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Torres-Urtizberea E, Borrell JI, Puig de la Bellacasa R, Estrada-Tejedor R. Rational Method for Structural Simplification as Key Step in Hit Discovery: The Case of FGFR2 and IGF1R Dual Inhibitors. Int J Mol Sci 2025; 26:4457. [PMID: 40362694 PMCID: PMC12072306 DOI: 10.3390/ijms26094457] [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: 03/22/2025] [Revised: 05/01/2025] [Accepted: 05/06/2025] [Indexed: 05/15/2025] Open
Abstract
In the classic medicinal chemistry hit discovery procedure, large virtual libraries undergo different filtering and prediction steps until a small group of molecules is selected for their subsequent synthesis and biological testing. The starting molecular libraries can easily be composed of millions of molecules, hindering the selection of the most representative and promising compounds. Moreover, the resulting molecular systems tend to be overcomplex structures, hardly attainable, and often involve extrapolations of the prediction models used. We present a rational-based method to reduce the structural complexity of molecular candidates without compromising their biological activity, improving the attainability and efficiency of hit discovery. This approach has been successfully applied to identify potential tyrosine kinase dual inhibitors against Fibroblast Growth Factor Receptor 2 (FGFR2) and Insulin-Like Growth Factor 1 Receptor (IGF1R), a set of overexpressed proteins in different cancers, such as pancreatic ductal adenocarcinoma (PDAC).
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Affiliation(s)
| | | | | | - Roger Estrada-Tejedor
- Grup de Química Farmacèutica, IQS School of Engineering, Universitat Ramon Llull, Via Augusta 390, E-08017 Barcelona, Spain; (E.T.-U.); (J.I.B.); (R.P.d.l.B.)
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2
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Orlandi E, Guasconi M, Vecchia S, Trubini S, Giuffrida M, Proietto M, Anselmi E, Capelli P, Romboli A. Exploring the Horizon: Anti-Fibroblast Growth Factor Receptor Therapy in Pancreatic Cancer with Aberrant Fibroblast Growth Factor Receptor Expression-A Scoping Review. Cancers (Basel) 2024; 16:2912. [PMID: 39199681 PMCID: PMC11352631 DOI: 10.3390/cancers16162912] [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: 06/16/2024] [Revised: 08/13/2024] [Accepted: 08/20/2024] [Indexed: 09/01/2024] Open
Abstract
Pancreatic cancer is a highly lethal disease, often diagnosed at advanced stages, with a 5-year overall survival rate of around 10%. Current treatments have limited effectiveness, underscoring the need for new therapeutic options. This scoping review aims to identify and summarize preclinical and clinical studies on FGFR (Fibroblast Growth Factor Receptor) inhibitors, including tyrosine kinase inhibitors (TKIs) and FGFR-specific inhibitors, in pancreatic cancer with FGFR alterations. We included studies analyzing efficacy, safety, and survival outcomes in various populations. A comprehensive search across major databases identified 73 relevant studies: 32 preclinical, 16 clinical, and 25 from gray literature. The clinical trials focused primarily on efficacy (20 studies) and safety (14 studies), with fewer studies addressing survival outcomes. FGFR1 was the most studied alteration, followed by FGFR2 and FGFR4. Although FGFR alterations are relatively rare in pancreatic cancer, the available data, including promising real-life outcomes, suggest significant potential for FGFR inhibitors. However, more extensive research is needed to identify the correct genetic drivers and gather robust survival data. Ongoing and future trials are expected to provide more comprehensive insights, potentially leading to improved targeted therapies for pancreatic cancer patients with FGFR alterations.
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Affiliation(s)
- Elena Orlandi
- Department of Oncology-Hematology, Azienda USL of Piacenza, 29121 Piacenza, Italy; (S.T.); (M.P.); (E.A.)
| | - Massimo Guasconi
- Department of Medicine and Surgery, University of Parma, 43121 Parma, Italy;
- Department of Health Professions Management, Azienda USL of Piacenza, 29121 Piacenza, Italy
| | - Stefano Vecchia
- Department of Pharmacy, Azienda USL of Piacenza, 29121 Piacenza, Italy;
| | - Serena Trubini
- Department of Oncology-Hematology, Azienda USL of Piacenza, 29121 Piacenza, Italy; (S.T.); (M.P.); (E.A.)
| | - Mario Giuffrida
- Department of General Surgery, Azienda USL of Piacenza, 29121 Piacenza, Italy; (M.G.); (P.C.); (A.R.)
| | - Manuela Proietto
- Department of Oncology-Hematology, Azienda USL of Piacenza, 29121 Piacenza, Italy; (S.T.); (M.P.); (E.A.)
| | - Elisa Anselmi
- Department of Oncology-Hematology, Azienda USL of Piacenza, 29121 Piacenza, Italy; (S.T.); (M.P.); (E.A.)
| | - Patrizio Capelli
- Department of General Surgery, Azienda USL of Piacenza, 29121 Piacenza, Italy; (M.G.); (P.C.); (A.R.)
| | - Andrea Romboli
- Department of General Surgery, Azienda USL of Piacenza, 29121 Piacenza, Italy; (M.G.); (P.C.); (A.R.)
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3
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Githaka JM, Pirayeshfard L, Goping IS. Cancer invasion and metastasis: Insights from murine pubertal mammary gland morphogenesis. Biochim Biophys Acta Gen Subj 2023; 1867:130375. [PMID: 37150225 DOI: 10.1016/j.bbagen.2023.130375] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2022] [Revised: 04/20/2023] [Accepted: 05/02/2023] [Indexed: 05/09/2023]
Abstract
Cancer invasion and metastasis accounts for the majority of cancer related mortality. A better understanding of the players that drive the aberrant invasion and migration of tumors cells will provide critical targets to inhibit metastasis. Postnatal pubertal mammary gland morphogenesis is characterized by highly proliferative, invasive, and migratory normal epithelial cells. Identifying the molecular regulators of pubertal gland development is a promising strategy since tumorigenesis and metastasis is postulated to be a consequence of aberrant reactivation of developmental stages. In this review, we summarize the pubertal morphogenesis regulators that are involved in cancer metastasis and revisit pubertal mammary gland transcriptome profiling to uncover both known and unknown metastasis genes. Our updated list of pubertal morphogenesis regulators shows that most are implicated in invasion and metastasis. This review highlights molecular linkages between development and metastasis and provides a guide for exploring novel metastatic drivers.
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Affiliation(s)
- John Maringa Githaka
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
| | - Leila Pirayeshfard
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada
| | - Ing Swie Goping
- Department of Biochemistry, University of Alberta, Edmonton, AB T6G 2H7, Canada; Department of Oncology, University of Alberta, Edmonton, AB T6G 2H7, Canada.
