells that have stem-cell-like specifications was named Cancer Stem Cells (CSCs). The unique features that distinguish this type of cancer cell are self-renewing, generating clones of the tumor, plasticity, recurrence, and resistance to therapies. There are various mechanisms that contribute to the drug resistance of CSCs, such as CSCs markers, Epithelial mesenchymal transition, hypoxia, other cells, inflammation, and signaling pathways. Recent investigations have revealed the primary role of HMGA2 in the development and invasion of cancer cells. Importantly, HMGA2 also plays a key role in resistance to treatment through their function in the drug resistance mechanisms of CSCs and challenge it. Therefore, a deep understanding of this issue can provide a clearer perspective for researchers in the face of this problem.
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Affiliation(s)
- Huldani Huldani
- Department of Physiology, Lambung Mangkurat University, Banjarmasin, South Borneo, Indonesia
| | - Saade Abdalkareem Jasim
- Medical Laboratory Techniques Department, Al-Maarif University College, Al-Anbar-Ramadi, Iraq
| | - Klunko Nataliya Sergeenva
- Department of post-graduate and doctoral programs, Russian New University, Building 5, Radio Street, Moscow City, Russian Federation
| | - Dmitry Olegovich Bokov
- Institute of Pharmacy, Sechenov First Moscow State Medical University, 8 Trubetskaya St., Bldg. 2, Moscow 119991, Russian Federation
| | - Walid Kamal Abdelbasset
- Department of Health and Rehabilitation Sciences, College of Applied Medical Sciences, Prince Sattam bin Abdulaziz University, Al Kharj, Saudi Arabia; Department of Physical Therapy, Kasr Al-Aini Hospital, Cairo University, Giza, Egypt
| | - Rustam Turakulov
- Department of Internal diseases, Tashkent Medical Academy, Tashkent, Uzbekistan
| | | | - Behnam Ahmadzadeh
- Doctoral School of the University of Szczecin, Institute of Biology, University of Szczecin, 71-412 Szczecin, Poland
| | - Zanko Hassan Jawhar
- Department of Medical Laboratory Science, College of Health Science, Lebanese French University, Kurdistan Region, Iraq
| | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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12
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Salimiyan S, Mohammadi M, Aliakbari S, Kazemi R, Amini AA, Rahmani MR. Hydrocortisone Long-term Treatment Effect on Immunomodulatory Properties of Human Adipose-Derived Mesenchymal Stromal/Stem Cells. J Interferon Cytokine Res 2022; 42:72-81. [PMID: 35171704 DOI: 10.1089/jir.2021.0120] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Cortisol is secreted in prolonged stress and has therapeutic effects in inflammatory diseases. Considering the immunomodulatory effects of mesenchymal stem cells, here we investigated the effect of hydrocortisone (HC) long-term treatment on immunomodulatory properties of human adipose-derived mesenchymal stromal/stem cells (ASCs). Isolated ASCs from healthy subjects were treated with different HC concentrations for 14 days. The effect of HC-treated ASCs on the proliferative response of peripheral blood mononuclear cells (PBMCs) was evaluated in ASCs/2-way mixed leukocyte reaction coculture using 2,3-bis-(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide (XTT)-assay. HC-treated ASCs were further divided into interferon gamma (IFN-γ) stimulated and unstimulated groups. Transforming growth factor beta 1 (TGF-β1) and interleukin (IL)-6 levels were measured in culture supernatants by enzyme-linked immunosorbent assay. Relative expression of cyclooxygenase-2 (COX-2), hepatocyte growth factor, indoleamine dioxygenase, and programmed death-ligand 1 genes was assessed by real-time PCR. Levels of TGF-β1 and COX-2 expression were elevated in unstimulated ASCs, while exposure to high concentration of HC significantly increased TGF-β1 levels and reduced COX-2 expression. Unstimulated HC-5-μM-treated ASCs increased PBMC proliferation ratio on day 2 of coculture compared to the control group (P = 0.05). In IFN-γ stimulated condition, pretreatment with HC-5 μM resulted in a significantly increased IL-6 and significantly decreased COX-2 expression compared to the HC untreated control group. In conclusion, our results showed various alterations of ASC immunomodulatory related features as a result of long-term exposure of different concentrations of HC. It seems that HC at low concentration pushed the balance toward extended immune response in ASCs, while this observation wasn't persistent in ASCs treated with higher concentrations of HC.
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Affiliation(s)
- Samira Salimiyan
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mobin Mohammadi
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Sara Aliakbari
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Romina Kazemi
- Student Research Committee, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Abbas Ali Amini
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Cancer and Immunology Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
| | - Mohammad Reza Rahmani
- Department of Immunology, Faculty of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.,Zoonosis Research Center, Research Institute for Health Development, Kurdistan University of Medical Sciences, Sanandaj, Iran
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13
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Fronik P, Poetsch I, Kastner A, Mendrina T, Hager S, Hohenwallner K, Schueffl H, Herndler-Brandstetter D, Koellensperger G, Rampler E, Kopecka J, Riganti C, Berger W, Keppler BK, Heffeter P, Kowol CR. Structure-Activity Relationships of Triple-Action Platinum(IV) Prodrugs with Albumin-Binding Properties and Immunomodulating Ligands. J Med Chem 2021; 64:12132-12151. [PMID: 34403254 PMCID: PMC8404199 DOI: 10.1021/acs.jmedchem.1c00770] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Indexed: 12/27/2022]
Abstract
Chemotherapy with platinum complexes is essential for clinical anticancer therapy. However, due to side effects and drug resistance, further drug improvement is urgently needed. Herein, we report on triple-action platinum(IV) prodrugs, which, in addition to tumor targeting via maleimide-mediated albumin binding, release the immunomodulatory ligand 1-methyl-d-tryptophan (1-MDT). Unexpectedly, structure-activity relationship analysis showed that the mode of 1-MDT conjugation distinctly impacts the reducibility and thus activation of the prodrugs. This in turn affected ligand release, pharmacokinetic properties, efficiency of immunomodulation, and the anticancer activity in vitro and in a mouse model in vivo. Moreover, we could demonstrate that the design of albumin-targeted multi-modal prodrugs using platinum(IV) is a promising strategy to enhance the cellular uptake of bioactive ligands with low cell permeability (1-MDT) and to improve their selective delivery into the malignant tissue. This will allow tumor-specific anticancer therapy supported by a favorably tuned immune microenvironment.