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Wang Q, Zou B, Wei X, Lin H, Pang C, Wang L, Zhong J, Chen H, Gao X, Li M, Ong ACM, Yue Z, Sun L. Identification of renal cyst cells of type I Nephronophthisis by single-nucleus RNA sequencing. Front Cell Dev Biol 2023; 11:1192935. [PMID: 37583898 PMCID: PMC10423821 DOI: 10.3389/fcell.2023.1192935] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 07/20/2023] [Indexed: 08/17/2023] Open
Abstract
Background: Nephronophthisis (NPH) is the most common genetic cause of end-stage renal disease (ESRD) in childhood, and NPHP1 is the major pathogenic gene. Cyst formation at the corticomedullary junction is a pathological feature of NPH, but the mechanism underlying cystogenesis is not well understood. The isolation and identification of cystic cell subpopulation could help to identify their origins and provide vital clues to the mechanisms underlying cystogenesis in NPH. Methods: Single-nucleus RNA sequencing (snRNA-seq) was performed to produce an atlas of NPHP1 renal cells. Kidney samples were collected from WT (Nphp1 +/+) mice and NPHP1 (Nphp1 del2-20/del2-20) model mice. Results: A comprehensive atlas of the renal cellular landscape in NPHP1 was generated, consisting of 14 basic renal cell types as well as a subpopulation of DCT cells that was overrepresented in NPHP1 kidneys compared to WT kidneys. GO analysis revealed significant downregulation of genes associated with tubular development and kidney morphogenesis in this subpopulation. Furthermore, the reconstruction of differentiation trajectories of individual cells within this subpopulation confirmed that a specific group of cells in NPHP1 mice become arrested at an early stage of differentiation and proliferate to form cysts. We demonstrate that Niban1 is a specific molecular marker of cystic cells in both mice and human NPHP1. Conclusion: In summary, we report a novel subpopulation of DCT cells, marked by Niban1, that are classified as cystic cells in the NPHP1 mice kidney. These results offer fresh insights into the cellular and molecular basis of cystogenesis in NPH.
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Affiliation(s)
- Qianying Wang
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Baojuan Zou
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xiaoya Wei
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hongrong Lin
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Changmiao Pang
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Lei Wang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Jinglin Zhong
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Huamu Chen
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xuefei Gao
- Department of Physiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Min Li
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Albert C. M. Ong
- Kidney Genetics Group, Academic Nephrology Unit, Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom
| | - Zhihui Yue
- Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Liangzhong Sun
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
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Varna D, Geromichalou E, Karlioti G, Papi R, Dalezis P, Hatzidimitriou AG, Psomas G, Choli-Papadopoulou T, Trafalis DT, Angaridis PA. Inhibition of Cancer Cell Proliferation and Bacterial Growth by Silver(I) Complexes Bearing a CH 3-Substituted Thiadiazole-Based Thioamide. MOLECULES (BASEL, SWITZERLAND) 2023; 28:molecules28010336. [PMID: 36615533 PMCID: PMC9823356 DOI: 10.3390/molecules28010336] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/21/2022] [Accepted: 12/22/2022] [Indexed: 01/04/2023]
Abstract
Ag(I) coordination compounds have recently attracted much attention as antiproliferative and antibacterial agents against a wide range of cancer cell lines and pathogens. The bioactivity potential of these complexes depends on their structural characteristics and the nature of their ligands. Herein, we present a series of four Ag(I) coordination compounds bearing as ligands the CH3-substituted thiadiazole-based thioamide 5-methyl-1,3,4-thiadiazole-2-thiol (mtdztH) and phosphines, i.e., [AgCl(mtdztH)(PPh3)2] (1), [Ag(mtdzt)(PPh3)3] (2), [AgCl(mtdztH)(xantphos)] (3), and [AgmtdztH)(dppe)(NO3)]n (4), where xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene and dppe = 1,2-bis(diphenylphosphino)ethane, and the assessment of their in vitro antibacterial and anti-cancer efficiency. Among them, diphosphine-containing compounds 3 and 4 were found to exhibit broad-spectrum antibacterial activity characteristics against both Gram-(+) and Gram-(-) bacterial strains, showing high in vitro bioactivity with IC50 values as low as 4.6 μΜ. In vitro cytotoxicity studies against human ovarian, pancreatic, lung, and prostate cancer cell lines revealed the strong cytotoxic potential of 2 and 4, with IC50 values in the range of 3.1-24.0 μΜ, while 3 and 4 maintained the normal fibroblast cells' viability at relatively higher levels. Assessment of these results, in combination with those obtained for analogous Ag(I) complexes bearing similar heterocyclic thioamides, suggest the pivotal role of the substituent groups of the thioamide heterocyclic ring in the antibacterial and anti-cancer efficacy of the respective Ag(I) complexes. Compounds 1-4 exhibited moderate in vitro antioxidant capacity for free radicals scavenging, as well as reasonably strong ability to interact with calf-thymus DNA, suggesting the likely implication of these properties in their bioactivity mechanisms. Complementary insights into the possible mechanism of their anti-cancer activity were provided by molecular docking calculations, exploring their ability to bind to the overexpressed fibroblast growth factor receptor 1 (FGFR1), affecting cancer cells' functionalities.
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Affiliation(s)
- Despoina Varna
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Elena Geromichalou
- Laboratory of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Georgia Karlioti
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Rigini Papi
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Panagiotis Dalezis
- Laboratory of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
| | - Antonios G. Hatzidimitriou
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - George Psomas
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Theodora Choli-Papadopoulou
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
| | - Dimitrios T. Trafalis
- Laboratory of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece
- Correspondence: (D.T.T.); (P.A.A.)
| | - Panagiotis A. Angaridis
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece
- Correspondence: (D.T.T.); (P.A.A.)
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6
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FGF9 promotes cell proliferation and tumorigenesis in TM3 mouse Leydig progenitor cells. Am J Cancer Res 2022; 12:5613-5630. [PMID: 36628285 PMCID: PMC9827084] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 12/06/2022] [Indexed: 01/12/2023] Open
Abstract
Fibroblast growth factor 9 (FGF9) modulates cell proliferation, differentiation and motility for development and tissue repair in normal cells. Growing evidence shows that abnormal activation of FGF9 signaling is associated with tumor malignancy. We have previously reported that FGF9 increases MA-10 mouse Leydig tumor cell proliferation, in vitro, and tumor growth, in vivo. Also, FGF9 promotes the tumor growth and liver metastasis of mouse Lewis lung cancer cells, in vivo. However, the effects of FGF9 in the early stage of tumorigenesis remains elusive. In this study, TM3 mouse Leydig progenitor cells, that are not tumorigenic in immunocompromised mice, were used as a model cell line to investigate the role of FGF9 in tumorigenesis. The results demonstrated that FGF9 significantly induced cell proliferation and activated the MAPK, PI3K and PLCγ signaling pathways in TM3 cells. The percentage of the cell number in G1 phase was reduced and that in S and G2/M phases was increased after FGF9 stimulation in TM3 cells. Cyclin D1, cyclin A1, CDK2, CDK1, and p21 expressions and the phosphorylation level of Rb were all induced in FGF9-treated TM3 cells. In addition, FGF9 increased the expression of FGF receptor 1-4 in TM3 cells, suggesting the positive feedback loop between FGF9 and FGFRs. Furthermore, in the allograft mouse model, FGF9 promoted the tumorigenesis of TM3 cells characterized by higher expression of tumor markers, such as tumor necrosis factor alpha (TNFα) and α-fetoprotein (AFP), in the subcutaneously inoculated TM3 cell tissue. Conclusively, FGF9 induced cell cycle to increase cell proliferation of TM3 cells through FAK, MAPK, PI3K/Akt and PLCγ signaling pathways, in vitro, and promoted the tumorigenesis of TM3 cell allograft tissue, in vivo, which is a potential marker for tumor as well as a target for cancer therapeutic strategies.
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7
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Varna D, Geromichalou E, Hatzidimitriou AG, Papi R, Psomas G, Dalezis P, Aslanidis P, Choli-Papadopoulou T, Trafalis DT, Angaridis PA. Silver(I) complexes bearing heterocyclic thioamide ligands with NH 2 and CF 3 substituents: effect of ligand group substitution on antibacterial and anticancer properties. Dalton Trans 2022; 51:9412-9431. [PMID: 35674362 DOI: 10.1039/d2dt00793b] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
In recent years, there has been an increasing interest in the study of Ag(I) coordination compounds as potent antibacterial and anticancer agents. Herein, a series of Ag(I) complexes bearing phosphines and heterocyclic thioamide ligands with highly electronegative NH2- and CF3-group substituents, i.e. [AgCl(atdztH)(xantphos)] (1), [Ag(μ-atdztH)(DPEphos)]2(NO3)2 (2), [Ag(atdzt)(PPh3)3] (3), [Ag(μ-atdzt)(DPEphos)]2 (4), and [Ag(μ-mtft)(DPEphos)]2 (5), where atdztH = 5-amino-1,3,4-thiadiazole-2-thiol, mtftH = 4-methyl-5-(trifluoromethyl)-1,2,4-triazol-3-thiol, xantphos = 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, and DPEphos = bis(2-diphenylphosphino-phenyl)ether, were synthesized, and their in vitro antibacterial and anticancer properties were evaluated. Complexes 1-4 bearing the NH2-substituted thioamide exhibited moderate-to-high activity against S. aureus, B. subtilis, B. cereus and E. coli bacterial strains. A high antiproliferative activity was also observed for 1-3 against SKOV-3, Hup-T3, DMS114 and PC3 cancer cell lines (IC50 = 4.0-11.7 μM), as well as some degree of selectivity against MRC-5 normal cells. Interestingly, 5 bearing the CF3-substituted thioamide is completely inactive in all bioactivity studies. Binding of 1-3 to drug-carrier proteins BSA and HSA is reasonably strong for their uptake and subsequent release to possible target sites. The three complexes show a significant in vitro antioxidant ability for scavenging free radicals, suggesting likely implication of this property in the mechanism of their bioactivity, but a low potential to destroy the double-strand structure of CT-DNA by intercalation. Complementary insights into possible bioactivity mechanisms were provided by molecular docking calculations, exploring the ability of complexes to bind to bacterial DNA gyrase, and to the overexpressed in the aforementioned cancer cells Fibroblast Growth Factor Receptor 1, affecting their functionalities.
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Affiliation(s)
- Despoina Varna
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
| | - Elena Geromichalou
- Laboratory of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece.
| | - Antonios G Hatzidimitriou
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
| | - Rigini Papi
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - George Psomas
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
| | - Panagiotis Dalezis
- Laboratory of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece.
| | - Paraskevas Aslanidis
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
| | - Theodora Choli-Papadopoulou
- Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki 54124, Greece
| | - Dimitrios T Trafalis
- Laboratory of Pharmacology, Medical School, National and Kapodistrian University of Athens, 75 Mikras Asias Street, 11527 Athens, Greece.
| | - Panagiotis A Angaridis
- Laboratory of Inorganic Chemistry, Department of Chemistry, Aristotle University of Thessaloniki, 54124 Thessaloniki, Greece.
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Ceci C, Lacal PM, Graziani G. Antibody-drug conjugates: Resurgent anticancer agents with multi-targeted therapeutic potential. Pharmacol Ther 2022; 236:108106. [PMID: 34990642 DOI: 10.1016/j.pharmthera.2021.108106] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Revised: 12/23/2021] [Accepted: 12/29/2021] [Indexed: 12/18/2022]
Abstract
Antibody-drug conjugates (ADCs) constitute a relatively new group of anticancer agents, whose first appearance took place about two decades ago, but a renewed interest occurred in recent years, following the success of anti-cancer immunotherapy with monoclonal antibodies. Indeed, an ADC combines the selectivity of a monoclonal antibody with the cell killing properties of a chemotherapeutic agent (payload), joined together through an appropriate linker. The antibody moiety targets a specific cell surface antigen expressed by tumor cells and/or cells of the tumor microenvironment and acts as a carrier that delivers the cytotoxic payload within the tumor mass. Despite advantages in terms of selectivity and potency, the development of ADCs is not devoid of challenges, due to: i) low tumor selectivity when the target antigens are not exclusively expressed by cancer cells; ii) premature release of the cytotoxic drug into the bloodstream as a consequence of linker instability; iii) development of tumor resistance mechanisms to the payload. All these factors may result in lack of efficacy and/or in no safety improvement compared to unconjugated cytotoxic agents. Nevertheless, the development of antibodies engineered to remain inert until activated in the tumor (e.g., antibodies activated proteolytically after internalization or by the acidic conditions of the tumor microenvironment) together with the discovery of innovative targets and cytotoxic or immunomodulatory payloads, have allowed the design of next-generation ADCs that are expected to possess improved therapeutic properties. This review provides an overview of approved ADCs, with related advantages and limitations, and of novel targets exploited by ADCs that are presently under clinical investigation.
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Affiliation(s)
- Claudia Ceci
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
| | | | - Grazia Graziani
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy; IDI-IRCCS, Via Monti di Creta 104, 00167 Rome, Italy.