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Affiliation(s)
- Philipp Fronik
- Faculty
of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria
| | - Isabella Poetsch
- Faculty
of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria
- Institute
of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
- Research
Cluster “Translational Cancer Therapy Research”, 1090 Vienna, Austria
| | - Alexander Kastner
- Faculty
of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria
| | - Theresa Mendrina
- Institute
of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Sonja Hager
- Institute
of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Katharina Hohenwallner
- Faculty
of Chemistry, Institute of Analytical Chemistry, University of Vienna, Waehringer Strasse 38, 1090 Vienna, Austria
| | - Hemma Schueffl
- Institute
of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Dietmar Herndler-Brandstetter
- Institute
of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
| | - Gunda Koellensperger
- Faculty
of Chemistry, Institute of Analytical Chemistry, University of Vienna, Waehringer Strasse 38, 1090 Vienna, Austria
| | - Evelyn Rampler
- Faculty
of Chemistry, Institute of Analytical Chemistry, University of Vienna, Waehringer Strasse 38, 1090 Vienna, Austria
| | - Joanna Kopecka
- Department
of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
| | - Chiara Riganti
- Department
of Oncology, University of Torino, via Santena 5/bis, 10126 Torino, Italy
| | - Walter Berger
- Institute
of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
- Research
Cluster “Translational Cancer Therapy Research”, 1090 Vienna, Austria
| | - Bernhard K. Keppler
- Faculty
of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria
- Research
Cluster “Translational Cancer Therapy Research”, 1090 Vienna, Austria
| | - Petra Heffeter
- Institute
of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria
- Research
Cluster “Translational Cancer Therapy Research”, 1090 Vienna, Austria
| | - Christian R. Kowol
- Faculty
of Chemistry, Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria
- Research
Cluster “Translational Cancer Therapy Research”, 1090 Vienna, Austria
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14
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Ala M. Tryptophan metabolites modulate inflammatory bowel disease and colorectal cancer by affecting immune system. Int Rev Immunol 2021; 41:326-345. [PMID: 34289794 DOI: 10.1080/08830185.2021.1954638] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Tryptophan is an essential amino acid, going through three different metabolic pathways in the intestines. Indole pathway in the gut microbiota, serotonin system in the enterochromaffin cells and kynurenine pathway in the immune cells and intestinal lining are the three arms of tryptophan metabolism in the intestines. Clinical, in vivo and in vitro studies showed that each one of these arms has a significant impact on IBD. This review explains how different metabolites of tryptophan are involved in the pathophysiology of IBD and colorectal cancer, as a major complication of IBD. Indole metabolites alleviate colitis and protect against colorectal cancer while serotonin arm follows a more complicated and receptor-specific pattern. Indole metabolites and kynurenine interact with aryl hydrocarbon receptor (AHR) to induce T regulatory cells differentiation, confine Th17 and Th1 response and produce anti-inflammatory mediators. Kynurenine decreases tumor-infiltrating CD8+ cells and mediates tumor cells immune evasion. Serotonin system also increases colorectal cancer cells proliferation and metastasis while, indole metabolites can profoundly decrease colorectal cancer growth. Targeted therapy for tryptophan metabolites may improve the management of IBD and colorectal cancer, e.g. supplementation of indole metabolites such as indole-3-carbinol (I3C), inhibition of kynurenine monooxygenase (KMO) and selective stimulation or inhibition of specific serotonergic receptors can mitigate colitis. Furthermore, it will be explained how indole metabolites supplementation, inhibition of indoleamine 2,3-dioxygenase 1 (IDO1), KMO and serotonin receptors can protect against colorectal cancer. Additionally, extensive molecular interactions between tryptophan metabolites and intracellular signaling pathways will be thoroughly discussed.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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15
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Tahaghoghi-Hajghorbani S, Khoshkhabar R, Rafiei A, Ajami A, Nikpoor AR, Jaafari MR, Badiee A. Development of a novel formulation method to prepare liposomal Epacadostat. Eur J Pharm Sci 2021; 165:105954. [PMID: 34289341 DOI: 10.1016/j.ejps.2021.105954] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 06/30/2021] [Accepted: 07/15/2021] [Indexed: 11/25/2022]
Abstract
BACKGROUND One of the important metabolic pathways in cancer progression is tryptophan catabolism by the indoleamin-2,3-dioxygenase (IDO) enzyme, which suppresses the immune system and induces tolerance. Inhibition of IDO1 is an important therapeutic goal for immunotherapy in many cancers such as metastatic melanoma. Epacadostat (EPA) is a very strong inhibitor of IDO1, and its clinical studies are being performed in a higher clinical phase than other inhibitors. In this study, we have developed a new liposomal EPA formulation to reduce the dose, side effects, and treatment costs. METHODS Liposomes containing EPA were formulated using a novel remote loading method. Their morphology, particle size, surface charge, total phospholipid content, and drug loading were evaluated. Validation method studies to assay of EPA were carried out according to ICHQ2B guidelines. For in-vivo study, B16F10 melanoma bearing C57BL/6 mice were treated with the free or liposomal forms of EPA, and then monitored for tumor size and survival rate. RESULTS A validated method for EPA determination in liposomal form using UV-visible spectrophotometry was developed which was a precise, accurate and robust method. The particle size, zeta potential, and encapsulation efficacy of liposomes was 128.1 ± 1.1 nm, -16.5 ± 1 mV, and 64.9 ± 3.5, respectively. The half maximal inhibitory concentration (IC50) of liposomal EPA was 64 ng/ml that was lower than free EPA (128 ng/ml). In-vivo results also showed that tumor growth was slower in mice receiving liposomal EPA than in the group receiving free EPA. CONCLUSION A new method was developed to load EPA into liposomes. Moreover, the use of the nanoliposomal EPA showed more efficacy than EPA in inhibiting the tumor growth in melanoma model. Therefore, it might be used in further clinical studies as a good candidate for immunotherapy alone or in combination with other treatments.