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9
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Dissecting FGF Signalling to Target Cellular Crosstalk in Pancreatic Cancer. Cells 2021; 10:cells10040847. [PMID: 33918004 PMCID: PMC8068358 DOI: 10.3390/cells10040847] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Revised: 03/25/2021] [Accepted: 04/04/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis with a 5 year survival rate of less than 8%, and is predicted to become the second leading cause of cancer-related death by 2030. Alongside late detection, which impacts upon surgical treatment, PDAC tumours are challenging to treat due to their desmoplastic stroma and hypovascular nature, which limits the effectiveness of chemotherapy and radiotherapy. Pancreatic stellate cells (PSCs), which form a key part of this stroma, become activated in response to tumour development, entering into cross-talk with cancer cells to induce tumour cell proliferation and invasion, leading to metastatic spread. We and others have shown that Fibroblast Growth Factor Receptor (FGFR) signalling can play a critical role in the interactions between PDAC cells and the tumour microenvironment, but it is clear that the FGFR signalling pathway is not acting in isolation. Here we describe our current understanding of the mechanisms by which FGFR signalling contributes to PDAC progression, focusing on its interaction with other pathways in signalling networks and discussing the therapeutic approaches that are being developed to try and improve prognosis for this terrible disease.
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10
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Yao J, Tang YC, Yi B, Yang J, Chai Y, Yin N, Zhang ZX, Wei YJ, Li DC, Zhou J. Signature of gene aberrant alternative splicing events in pancreatic adenocarcinoma prognosis. J Cancer 2021; 12:3164-3179. [PMID: 33976726 PMCID: PMC8100795 DOI: 10.7150/jca.48661] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2020] [Accepted: 03/15/2021] [Indexed: 12/17/2022] Open
Abstract
Alternative splicing (AS), as an effective and universal mechanism of transcriptional regulation, is involved in the development and progression of cancer. Therefore, systematic analysis of alternative splicing in pancreatic adenocarcinoma (PAAD) is warranted. The corresponding clinical information of the RNA-Seq data and PAAD cohort was downloaded from the TCGA data portal. Then, a java application, SpliceSeq, was used to evaluate the RNA splicing pattern and calculate the splicing percentage index (PSI). Differentially expressed AS events (DEAS) were identified based on PSI values between PAAD cancer samples and normal samples of adjacent tissues. Kaplan-Meier and Cox regression analyses were used to assess the association between DEAS and patient clinical characteristics. Unsupervised cluster analysis used to reveal four clusters with different survival patterns. At the same time, GEO and TCGA combined with GTEx to verify the differential expression of AS gene and splicing factor. After rigorous filtering, a total of 45,313 AS events were identified, 1,546 of which were differentially expressed AS events. Nineteen DEAS were found to be associated with OS with a five-year overall survival rate of 0.946. And the subtype clusters results indicate that there are differences in the nature of individual AS that affect clinical outcomes. Results also identified 15 splicing factors associated with the prognosis of PAAD. And the splicing factors ESRP1 and RBM5 played an important role in the PAAD-associated AS events. The PAAD-associated AS events, splicing networks, and clusters identified in this study are valuable for deciphering the underlying mechanisms of AS in PAAD and may facilitate the establishment of therapeutic goals for further validation.
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Affiliation(s)
- Jun Yao
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
| | - Yu-Chen Tang
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
| | - Bin Yi
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
| | - Jian Yang
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
| | - Yun Chai
- Department of Plastic Surgery, Suzhou Municipal Hospital, Suzhou, Jiangsu, 215006, China
| | - Ni Yin
- Department of Oncology, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
| | - Zi-Xiang Zhang
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
| | - Yi-Jun Wei
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
| | - De-Chun Li
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
| | - Jian Zhou
- Department of General Surgery, the First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
- Pancreatic Disease Research Centre, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China
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11
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Park T. Crk and CrkL as Therapeutic Targets for Cancer Treatment. Cells 2021; 10:cells10040739. [PMID: 33801580 PMCID: PMC8065463 DOI: 10.3390/cells10040739] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 03/20/2021] [Accepted: 03/24/2021] [Indexed: 02/03/2023] Open
Abstract
Crk and CrkL are cellular counterparts of the viral oncoprotein v-Crk. Crk and CrkL are overexpressed in many types of human cancer, correlating with poor prognosis. Furthermore, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions, including cell proliferation, transformation, migration, invasion, epithelial-mesenchymal transition, resistance to chemotherapy drugs, and in vivo tumor growth and metastasis. Conversely, overexpression of tumor cells with Crk or CrkL enhances tumor cell functions. Therefore, Crk and CrkL have been proposed as therapeutic targets for cancer treatment. However, it is unclear whether Crk and CrkL make distinct or overlapping contributions to tumor cell functions in various cancer types because Crk or CrkL have been examined independently in most studies. Two recent studies using colorectal cancer and glioblastoma cells clearly demonstrated that Crk and CrkL need to be ablated individually and combined to understand distinct and overlapping roles of the two proteins in cancer. A comprehensive understanding of individual and overlapping roles of Crk and CrkL in tumor cell functions is necessary to develop effective therapeutic strategies. This review systematically discusses crucial functions of Crk and CrkL in tumor cell functions and provides new perspectives on targeting Crk and CrkL in cancer therapy.
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Affiliation(s)
- Taeju Park
- Children's Mercy Research Institute, Children's Mercy Kansas City, Department of Pediatrics, University of Missouri Kansas City School of Medicine, Kansas City, MO 64108, USA
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12
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Quan MY, Guo Q, Liu J, Yang R, Bai J, Wang W, Cai Y, Han R, Lv YQ, Ding L, Billadeau DD, Lou Z, Bellusci S, Li X, Zhang JS. An FGFR/AKT/SOX2 Signaling Axis Controls Pancreatic Cancer Stemness. Front Cell Dev Biol 2020; 8:287. [PMID: 32457900 PMCID: PMC7221133 DOI: 10.3389/fcell.2020.00287] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Accepted: 04/02/2020] [Indexed: 12/20/2022] Open
Abstract
Cancer stemness is associated with high malignancy and low differentiation, as well as therapeutic resistance of tumors including pancreatic ductal adenocarcinoma (PDAC). Fibroblast growth factors (FGFs) exert pleiotropic effects on a variety of cellular processes and functions including embryonic stem cell pluripotency and cancer cell stemness via the activation of four tyrosine kinase FGF receptors (FGFRs). FGF ligands have been a major component of the cocktail of growth factors contained in the cancer stemness-inducing (CSI) and organoid culture medium. Although FGF/FGFR signaling has been hypothesized to maintain cancer stemness, its function in this process is still unclear. We report that inhibition of FGF/FGFR signaling impairs sphere-forming ability of PDAC in vitro, and knocking down FGFR1 and FGFR2 decreased their tumorigenesis abilities in vivo. Mechanistically, we demonstrated that SOX2 is down-regulated upon loss of FGFR signaling. The overexpression of SOX2 in SOX2-negative cells, which normally do not display stemness capabilities, is sufficient to induce spheroid formation. Additionally, we found that AKT phosphorylation was reduced upon FGFR signaling inhibition. The inhibition of AKT using specific pharmacological inhibitors in the context of CSI medium leads to the loss of spheroid formation associated with loss of SOX2 nuclear expression and increased degradation. We demonstrate that an FGFR/AKT/SOX2 axis controls cancer stemness in PDAC and therefore may represent an important therapeutic target in the fight against this very aggressive form of cancer.
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Affiliation(s)
- Mei-Yu Quan
- School of Pharmaceutical Sciences and International Collaborative Center on Growth Factor Research, Wenzhou Medical University, Wenzhou, China
| | - Qiang Guo
- School of Pharmaceutical Sciences and International Collaborative Center on Growth Factor Research, Wenzhou Medical University, Wenzhou, China
| | - Jiayu Liu
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Ruo Yang
- School of Pharmaceutical Sciences and International Collaborative Center on Growth Factor Research, Wenzhou Medical University, Wenzhou, China
| | - Jing Bai
- School of Pharmaceutical Sciences and International Collaborative Center on Growth Factor Research, Wenzhou Medical University, Wenzhou, China
| | - Wei Wang
- School of Pharmaceutical Sciences and International Collaborative Center on Growth Factor Research, Wenzhou Medical University, Wenzhou, China
| | - Yaxin Cai
- Institute of Life Sciences, Wenzhou University, Wenzhou, China
| | - Rui Han
- School of Pharmaceutical Sciences and International Collaborative Center on Growth Factor Research, Wenzhou Medical University, Wenzhou, China
| | - Yu-Qing Lv
- Center for Precision Medicine, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
| | - Li Ding
- Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Daniel D Billadeau
- Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Zhenkun Lou
- Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Saverio Bellusci
- Institute of Life Sciences, Wenzhou University, Wenzhou, China.,Cardio-Pulmonary Institute, Member of the German Lung Center, Justus Liebig University Giessen, Giessen, Germany
| | - Xiaokun Li
- School of Pharmaceutical Sciences and International Collaborative Center on Growth Factor Research, Wenzhou Medical University, Wenzhou, China
| | - Jin-San Zhang
- School of Pharmaceutical Sciences and International Collaborative Center on Growth Factor Research, Wenzhou Medical University, Wenzhou, China.,Division of Oncology Research and Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, MN, United States
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13
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First-in-Human Phase I Study of Aprutumab Ixadotin, a Fibroblast Growth Factor Receptor 2 Antibody-Drug Conjugate (BAY 1187982) in Patients with Advanced Cancer. Target Oncol 2020; 14:591-601. [PMID: 31502117 PMCID: PMC6797631 DOI: 10.1007/s11523-019-00670-4] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Background Fibroblast growth factor receptor (FGFR) 2 is overexpressed in several tumor types, including triple-negative breast cancer and gastric cancer, both of which have a high unmet medical need. Aprutumab ixadotin (BAY 1187982) is the first antibody–drug conjugate (ADC) to target FGFR2 and the first to use a novel auristatin-based payload. Objective This first-in-human trial was conducted to determine the safety, tolerability, and maximum tolerated dose (MTD) of aprutumab ixadotin in patients with advanced solid tumors from cancer indications known to be FGFR2-positive. Patients and Methods In this open-label, multicenter, phase I dose-escalation trial (NCT02368951), patients with advanced solid tumors received escalating doses of aprutumab ixadotin (starting at 0.1 mg/kg body weight), administered intravenously on day 1 of every 21-day cycle. Primary endpoints included safety, tolerability, and the MTD of aprutumab ixadotin; secondary endpoints were pharmacokinetic evaluation and tumor response to aprutumab ixadotin. Results Twenty patients received aprutumab ixadotin across five cohorts, at doses of 0.1–1.3 mg/kg. The most common grade ≥ 3 drug-related adverse events were anemia, aspartate aminotransferase increase, proteinuria, and thrombocytopenia. Dose-limiting toxicities were thrombocytopenia, proteinuria, and corneal epithelial microcysts, and were only seen in the two highest dosing cohorts. The MTD was determined to be 0.2 mg/kg due to lack of quantitative data following discontinuations at 0.4 and 0.8 mg/kg doses. One patient had stable disease; no responses were reported. Conclusions Aprutumab ixadotin was poorly tolerated, with an MTD found to be below the therapeutic threshold estimated preclinically; therefore, the trial was terminated early. ClinicalTrials.gov Identifier NCT02368951. Electronic supplementary material The online version of this article (10.1007/s11523-019-00670-4) contains supplementary material, which is available to authorized users.
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14
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Xu Q, Song A, Xie Q. The Integrated Analyses of Driver Genes Identify Key Biomarkers in Thyroid Cancer. Technol Cancer Res Treat 2020; 19:1533033820940440. [PMID: 32812852 PMCID: PMC7440732 DOI: 10.1177/1533033820940440] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 02/28/2020] [Accepted: 05/14/2020] [Indexed: 01/13/2023] Open
Abstract
AIM Thyroid cancer is the most common endocrine cancer, the incidence rate has continuously increased worldwide. However, there are still lack of effective molecular biomarkers for the diagnosis and treatment of the disease. The study was conducted to identify driver genes that may serve as potential biomarkers for the disease. METHODS The computational tools oncodriveCLUST, oncodriveFM, icages and drgap were used to detect driver genes in thyroid cancer using somatic mutations from The Cancer Genome Atlas database. Integrated analyses were performed on the driver genes using multiomics data from the TCGA database. RESULTS A set of 291 driver genes were identified in thyroid cancer. BRAF, NRAS, HRAS, OTUD4, EIF1AX were the top 5 frequently mutated genes in thyroid cancer. The weighted gene co-expression network analysis identified 4 coexpression modules. The modules 1-3 were significantly associated with patients' tumor size, residual tumor, cancer stage, distant metastasis and multifocality. SEC24B, MET and ITGAL were the hub genes in the modules 1-3 respectively. Hierarchical clustering analysis of the 20 driver genes with the most frequent copy number changes revealed 3 clusters of PRAD patients. Cluster 1 tumors exhibited significantly older age, tumor size, cancer stages, and poorer prognosis than cluster 2 and 3 tumors. 16 genes were significantly associated with number of lymph nodes, tumor size and pathologic stage, such as IL7 R, IRS1, PTK2B, MAP3K3 and FGFR2. CONCLUSIONS The set of cancer genes and subgroups of patients shed insight on the tumorigenesis of thyroid cancer and open up avenues for developing prognostic biomarkers and driver gene-targeted therapies in thyroid cancer.