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Affiliation(s)
- Sahar Tahaghoghi-Hajghorbani
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Rahimeh Khoshkhabar
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Alireza Rafiei
- Department of Immunology, Molecular and Cell Biology Research Center, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Abolghasem Ajami
- Department of Immunology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Amin Reza Nikpoor
- Department of Immunology, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Mahmoud Reza Jaafari
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ali Badiee
- Nanotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Pharmaceutical Nanotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
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16
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Wangpaichitr M, Theodoropoulos G, Nguyen DJM, Wu C, Spector SA, Feun LG, Savaraj N. Cisplatin Resistance and Redox-Metabolic Vulnerability: A Second Alteration. Int J Mol Sci 2021; 22:7379. [PMID: 34298999 PMCID: PMC8304747 DOI: 10.3390/ijms22147379] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 07/01/2021] [Accepted: 07/05/2021] [Indexed: 01/17/2023] Open
Abstract
The development of drug resistance in tumors is a major obstacle to effective cancer chemotherapy and represents one of the most significant complications to improving long-term patient outcomes. Despite early positive responsiveness to platinum-based chemotherapy, the majority of lung cancer patients develop resistance. The development of a new combination therapy targeting cisplatin-resistant (CR) tumors may mark a major improvement as salvage therapy in these patients. The recent resurgence in research into cellular metabolism has again confirmed that cancer cells utilize aerobic glycolysis ("the Warburg effect") to produce energy. Hence, this observation still remains a characteristic hallmark of altered metabolism in certain cancer cells. However, recent evidence promotes another concept wherein some tumors that acquire resistance to cisplatin undergo further metabolic alterations that increase tumor reliance on oxidative metabolism (OXMET) instead of glycolysis. Our review focuses on molecular changes that occur in tumors due to the relationship between metabolic demands and the importance of NAD+ in redox (ROS) metabolism and the crosstalk between PARP-1 (Poly (ADP ribose) polymerase-1) and SIRTs (sirtuins) in CR tumors. Finally, we discuss a role for the tumor metabolites of the kynurenine pathway (tryptophan catabolism) as effectors of immune cells in the tumor microenvironment during acquisition of resistance in CR cells. Understanding these concepts will form the basis for future targeting of CR cells by exploiting redox-metabolic changes and their consequences on immune cells in the tumor microenvironment as a new approach to improve overall therapeutic outcomes and survival in patients who fail cisplatin.
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Affiliation(s)
- Medhi Wangpaichitr
- Department of Veterans Affairs, Miami VA Healthcare System, Research Service (151), Miami, FL 33125, USA; (G.T.); (D.J.M.N.); (C.W.); (S.A.S.)
- Department of Surgery, Cardiothoracic Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, USA
| | - George Theodoropoulos
- Department of Veterans Affairs, Miami VA Healthcare System, Research Service (151), Miami, FL 33125, USA; (G.T.); (D.J.M.N.); (C.W.); (S.A.S.)
| | - Dan J. M. Nguyen
- Department of Veterans Affairs, Miami VA Healthcare System, Research Service (151), Miami, FL 33125, USA; (G.T.); (D.J.M.N.); (C.W.); (S.A.S.)
| | - Chunjing Wu
- Department of Veterans Affairs, Miami VA Healthcare System, Research Service (151), Miami, FL 33125, USA; (G.T.); (D.J.M.N.); (C.W.); (S.A.S.)
| | - Sydney A. Spector
- Department of Veterans Affairs, Miami VA Healthcare System, Research Service (151), Miami, FL 33125, USA; (G.T.); (D.J.M.N.); (C.W.); (S.A.S.)
| | - Lynn G. Feun
- Department of Medicine, Hematology/Oncology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (L.G.F.); (N.S.)
| | - Niramol Savaraj
- Department of Medicine, Hematology/Oncology, Miller School of Medicine, University of Miami, Miami, FL 33136, USA; (L.G.F.); (N.S.)
- Department of Veterans Affairs, Miami VA Healthcare System, Hematology/Oncology, 1201 NW 16 Street, Room D1010, Miami, FL 33125, USA
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17
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Ala M. The footprint of kynurenine pathway in every cancer: a new target for chemotherapy. Eur J Pharmacol 2021; 896:173921. [PMID: 33529725 DOI: 10.1016/j.ejphar.2021.173921] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 01/08/2021] [Accepted: 01/26/2021] [Indexed: 02/06/2023]
Abstract
Treatment of cancers has always been a challenge for physicians. Typically, several groups of anti-cancer medications are needed for effective management of an invasive and metastatic cancer. Recently, therapeutic potentiation of immune system markedly improved treatment of cancers. Kynurenine pathway has an interwoven correlation with immune system. Kynurenine promotes T Reg (regulatory) differentiation, which leads to increased production of anti-inflammatory cytokines and suppression of cytotoxic activity of T cells. Overactivation of kynurenine pathway in cancers provides an immunologically susceptible microenvironment for mutant cells to survive and invade surrounding tissues. Interestingly, kynurenine pathway vigorously interacts with other molecular pathways involved in tumorigenesis. For instance, kynurenine pathway interacts with phospoinosisitide-3 kinase (PI3K), extracellular signal-regulated kinase (ERK), Wnt/β-catenin, P53, bridging integrator 1 (BIN-1), cyclooxygenase 2 (COX-2), cyclin-dependent kinase (CDK) and collagen type XII α1 chain (COL12A1). Overactivation of kynurenine pathway, particularly overactivation of indoleamine 2,3-dioxygenase (IDO) predicts poor prognosis of several cancers such as gastrointestinal cancers, gynecological cancers, hematologic malignancies, breast cancer, lung cancer, glioma, melanoma, prostate cancer and pancreatic cancer. Furthermore, kynurenine increases the invasion, metastasis and chemoresistance of cancer cells. Recently, IDO inhibitors entered clinical trials and successfully passed their safety tests and showed promising therapeutic efficacy for cancers such as melanoma, brain cancer, renal cell carcinoma, prostate cancer and pancreatic cancer. However, a phase III trial of epacadostat, an IDO inhibitor, could not increase the efficacy of treatment with pembrolizumab for melanoma. In this review the expanding knowledge towards kynurenine pathway and its application in each cancer is discussed separately.
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Affiliation(s)
- Moein Ala
- School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.
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18
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Wu F, Cheng Y, Wu L, Zhang W, Zheng W, Wang Q, Cao H, Pan X, Tang W. Emerging Landscapes of Tumor Immunity and Metabolism. Front Oncol 2020; 10:575037. [PMID: 33117713 PMCID: PMC7575711 DOI: 10.3389/fonc.2020.575037] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2020] [Accepted: 09/11/2020] [Indexed: 12/14/2022] Open
Abstract
The metabolic reprogramming of cancer tissue has higher metabolic activity than surrounding tissues. At the same time, the local infiltration of immunosuppressive cells is also significantly increased, resulting in a significant decrease in tumor immunity. During the progression of cancer cells, immunosuppressive tumor microenvironment is formed around the tumor due to their metabolic reprogramming. In addition, it is the changes in metabolic patterns that make tumor cells resistant to certain drugs, impeding cancer treatment. This article reviews the mechanisms of immune escape caused by metabolic reprogramming, and aims to provide new ideas for clinical tumor immunotherapy combined with metabolic intervention for tumor treatment.