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Affiliation(s)
- Qili Xu
- Department of General Surgery, Jiaozhou People’s Hospital, Jiaozhou, Shandong, China
| | - Aili Song
- Jiaozhou Emergency Center, Jiaozhou, Shandong, China
| | - Qigui Xie
- Department of Gynaecology and Obstetrics, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, China
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15
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Kang X, Lin Z, Xu M, Pan J, Wang ZW. Deciphering role of FGFR signalling pathway in pancreatic cancer. Cell Prolif 2019; 52:e12605. [PMID: 30945363 PMCID: PMC6536421 DOI: 10.1111/cpr.12605] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 02/25/2019] [Accepted: 02/26/2019] [Indexed: 12/24/2022] Open
Abstract
Recently, fibroblast growth factors are identified to play a vital role in the development and progression of human pancreatic cancer. FGF pathway is critical involved in numerous cellular processes through regulation of its downstream targets, including proliferation, apoptosis, migration, invasion, angiogenesis and metastasis. In this review article, we describe recent advances of FGFR signalling pathway in pancreatic carcinogenesis and progression. Moreover, we highlight the available chemical inhibitors of FGFR pathway for potential treatment of pancreatic cancer. Furthermore, we discuss whether targeting FGFR pathway is a novel therapeutic strategy for pancreatic cancer clinical management.
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Affiliation(s)
- Xiaodiao Kang
- Department of Orthopaedics Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zeng Lin
- Department of Orthopaedics Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Minhui Xu
- Department of Orthopaedics Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jun Pan
- Department of Orthopaedics Surgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Zhi-Wei Wang
- Center of Scientific Research, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.,Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
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16
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Xie ZB, Zhang YF, Jin C, Mao YS, Fu DL. LRG-1 promotes pancreatic cancer growth and metastasis via modulation of the EGFR/p38 signaling. J Exp Clin Cancer Res 2019; 38:75. [PMID: 30760292 PMCID: PMC6374912 DOI: 10.1186/s13046-019-1088-0] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2018] [Accepted: 02/06/2019] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND The abnormal expression of leucine-rich-alpha-2-glycoprotein 1 (LRG-1) is reported to be associated with multiple malignancies, but its role in the progression of pancreatic ductal adenocarcinoma (PDAC) remains to be determined. METHODS The expression of LRG-1 was assessed in PDAC tissues by RT-PCR, Western blot and immunohistochemistry. LRG-1-silenced or overexpressed cell lines were constructed using shRNA or LRG-1-overexpressing plasmids. EdU incorporation assay, Transwell invasion and wound-healing assays were performed to evaluate the proliferation, invasion and migration of PDAC cells. In addition, protein expression of the mitogen-activated protein kinase (MAPK) pathway was detected using Western blot. Finally, Co-immunoprecipitation assay was conducted in search of the potential interaction between LRG-1 and epidermal growth factor receptor (EGFR). RESULTS The expression of LRG-1 in PDAC tissue was significantly higher than that in adjacent normal tissue, and high LRG-1 expression predicted poor survival and a late tumor stage. In addition, LRG-1 markedly promoted the viability, proliferation, migration and invasion of PDAC cells in vitro and facilitated tumor growth in vivo. More importantly, we revealed that these bioactivities of LRG-1 might result from its selective interaction with EGFR, which might further activate the p38/MAPK signaling pathways. CONCLUSION LRG-1 may prove to be a promising biomarker for predicting prognosis of PDAC patients. Inhibition of LRG-1 or its downstream pathway could be a potential therapeutic target for the treatment of PDAC.
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Affiliation(s)
- Zhi-Bo Xie
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, 12 Central Urumqi Road, Shanghai, 200040 China
| | - Yi-Fan Zhang
- Department of Plastic & Reconstructive Surgery, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, 639 ZhizaojuRoad, Shanghai, 200011 China
| | - Chen Jin
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, 12 Central Urumqi Road, Shanghai, 200040 China
| | - Yi-Shen Mao
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, 12 Central Urumqi Road, Shanghai, 200040 China
| | - De-Liang Fu
- Department of Pancreatic Surgery, Huashan Hospital, Fudan University, 12 Central Urumqi Road, Shanghai, 200040 China
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17
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Li N, Zhao X, You S. Identification of key regulators of pancreatic ductal adenocarcinoma using bioinformatics analysis of microarray data. Medicine (Baltimore) 2019; 98:e14074. [PMID: 30633213 PMCID: PMC6336631 DOI: 10.1097/md.0000000000014074] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and its etiology remains largely unknown. This study aimed to screen a panel of key genes and to identify their potential impact on the molecular pathways associated with the development of PDAC. Four gene expression profiles, GSE28735, GSE15471, GSE102238, and GSE43795, were downloaded from the Gene Expression Omnibus (GEO) database. The intersection of the differentially expressed genes (DEGs) in each dataset was obtained using Venn analysis. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) analysis were subsequently carried out. To screen for hub genes, a protein-protein interaction (PPI) network was constructed.The intersection of the DEGs revealed 7 upregulated and 9 downregulated genes. Upon relaxation of the selection criteria, 58 upregulated and 32 downregulated DEGs were identified. The top 5 biological processes identified by GO analysis involved peptide cross-linking, extracellular matrix (ECM) disassembly, regulation of the fibroblast growth factor receptor signaling pathway, mesoderm morphogenesis, and lipid digestion. The results of KEGG analysis revealed that the DEGs were significantly enriched in pathways involved in protein digestion and absorption, ECM-receptor interaction, pancreatic secretion, and fat digestion and absorption. The top ten hub genes were identified based on the PPI network.In conclusion, the identified hub genes may contribute to the elucidation of the underlying molecular mechanisms of PDAC and serve as promising candidates that can be utilized for the early diagnosis and prognostic prediction of PDAC. However, further experimental validation is required to confirm these results.
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Affiliation(s)
- Nan Li
- Department of General Surgery, Tianjin Medical University General Hospital
| | - Xin Zhao
- Tianjin Medical University, Tianjin, China
| | - Shengyi You
- Department of General Surgery, Tianjin Medical University General Hospital
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18
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Chang MM, Lai MS, Hong SY, Pan BS, Huang H, Yang SH, Wu CC, Sun HS, Chuang JI, Wang CY, Huang BM. FGF9/FGFR2 increase cell proliferation by activating ERK1/2, Rb/E2F1, and cell cycle pathways in mouse Leydig tumor cells. Cancer Sci 2018; 109:3503-3518. [PMID: 30191630 PMCID: PMC6215879 DOI: 10.1111/cas.13793] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 08/27/2018] [Accepted: 08/30/2018] [Indexed: 12/19/2022] Open
Abstract
Fibroblast growth factor 9 (FGF9) promotes cancer progression; however, its role in cell proliferation related to tumorigenesis remains elusive. We investigated how FGF9 affected MA‐10 mouse Leydig tumor cell proliferation and found that FGF9 significantly induced cell proliferation by activating ERK1/2 and retinoblastoma (Rb) phosphorylations within 15 minutes. Subsequently, the expressions of E2F1 and the cell cycle regulators: cyclin D1, cyclin E1 and cyclin‐dependent kinase 4 (CDK4) in G1 phase and cyclin A1, CDK2 and CDK1 in S‐G2/M phases were increased at 12 hours after FGF9 treatment; and cyclin B1 in G2/M phases were induced at 24 hours after FGF9 stimulation, whereas the phosphorylations of p53, p21 and p27 were not affected by FGF9. Moreover, FGF9‐induced effects were inhibited by MEK inhibitor PD98059, indicating FGF9 activated the Rb/E2F pathway to accelerate MA‐10 cell proliferation by activating ERK1/2. Immunoprecipitation assay and ChIP‐quantitative PCR results showed that FGF9‐induced Rb phosphorylation led to the dissociation of Rb‐E2F1 complexes and thereby enhanced the transactivations of E2F1 target genes, Cyclin D1, Cyclin E1 and Cyclin A1. Silencing of FGF receptor 2 (FGFR2) using lentiviral shRNA inhibited FGF9‐induced ERK1/2 phosphorylation and cell proliferation, indicating that FGFR2 is the obligate receptor for FGF9 to bind and activate the signaling pathway in MA‐10 cells. Furthermore, in a severe combined immunodeficiency mouse xenograft model, FGF9 significantly promoted MA‐10 tumor growth, a consequence of increased cell proliferation and decreased apoptosis. Conclusively, FGF9 interacts with FGFR2 to activate ERK1/2, Rb/E2F1 and cell cycle pathways to induce MA‐10 cell proliferation in vitro and tumor growth in vivo.
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Affiliation(s)
- Ming-Min Chang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Meng-Shao Lai
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Siou-Ying Hong
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Bo-Syong Pan
- Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Hsin Huang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Shang-Hsun Yang
- Department of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Ching Wu
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - H Sunny Sun
- Department of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Institute of Molecular Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Jih-Ing Chuang
- Department of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Chia-Yih Wang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan
| | - Bu-Miin Huang
- Department of Cell Biology and Anatomy, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Basic Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.,Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
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19
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Tokunaga R, Imamura Y, Nakamura K, Ishimoto T, Nakagawa S, Miyake K, Nakaji Y, Tsuda Y, Iwatsuki M, Baba Y, Sakamoto Y, Miyamoto Y, Saeki H, Yoshida N, Oki E, Watanabe M, Oda Y, Bass AJ, Maehara Y, Baba H. Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma. Oncotarget 2017; 7:19748-61. [PMID: 26933914 PMCID: PMC4991416 DOI: 10.18632/oncotarget.7782] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 01/31/2016] [Indexed: 12/12/2022] Open
Abstract
Background Fibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer. We hypothesized that FGFR2 amplification is associated with FGFR2 expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma. Patients and Methods A total of 176 consecutive chemo-naive patients with EGJ adenocarcinoma were enrolled from two academic institutions. FGFR2 amplification was examined by real-time PCR (N = 140) and FGFR2 expression with immunohistochemical staining (N = 176), and compared against clinicopathological factors and patient outcomes. The effects of FGFR2 inhibition or overexpression on cell proliferation, cell cycle, and apoptosis assays were investigated in EGJ adenocarcinoma cell lines. Downstream FGFR2, AKT and ERK were also examined. Results Based on the correlation between FGFR2 levels and FGFR2 overexpression in vitro, FGFR2 amplification was defined as copy number > 3.0. In clinical samples, FGFR2 amplification and FGFR2 IHC expression were 15% and 61%, respectively. Although these two statuses were significantly correlated (P < 0.05), only FGFR2 IHC expression was significantly associated with tumor depth (multivariate P < 0.001) and overall survival of patients (univariate P = 0.007). Supporting these findings, FGFR2 overexpression was associated with tumor cell proliferation, cell cycle progression, and anti-apoptosis. Selective inhibition of FGFR2 sufficiently suppressed tumor cell proliferation through de-phosphorylation of AKT and ERK. Conclusions FGFR2 amplification was significantly associated with FGFR2 expression. FGFR2 expression (but not FGFR2 amplification) was associated with tumor growth and patient outcomes. Our findings support FGFR2 as a novel therapeutic target for EGJ adenocarcinoma.
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Affiliation(s)
- Ryuma Tokunaga
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yu Imamura
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.,Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Kenichi Nakamura
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Takatsugu Ishimoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Keisuke Miyake
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yu Nakaji
- Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.,Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yasuo Tsuda
- Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masaaki Iwatsuki
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yoshifumi Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yasuo Sakamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Yuji Miyamoto
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Hiroshi Saeki
- Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Naoya Yoshida
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Eiji Oki
- Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Masayuki Watanabe
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.,Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yoshinao Oda
- Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Adam J Bass
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.,Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Yoshihiko Maehara
- Department of Surgery and Sciences, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
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20
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Zhou J, He L, Pang Z, Appelman HD, Kuick R, Beer DG, Li M, Wang TD. Identification and validation of FGFR2 peptide for detection of early Barrett's neoplasia. Oncotarget 2017; 8:87095-87106. [PMID: 29152066 PMCID: PMC5675618 DOI: 10.18632/oncotarget.19764] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2017] [Accepted: 07/03/2017] [Indexed: 02/07/2023] Open
Abstract
The incidence of esophageal adenocarcinoma (EAC) is rising rapidly, and early detection within the precursor state of Barrett's esophagus (BE) is challenged by flat premalignant lesions that are difficult detect with conventional endoscopic surveillance. Overexpression of cell surface fibroblast growth factor receptor 2 (FGFR2) is an early event in progression of BE to EAC, and is a promising imaging target. We used phage display to identify the peptide SRRPASFRTARE that binds specifically to the extracellular domain of FGFR2. We labeled this peptide with a near-infrared fluorophore Cy5.5, and validated the specific binding to FGFR2 overexpressed in cells in vitro. We found high affinity kd = 68 nM and rapid binding k = 0.16 min-1 (6.2 min). In human esophageal specimens, we found significantly greater peptide binding to high-grade dysplasia (HGD) versus either BE or normal squamous epithelium, and good correlation with anti-FGFR2 antibody. We also observed significantly greater peptide binding to excised specimens of esophageal squamous cell carcinoma and gastric cancer compared to normal mucosa. These results demonstrate potential for this FGFR2 peptide to be used as a clinical imaging agent to guide tissue biopsy and improve methods for early detection of EAC and potentially other epithelial-derived cancers.