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Affiliation(s)
- Fan Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Ye Cheng
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Liangliang Wu
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Wenling Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wubing Zheng
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Qian Wang
- Research Unit Analytical Pathology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Hongyong Cao
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
| | - Xiongxiong Pan
- Department of Anesthesiology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Weiwei Tang
- Department of General Surgery, Nanjing First Hospital, Nanjing Medical University, Nanjing, China
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19
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Sayegh S, El Atat O, Diallo K, Rauwel B, Degboé Y, Cavaignac E, Constantin A, Cantagrel A, Trak-Smayra V, Alaaeddine N, Davignon JL. Rheumatoid Synovial Fluids Regulate the Immunomodulatory Potential of Adipose-Derived Mesenchymal Stem Cells Through a TNF/NF-κB-Dependent Mechanism. Front Immunol 2019; 10:1482. [PMID: 31316519 PMCID: PMC6611153 DOI: 10.3389/fimmu.2019.01482] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 06/13/2019] [Indexed: 12/20/2022] Open
Abstract
Introduction: Adipose-derived mesenchymal stem cells (ADSC) have been shown to have remarkable immune-modulating effects. However, their efficacy in clinical trials has yet to be fully demonstrated. This could be due to a lack of a proper inflammatory environment in vivo that primes ADSC. Here, we define how the articular microenvironment of rheumatoid arthritis (RA) patients modulates the therapeutic efficiency of ADSC. Methods: Synovial fluids (SF) were collected from 8 RA patients, 2 Spondyloarthritis patients and one control synovial fluid from a patient undergoing traumatic-related surgery. SF inflammatory status was determined by routine analysis and quantification of pro-inflammatory cytokines. ADSC were first treated with SF and ADSC proliferation and gene expression of immunomodulatory factors was evaluated. In order to determine the mechanisms underlying the effect of SF on ADSC, tumor necrosis factor (TNF), interleukin-6 (IL-6), and NF-κB neutralization assays were performed. To evaluate the effect of SF on ADSC functions, ADSC were pre-treated with SF and then co-cultured with either macrophages or T cells. The modulation of their phenotype was assessed by flow cytometry. Results: Pro-inflammatory RASF maintained the proliferative capacity of ADSC and upregulated the gene expression of cyclooxygenase-2 (COX2), indoleamine-1,2-dioxygenase (IDO), interleukin-6 (IL-6), tumor-necrosis factor stimulated gene 6 (TSG6), intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and programmed death-ligand 1 (PD-L1), all factors involved in ADSC immunomodulatory potential. The RASF-induced gene expression was mainly mediated by TNF alone or in combination with IL-6 and signaled through the NF-κB pathway. Conditioning ADSC with pro-inflammatory RASF enhanced their ability to induce CD4+Foxp3+CD25high regulatory T cells (Tregs) and inhibit pro-inflammatory markers CD40 and CD80 in activated macrophages. Conclusions: Inflammatory synovial fluids from RA patients had the capacity to modulate ADSC response, to induce Tregs and modulate the phenotype of macrophages. The clinical use of ADSC in affected joints should take into account the influence of the local articular environment on their potential. Having a sufficient pro-inflammatory microenvironment will determine whether optimal immunoregulatory response should be expected. Direct ADSC intra-articular delivery to patients could be a potential strategy to properly prime their immunomodulatory potential and enhance their clinical benefits.
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Affiliation(s)
- Souraya Sayegh
- Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, Toulouse, France.,Université Paul Sabatier Toulouse III, Toulouse, France.,Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon
| | - Oula El Atat
- Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon
| | - Katy Diallo
- Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, Toulouse, France.,Université Paul Sabatier Toulouse III, Toulouse, France
| | - Benjamin Rauwel
- Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, Toulouse, France
| | - Yannick Degboé
- Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, Toulouse, France.,Centre de Rhumatologie, CHU de Toulouse, Toulouse, France
| | - Etienne Cavaignac
- Centre de Chirurgie Orthopédique et Traumatologique, CHU de Toulouse, Toulouse, France
| | - Arnaud Constantin
- Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, Toulouse, France.,Université Paul Sabatier Toulouse III, Toulouse, France.,Centre de Rhumatologie, CHU de Toulouse, Toulouse, France
| | - Alain Cantagrel
- Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, Toulouse, France.,Université Paul Sabatier Toulouse III, Toulouse, France.,Centre de Rhumatologie, CHU de Toulouse, Toulouse, France
| | | | - Nada Alaaeddine
- Faculty of Medical Sciences, Neuroscience Research Center, Lebanese University, Beirut, Lebanon
| | - Jean-Luc Davignon
- Centre de Physiopathologie de Toulouse Purpan, INSERM UMR 1043, Toulouse, France.,Centre de Rhumatologie, CHU de Toulouse, Toulouse, France
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20
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Kopecka J, Gazzano E, Castella B, Salaroglio IC, Mungo E, Massaia M, Riganti C. Mitochondrial metabolism: Inducer or therapeutic target in tumor immune-resistance? Semin Cell Dev Biol 2019; 98:80-89. [PMID: 31100351 DOI: 10.1016/j.semcdb.2019.05.008] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2019] [Revised: 05/09/2019] [Accepted: 05/10/2019] [Indexed: 02/08/2023]
Abstract
Mitochondria have been considered for a long time only as the principal source of building blocks and energy upon aerobic conditions. Recently they emerged as key players in cell proliferation, invasion and resistance to therapy. The most aggressive tumors are able to evade the immune-surveillance. Alterations in the mitochondria metabolism either in cancer cells or in host immune system cells are involved in such tumor-induced immune-suppression. This review will focus on the main mitochondrial dysfunctions in tumor and immune cell populations determining immune-resistance, and on the therapies that may target mitochondrial metabolism and restore a powerful anti-tumor immune-activity.
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Affiliation(s)
- Joanna Kopecka
- Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy
| | - Elena Gazzano
- Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy
| | - Barbara Castella
- Laboratory of Blood Tumor Immunology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy
| | - Iris C Salaroglio
- Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy
| | - Eleonora Mungo
- Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy
| | - Massimo Massaia
- Laboratory of Blood Tumor Immunology, Department of Molecular Biotechnology and Health Sciences, University of Torino, Italy; Hematology Division, AO S Croce e Carle, Cuneo, Italy; Interdepartmental Center of Research in Molecular Biotechnology, University of Torino, Italy
| | - Chiara Riganti
- Department of Oncology, University of Torino, via Santena 5/bis, 10126, Torino, Italy; Interdepartmental Center of Research in Molecular Biotechnology, University of Torino, Italy.
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21
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Salaroglio IC, Kopecka J, Napoli F, Pradotto M, Maletta F, Costardi L, Gagliasso M, Milosevic V, Ananthanarayanan P, Bironzo P, Tabbò F, Cartia CF, Passone E, Comunanza V, Ardissone F, Ruffini E, Bussolino F, Righi L, Novello S, Di Maio M, Papotti M, Scagliotti GV, Riganti C. Potential Diagnostic and Prognostic Role of Microenvironment in Malignant Pleural Mesothelioma. J Thorac Oncol 2019; 14:1458-1471. [PMID: 31078776 DOI: 10.1016/j.jtho.2019.03.029] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 03/12/2019] [Accepted: 03/31/2019] [Indexed: 01/01/2023]
Abstract
INTRODUCTION A comprehensive analysis of the immune cell infiltrate collected from pleural fluid and from biopsy specimens of malignant pleural mesothelioma (MPM) may contribute to understanding the immune-evasion mechanisms related to tumor progression, aiding in differential diagnosis and potential prognostic stratification. Until now such approach has not routinely been verified. METHODS We enrolled 275 patients with an initial clinical diagnosis of pleural effusion. Specimens of pleural fluids and pleural biopsy samples used for the pathologic diagnosis and the immune phenotype analyses were blindly investigated by multiparametric flow cytometry. The results were analyzed using the Kruskal-Wallis test. The Kaplan-Meier and log-rank tests were used to correlate immune phenotype data with patients' outcome. RESULTS The cutoffs of intratumor T-regulatory (>1.1%) cells, M2-macrophages (>36%), granulocytic and monocytic myeloid-derived suppressor cells (MDSC; >5.1% and 4.2%, respectively), CD4 molecule-positive (CD4+) programmed death 1-positive (PD-1+) (>5.2%) and CD8+PD-1+ (6.4%) cells, CD4+ lymphocyte activating 3-positive (LAG-3+) (>2.8% ) and CD8+LAG-3+ (>2.8%) cells, CD4+ T cell immunoglobulin and mucin domain 3-positive (TIM-3+) (>2.5%), and CD8+TIM-3+ (>2.6%) cells discriminated MPM from pleuritis with 100% sensitivity and 89% specificity. The presence of intratumor MDSC contributed to the anergy of tumor-infiltrating lymphocytes. The immune phenotype of pleural fluid cells had no prognostic significance. By contrast, the intratumor T-regulatory and MDSC levels significantly correlated with progression-free and overall survival, the PD-1+/LAG-3+/TIM-3+ CD4+ tumor-infiltrating lymphocytes correlated with overall survival. CONCLUSIONS A clear immune signature of pleural fluids and tissues of MPM patients may contribute to better predict patients' outcome.
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Affiliation(s)
| | - Joanna Kopecka
- Department of Oncology, University of Torino, Torino, Italy
| | - Francesca Napoli
- Pathology Unit, Department of Oncology at San Luigi Hospital, University of Torino, Orbassano, Italy
| | - Monica Pradotto
- Thoracic Oncology Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, University of Torino Regione Gonzole 10, Orbassano, Italy
| | - Francesca Maletta
- Department of Oncology, University of Torino, Torino, Italy; Pathology Unit, Department of Oncology at AOU Città della Salute e della Scienza, Torino, Italy
| | - Lorena Costardi
- Thoracic Surgery Unit, Department of Surgery, AOU Città della Salute e Della Scienza, University of Torino, Torino, Italy
| | - Matteo Gagliasso
- Thoracic Surgery Unit, Department of Oncology at San Luigi Hospital, University of Torino, Orbassano, Italy
| | | | | | - Paolo Bironzo
- Department of Oncology, University of Torino, Torino, Italy; Thoracic Oncology Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, University of Torino Regione Gonzole 10, Orbassano, Italy
| | - Fabrizio Tabbò
- Department of Oncology, University of Torino, Torino, Italy; Thoracic Oncology Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, University of Torino Regione Gonzole 10, Orbassano, Italy
| | - Carlotta F Cartia
- Thoracic Surgery Unit, Department of Oncology at San Luigi Hospital, University of Torino, Orbassano, Italy
| | - Erika Passone
- Thoracic Surgery Unit, Department of Surgery, AOU Città della Salute e Della Scienza, University of Torino, Torino, Italy
| | - Valentina Comunanza
- Department of Oncology, University of Torino, Torino, Italy; Candiolo Cancer Institute - FPO IRCCS, Candiolo, Department of Oncology, University of Torino, Candiolo, Italy
| | - Francesco Ardissone
- Thoracic Surgery Unit, Department of Oncology at San Luigi Hospital, University of Torino, Orbassano, Italy
| | - Enrico Ruffini
- Thoracic Surgery Unit, Department of Surgery, AOU Città della Salute e Della Scienza, University of Torino, Torino, Italy
| | - Federico Bussolino
- Department of Oncology, University of Torino, Torino, Italy; Candiolo Cancer Institute - FPO IRCCS, Candiolo, Department of Oncology, University of Torino, Candiolo, Italy
| | - Luisella Righi
- Department of Oncology, University of Torino, Torino, Italy; Pathology Unit, Department of Oncology at San Luigi Hospital, University of Torino, Orbassano, Italy
| | - Silvia Novello
- Department of Oncology, University of Torino, Torino, Italy; Thoracic Oncology Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, University of Torino Regione Gonzole 10, Orbassano, Italy
| | - Massimo Di Maio
- Department of Oncology, University of Torino, Torino, Italy; Medical Oncology Division, Department of Oncology at AOU Ordine Mauriziano di Torino, Torino, Italy
| | - Mauro Papotti
- Department of Oncology, University of Torino, Torino, Italy; Pathology Unit, Department of Oncology at AOU Città della Salute e della Scienza, Torino, Italy
| | - Giorgio V Scagliotti
- Department of Oncology, University of Torino, Torino, Italy; Thoracic Oncology Unit and Medical Oncology Division, Department of Oncology at San Luigi Hospital, University of Torino Regione Gonzole 10, Orbassano, Italy
| | - Chiara Riganti
- Department of Oncology, University of Torino, Torino, Italy; Interdepartmental Center "G. Scansetti" for the Study of Asbestos and Other Toxic Particulates, University of Torino, Torino, Italy.
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22
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Engin AB, Engin A. Nanoparticles and neurotoxicity: Dual response of glutamatergic receptors. PROGRESS IN BRAIN RESEARCH 2019; 245:281-303. [PMID: 30961871 DOI: 10.1016/bs.pbr.2019.03.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Although the use of nanoparticles for neuro-diagnostic and neurotherapeutic purposes provides superior benefits than the conventional approaches, it may be potentially toxic in central nervous system. In this respect, nanotechnological research focuses on nanoneurotoxicity-nanoneurosafety concepts. Despite these efforts, nanoparticles (NPs) may cause neurotoxicity, neuroinflammation, and neurodegeneration by penetrating the brain-olfactory route and blood-brain barrier (BBB). Indeed, due to their unique structures nanomaterials can easily cross biological barriers, thus avoid drug delivery problems. Despite the advancement of nanotechnology for designing therapeutic agents, toxicity of these nanomaterials is still a concern. Activation of neurons by astrocytic glutamate is a result of NPs-mediated astrocyte-neuron crosstalk. Increased extracellular glutamate levels due to enhanced synthesis and reduced reuptake may induce neuronal damage by abnormal activation of extrasynaptic N-methyl d-aspartate receptor (NMDAR) subunits. NMDAR is the key factor that mediates the disturbances in intracellular calcium homeostasis, mitochondrial dysfunction and generation of reactive oxygen species in NPs exposed neurons. While some NPs cause neuronal death by inducing NMDARs, others may be neurotoxic through the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors or protect the neurons via blocking NMDARs. However, mechanisms of dual effects of NPs, neurotoxicity or neuroprotection are not precisely known. Some NPs present neuroprotective effect either by selectively inhibiting extrasynaptic subunit of NMDARs or by attenuating oxidative stress. NPs-related proinflammatory activation of microglia contributes to the dysfunction and cytotoxicity in neurons. Therefore, investigation of the interaction of NPs with the neuronal signaling molecules and neuronal receptors is necessary for the better understanding of the neurotoxicity or neurosafety of nanomaterials.
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Affiliation(s)
- Ayse Basak Engin
- Department of Toxicology, Faculty of Pharmacy, Gazi University, Ankara, Turkey.
| | - Atilla Engin
- Department of General Surgery, Faculty of Medicine, Gazi University, Ankara, Turkey
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23
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Recio C, Guerra B, Guerra-Rodríguez M, Aranda-Tavío H, Martín-Rodríguez P, de Mirecki-Garrido M, Brito-Casillas Y, García-Castellano JM, Estévez-Braun A, Fernández-Pérez L. Signal transducer and activator of transcription (STAT)-5: an opportunity for drug development in oncohematology. Oncogene 2019; 38:4657-4668. [DOI: 10.1038/s41388-019-0752-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Revised: 01/09/2019] [Accepted: 02/03/2019] [Indexed: 02/08/2023]
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24
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IL-13 Contributes to Drug Resistance of NK/T-Cell Lymphoma Cells by Regulating ABCC4. BIOMED RESEARCH INTERNATIONAL 2018; 2018:2606834. [PMID: 30643796 PMCID: PMC6311311 DOI: 10.1155/2018/2606834] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Revised: 11/08/2018] [Accepted: 12/02/2018] [Indexed: 12/18/2022]
Abstract
Background Extranodal natural killer/T (NK/T) cell lymphoma, nasal type (ENKTL), represents a rare subtype of T-cell lymphomas with aggressive clinical behavior and is relatively resistant to chemotherapy. However, there is relatively poor understanding of molecular pathogenesis of multidrug resistance in ENKTL. Here, we aimed to explore the biological roles and potential mechanism of IL-13 and ABCC4 in multidrug resistance of NK/T-cell lymphoma. Methods ELISA analysis was used to determine the level of serum IL-13 and immunohistochemical analysis was applied to detect the ABCC4 expression level in patients with human NK/T-cell lymphoma. Western blot assay was employed to measure the expression of ABCC4 in cells. Lenti-sh-ABCC4 viruses were constructed to knock down ABCC4 in YTS cells. CCK-8 assay and flow cytometric analysis were performed to detect the effects of IL-13 and ABCC4 on cell proliferation and apoptosis. CCK-8 assay was conducted to detect the effect of IL-13 and ABCC4 on cell sensitivity to adriamycin (ADM) in YTS cells. Results Levels of serum IL-13 and ABCC4 expression were observed to be upregulated in patients with human NK/T-cell lymphoma. Moreover, ABCC4 protein expression was also increased in NK/T-cell lymphoma YTS cells compared to the normal NK cells. Interestingly, IL-13 promoted ABCC4 expression in YTS cells. IL-13 promoted proliferation and suppressed apoptosis of YTS cells and reversed the effects of ABCC4 knockdown on promotive proliferation and inhibitory apoptosis. In addition, IL-13 enhanced YTS cell chemotherapy resistance to ADM by promoting ABCC4 expression. Conclusion Our findings concluded that IL-13 inhibited chemotherapy sensitivity of NK/T-cell lymphoma cells by regulating ABCC4, disrupting which may effectively improve the therapy protocols against resistant NK/T-cell lymphoma.
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25
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Mergola L, Orabona C, Albini E, Vasapollo G, Scorrano S, Del Sole R. Urinary l
-kynurenine quantification and selective extraction through a molecularly imprinted solid-phase extraction device. J Sep Sci 2018; 41:3204-3212. [DOI: 10.1002/jssc.201800458] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 06/12/2018] [Accepted: 06/15/2018] [Indexed: 12/27/2022]
Affiliation(s)
- Lucia Mergola
- Department of Engineering for Innovation; University of Salento; Lecce Italy
| | - Ciriana Orabona
- Section of Pharmacology, Department of Experimental Medicine; University of Perugia; Perugia Italy
| | - Elisa Albini
- Section of Pharmacology, Department of Experimental Medicine; University of Perugia; Perugia Italy
| | - Giuseppe Vasapollo
- Department of Engineering for Innovation; University of Salento; Lecce Italy
| | - Sonia Scorrano
- Department of Engineering for Innovation; University of Salento; Lecce Italy
| | - Roberta Del Sole
- Department of Engineering for Innovation; University of Salento; Lecce Italy
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26
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Fraietta JA, Lacey SF, Orlando EJ, Pruteanu-Malinici I, Gohil M, Lundh S, Boesteanu AC, Wang Y, O'Connor RS, Hwang WT, Pequignot E, Ambrose DE, Zhang C, Wilcox N, Bedoya F, Dorfmeier C, Chen F, Tian L, Parakandi H, Gupta M, Young RM, Johnson FB, Kulikovskaya I, Liu L, Xu J, Kassim SH, Davis MM, Levine BL, Frey NV, Siegel DL, Huang AC, Wherry EJ, Bitter H, Brogdon JL, Porter DL, June CH, Melenhorst JJ. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med 2018; 24:563-571. [PMID: 29713085 DOI: 10.1038/s41591-018-0010-1] [Citation(s) in RCA: 1232] [Impact Index Per Article: 176.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2017] [Accepted: 02/07/2018] [Indexed: 01/12/2023]
Abstract
Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2. We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete-responding patients with CLL were enriched in memory-related genes, including IL-6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27+CD45RO-CD8+ T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3-related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL-6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27+PD-1-CD8+ CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies.
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Affiliation(s)
- Joseph A Fraietta
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA.,Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA
| | - Simon F Lacey
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA.,Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA
| | - Elena J Orlando
- Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | | | - Mercy Gohil
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Stefan Lundh
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Alina C Boesteanu
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Yan Wang
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Roddy S O'Connor
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Wei-Ting Hwang
- Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA, USA
| | - Edward Pequignot
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - David E Ambrose
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Changfeng Zhang
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Nicholas Wilcox
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Felipe Bedoya
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Corin Dorfmeier
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Fang Chen
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Lifeng Tian
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Harit Parakandi
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Minnal Gupta
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Regina M Young
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - F Brad Johnson
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Irina Kulikovskaya
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Li Liu
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Jun Xu
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Sadik H Kassim
- Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | - Megan M Davis
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Bruce L Levine
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA
| | - Noelle V Frey
- Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA.,Division of Hematology-Oncology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Donald L Siegel
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA.,Division of Transfusion Medicine and Therapeutic Pathology, University of Pennsylvania, Philadelphia, PA, USA
| | - Alexander C Huang
- Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA.,Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - E John Wherry
- Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA.,Department of Microbiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Hans Bitter
- Novartis Institutes for BioMedical Research, Cambridge, MA, USA
| | | | - David L Porter
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Division of Hematology-Oncology, Department of Internal Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Carl H June
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA.,Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA.,Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA
| | - J Joseph Melenhorst
- Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA. .,Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA, USA. .,Parker Institute for Cancer Immunotherapy at University of Pennsylvania, Philadelphia, PA, USA.
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27
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Kopecka J, Porto S, Lusa S, Gazzano E, Salzano G, Pinzòn-Daza ML, Giordano A, Desiderio V, Ghigo D, De Rosa G, Caraglia M, Riganti C. Zoledronic acid-encapsulating self-assembling nanoparticles and doxorubicin: a combinatorial approach to overcome simultaneously chemoresistance and immunoresistance in breast tumors. Oncotarget 2018; 7:20753-72. [PMID: 26980746 PMCID: PMC4991490 DOI: 10.18632/oncotarget.8012] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 02/16/2016] [Indexed: 02/07/2023] Open
Abstract
The resistance to chemotherapy and the tumor escape from host immunosurveillance are the main causes of the failure of anthracycline-based regimens in breast cancer, where an effective chemo-immunosensitizing strategy is lacking. The clinically used aminobisphosphonate zoledronic acid (ZA) reverses chemoresistance and immunoresistance in vitro. Previously we developed a nanoparticle-based zoledronic acid-containing formulation (NZ) that allowed a higher intratumor delivery of the drug compared with free ZA in vivo. We tested its efficacy in combination with doxorubicin in breast tumors refractory to chemotherapy and immune system recognition as a new combinatorial approach to produce chemo- and immunosensitization. NZ reduced the IC50 of doxorubicin in human and murine chemoresistant breast cancer cells and restored the doxorubicin efficacy against chemo-immunoresistant tumors implanted in immunocompetent mice. By reducing the metabolic flux through the mevalonate pathway, NZ lowered the activity of Ras/ERK1/2/HIF-1α axis and the expression of P-glycoprotein, decreased the glycolysis and the mitochondrial respiratory chain, induced a cytochrome c/caspase 9/caspase 3-dependent apoptosis, thus restoring the direct cytotoxic effects of doxorubicin on tumor cell. Moreover, NZ restored the doxorubicin-induced immunogenic cell death and reversed the tumor-induced immunosuppression due to the production of kynurenine, by inhibiting the STAT3/indoleamine 2,3 dioxygenase axis. These events increased the number of dendritic cells and decreased the number of immunosuppressive T-regulatory cells infiltrating the tumors. Our work proposes the use of nanoparticle encapsulating zoledronic acid as an effective tool overcoming at the same time chemoresistance and immunoresistance in breast tumors, thanks to the effects exerted on tumor cell and tumor-infiltrating immune cells.
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Affiliation(s)
- Joanna Kopecka
- Department of Oncology, University of Turin, Turin, Italy
| | - Stefania Porto
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Sara Lusa
- Department of Pharmacy, Federico II University of Naples, Naples, Italy
| | - Elena Gazzano
- Department of Oncology, University of Turin, Turin, Italy
| | - Giuseppina Salzano
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA
| | - Martha Leonor Pinzòn-Daza
- Department of Oncology, University of Turin, Turin, Italy.,Universidad del Rosario, Facultad de Ciencias Naturales y Matemáticas, RG in Biochemistry and Biotechnology (BIO-BIO), Bogotá, Colombia
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Vincenzo Desiderio
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
| | - Dario Ghigo
- Department of Oncology, University of Turin, Turin, Italy
| | - Giuseppe De Rosa
- Department of Pharmacy, Federico II University of Naples, Naples, Italy
| | - Michele Caraglia
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Chiara Riganti
- Department of Oncology, University of Turin, Turin, Italy
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28
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Gene expression profiling of normal thyroid tissue from patients with thyroid carcinoma. Oncotarget 2018; 7:29677-88. [PMID: 27105534 PMCID: PMC5045425 DOI: 10.18632/oncotarget.8820] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Accepted: 03/28/2016] [Indexed: 12/21/2022] Open
Abstract
Gene expression profiling (GEP) of normal thyroid tissue from 43 patients with thyroid carcinoma, 6 with thyroid adenoma, 42 with multinodular goiter, and 6 with Graves-Basedow disease was carried out with the aim of achieving a better understanding of the genetic mechanisms underlying the role of normal cells surrounding the tumor in the thyroid cancer progression. Unsupervised and supervised analyses were performed to compare samples from neoplastic and non-neoplastic diseases. GEP and subsequent RT-PCR analysis identified 28 differentially expressed genes. Functional assessment revealed that they are involved in tumorigenesis and cancer progression. The distinct GEP is likely to reflect the onset and/or progression of thyroid cancer, its molecular classification, and the identification of new potential prognostic factors, thus allowing to pinpoint selective gene targets with the aim of realizing more precise preoperative diagnostic procedures and novel therapeutic approaches.
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29
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Kopecka J, Porto S, Lusa S, Gazzano E, Salzano G, Giordano A, Desiderio V, Ghigo D, Caraglia M, De Rosa G, Riganti C. Self-assembling nanoparticles encapsulating zoledronic acid revert multidrug resistance in cancer cells. Oncotarget 2016; 6:31461-78. [PMID: 26372812 PMCID: PMC4741618 DOI: 10.18632/oncotarget.5058] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2015] [Accepted: 08/27/2015] [Indexed: 01/23/2023] Open
Abstract
The overexpression of ATP binding cassette (ABC) transporters makes tumor cells simultaneously resistant to several cytotoxic drugs. Impairing the energy metabolism of multidrug resistant (MDR) cells is a promising chemosensitizing strategy, but many metabolic modifiers are too toxic in vivo. We previously observed that the aminobisphosphonate zoledronic acid inhibits the activity of hypoxia inducible factor-1α (HIF-1α), a master regulator of cancer cell metabolism. Free zoledronic acid, however, reaches low intratumor concentration. We synthesized nanoparticle formulations of the aminobisphosphonate that allow a higher intratumor delivery of the drug. We investigated whether they are effective metabolic modifiers and chemosensitizing agents against human MDR cancer cells in vitro and in vivo. At not toxic dosage, nanoparticles carrying zoledronic acid chemosensitized MDR cells to a broad spectrum of cytotoxic drugs, independently of the type of ABC transporters expressed. The nanoparticles inhibited the isoprenoid synthesis and the Ras/ERK1/2-driven activation of HIF-1α, decreased the transcription and activity of glycolytic enzymes, the glucose flux through the glycolysis and tricarboxylic acid cycle, the electron flux through the mitochondrial respiratory chain, the synthesis of ATP. So doing, they lowered the ATP-dependent activity of ABC transporters, increasing the chemotherapy efficacy in vitro and in vivo. These effects were more pronounced in MDR cells than in chemosensitive ones and were due to the inhibition of farnesyl pyrophosphate synthase (FPPS), as demonstrated in FPPS-silenced tumors. Our work proposes nanoparticle formulations of zoledronic acid as the first not toxic metabolic modifiers, effective against MDR tumors.
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Affiliation(s)
- Joanna Kopecka
- Department of Oncology, University of Torino, Torino, Italy
| | - Stefania Porto
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy
| | - Sara Lusa
- Department of Pharmacy, Federico II University of Naples, Naples, Italy
| | - Elena Gazzano
- Department of Oncology, University of Torino, Torino, Italy
| | - Giuseppina Salzano
- Center for Pharmaceutical Biotechnology and Nanomedicine, Northeastern University, Boston, MA, USA
| | - Antonio Giordano
- Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA.,Department of Medicine, Surgery and Neuroscience University of Siena, Siena, Italy
| | - Vincenzo Desiderio
- Department of Experimental Medicine, Second University of Naples, Naples, Italy
| | - Dario Ghigo
- Department of Oncology, University of Torino, Torino, Italy
| | - Michele Caraglia
- Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Naples, Italy.,Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA, USA
| | - Giuseppe De Rosa
- Department of Pharmacy, Federico II University of Naples, Naples, Italy
| | - Chiara Riganti
- Department of Oncology, University of Torino, Torino, Italy
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30
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Unique proteome signature of post-chemotherapy ovarian cancer ascites-derived tumor cells. Sci Rep 2016; 6:30061. [PMID: 27470985 PMCID: PMC4965858 DOI: 10.1038/srep30061] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2016] [Accepted: 06/27/2016] [Indexed: 12/25/2022] Open
Abstract
Eighty % of ovarian cancer patients diagnosed at an advanced-stage have complete remission after initial surgery and chemotherapy. However, most patients die within <5 years due to episodes of recurrences resulting from the growth of residual chemoresistant cells. In an effort to identify mechanisms associated with chemoresistance and recurrence, we compared the expression of proteins in ascites-derived tumor cells isolated from advanced-stage ovarian cancer patients obtained at diagnosis (chemonaive, CN) and after chemotherapy treatments (chemoresistant/at recurrence, CR) by using in-depth, high-resolution label-free quantitative proteomic profiling. A total of 2,999 proteins were identified. Using a stringent selection criterion to define only significantly differentially expressed proteins, we report identification of 353 proteins. There were significant differences in proteins encoding for immune surveillance, DNA repair mechanisms, cytoskeleton rearrangement, cell-cell adhesion, cell cycle pathways, cellular transport, and proteins involved with glycine/proline/arginine synthesis in tumor cells isolated from CR relative to CN patients. Pathway analyses revealed enrichment of metabolic pathways, DNA repair mechanisms and energy metabolism pathways in CR tumor cells. In conclusion, this is the first proteomics study to comprehensively analyze ascites-derived tumor cells from CN and CR ovarian cancer patients.
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31
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Cacalano NA. Regulation of Natural Killer Cell Function by STAT3. Front Immunol 2016; 7:128. [PMID: 27148255 PMCID: PMC4827001 DOI: 10.3389/fimmu.2016.00128] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2015] [Accepted: 03/21/2016] [Indexed: 01/05/2023] Open
Abstract
Natural killer (NK) cells, key members of a distinct hematopoietic lineage, innate lymphoid cells, are not only critical effectors that mediate cytotoxicity toward tumor and virally infected cells but also regulate inflammation, antigen presentation, and the adaptive immune response. It has been shown that NK cells can regulate the development and activation of many other components of the immune response, such as dendritic cells, which in turn, modulate the function of NK cells in multiple synergistic feed back loops driven by cell–cell contact, and the secretion of cytokines and chemokines that control effector function and migration of cells to sites of immune activation. The signal transducer and activator of transcription (STAT)-3 is involved in driving almost all of the pathways that control NK cytolytic activity as well as the reciprocal regulatory interactions between NK cells and other components of the immune system. In the context of tumor immunology, NK cells are a first line of defense that eliminates pre-cancerous and transformed cells early in the process of carcinogenesis, through a mechanism of “immune surveillance.” Even after tumors become established, NK cells are critical components of anticancer immunity: dysfunctional NK cells are often found in the peripheral blood of cancer patients, and the lack of NK cells in the tumor microenvironment often correlates to poor prognosis. The pathways and soluble factors activated in tumor-associated NK cells, cancer cells, and regulatory myeloid cells, which determine the outcome of cancer immunity, are all critically regulated by STAT3. Using the tumor microenvironment as a paradigm, we present here an overview of the research that has revealed fundamental mechanisms through which STAT3 regulates all aspects of NK cell biology, including NK development, activation, target cell killing, and fine tuning of the innate and adaptive immune responses.
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Affiliation(s)
- Nicholas A Cacalano
- Department of Radiation Oncology, David Geffen School of Medicine at UCLA , Los Angeles, CA , USA
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