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Affiliation(s)
- Juan Zhou
- Department of Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Lei He
- Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China
| | - Zhijun Pang
- Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China
| | - Henry D Appelman
- Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Rork Kuick
- Department of Biostatistics, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - David G Beer
- Department of Surgery, Section of Thoracic Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Meng Li
- Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, Xi'an 710032, China
| | - Thomas D Wang
- Department of Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan 48109, USA.,Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA.,Department of Mechanical Engineering, University of Michigan, Ann Arbor, Michigan 48109, USA
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21
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Culturing and transcriptome profiling of progenitor-like colonies derived from adult mouse pancreas. Stem Cell Res Ther 2017; 8:172. [PMID: 28747214 PMCID: PMC5530554 DOI: 10.1186/s13287-017-0626-y] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2017] [Revised: 06/16/2017] [Accepted: 07/03/2017] [Indexed: 12/18/2022] Open
Abstract
Background Transplantation of insulin-producing cells is considered an important diabetes therapy. Many research studies have shown that insulin-producing cells can be derived from the in-vitro cultured pancreatic colonies with self-renewal ability and multilineage potential. Even though these progenitor-like colonies have been prepared from adult pancreas cells, the efficient culture method is hardly established and regulation of the colonies is rarely known. We confirmed previously that single cells acquired from adult mouse pancreas could form cyst-like colonies in a 3D semi-solid system containing Matrigel and methylcellulose. These colonies could be passaged continuously without losing progenitor-like capacity. In the previous culturing system, however, conditioned medium from murine embryonic-stem-cell-derived pancreatic-like cells was used. This unregulated ingredient may reduce repeatability and affect following study. Thus, a new culturing system with certain components needs to be developed. Methods Single cell suspension was acquired from adult mouse pancreas and cultured in a Matrigel-based 3D system with epidermal growth factor, Nicotinamide, B27, and Noggin to form ring colonies. Serial-passage assay was performed to evaluate self-renewal ability. Real-time polymerase chain reaction and immunostaining were used to detect the expression of progenitor-related genes. A 2D differentiation method was used to testify the multilineage potency of the colonies. High-throughput sequencing (HTS) of the colonies was performed to profile the differentially expressed genes. Results We developed a 3D culturing system deprived of conditioned medium to propagate those colonies with high proliferative efficiency. HTS of the transcriptome of mRNAs, microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) showed differentially expressed genes compared to the whole pancreas (as control). In mRNAs, several surface marker genes were identified in the colonies. Moreover in noncoding RNAs, miR-21a, miR-31 and miR-155 were upregulated and miR-217, miR-802 and miR-375 were downregulated in colonies along with a number of other miRNAs and lncRNAs. Conclusions Our results offer an efficient culture system for pancreatic progenitor-like colonies and HTS of the colonies serves as a target resource for following study of in-vitro cultured pancreatic progenitors. These findings should also contribute to our understanding of the transcriptional regulation of these progenitor-like colonies and the mechanisms behind their functions. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0626-y) contains supplementary material, which is available to authorized users.
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22
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Liu G, Xiong D, Xiao R, Huang Z. Prognostic role of fibroblast growth factor receptor 2 in human solid tumors: A systematic review and meta-analysis. Tumour Biol 2017; 39:1010428317707424. [PMID: 28618942 DOI: 10.1177/1010428317707424] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
In the past decades, the oncogenic role of fibroblast growth factor receptor 2 has been demonstrated in a number of cancer types. However, studies have reported contradictory findings concerning the correlation between fibroblast growth factor receptor 2 expression and prognosis in solid tumors. To address this discrepancy, we performed a meta-analysis with 18 published studies (2975 patients) retrieved from PubMed, EMBASE, and Web of science. Data were extracted and computed into odds ratios. The results showed that fibroblast growth factor receptor 2 overexpression was significantly associated with decreased 3-year overall survival (odds ratio = 1.93, 95% confidence interval: 1.30-2.85, p = 0.001) and 5-year overall survival (odds ratio = 1.62, 95% confidence interval: 1.07-2.44, p = 0.02) in patients with solid tumors. Subgroup analysis revealed that high fibroblast growth factor receptor 2 expression was also associated with poor prognosis of gastric cancer, hepatocellular carcinoma, and esophageal cancer, but not correlated with pancreatic cancer. In conclusion, fibroblast growth factor receptor 2 overexpression is correlated with decreased survival in most solid tumors, suggesting that the expression status of fibroblast growth factor receptor 2 is a valuable prognostic biomarker and a novel therapeutic target in human solid tumors.
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Affiliation(s)
- Gang Liu
- 1 Department of Gastrointestinal Surgery, Xiamen Cancer Hospital of the First Affiliated Hospital of Xiamen University, Xiamen, People's Republic of China
| | - Disheng Xiong
- 1 Department of Gastrointestinal Surgery, Xiamen Cancer Hospital of the First Affiliated Hospital of Xiamen University, Xiamen, People's Republic of China.,2 Department of Gastrointestinal Surgery, First Clinical Medical College of Fujian Medical University, Fuzhou, People's Republic of China
| | - Rui Xiao
- 1 Department of Gastrointestinal Surgery, Xiamen Cancer Hospital of the First Affiliated Hospital of Xiamen University, Xiamen, People's Republic of China.,2 Department of Gastrointestinal Surgery, First Clinical Medical College of Fujian Medical University, Fuzhou, People's Republic of China
| | - Zhengjie Huang
- 1 Department of Gastrointestinal Surgery, Xiamen Cancer Hospital of the First Affiliated Hospital of Xiamen University, Xiamen, People's Republic of China.,2 Department of Gastrointestinal Surgery, First Clinical Medical College of Fujian Medical University, Fuzhou, People's Republic of China
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23
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Gnatenko DA, Kopantsev EP, Sverdlov ED. The role of the signaling pathway FGF/FGFR in pancreatic cancer. BIOCHEMISTRY MOSCOW-SUPPLEMENT SERIES B-BIOMEDICAL CHEMISTRY 2017. [DOI: 10.1134/s1990750817020032] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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24
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Yang W, Wang XM, Yuan HY, Liu ZH, Gao S, Peng L. Exploring the mechanism of WWOX growth inhibitory effects on oral squamous cell carcinoma. Oncol Lett 2017; 13:3198-3204. [PMID: 28521426 DOI: 10.3892/ol.2017.5850] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2015] [Accepted: 01/17/2017] [Indexed: 12/14/2022] Open
Abstract
Oral squamous cell carcinoma (OSCC) is one of the most common types of head and neck neoplasms in the world. Patients diagnosed with OSCC exhibit a poor prognosis. WW domain-containing oxidoreductase (WWOX), as a candidate tumor-suppressor gene, is involved in the genesis and progression of tumors. The deletion of the WWOX gene has been identified in OSCC and oral leukoplakia, but the function and mechanism of WWOX in OSCC remain unknown. Therefore, the present study investigated the role of WWOX in oral squamous carcinoma cells. The results revealed that an elevation of WWOX expression had an inhibitory effect on the growth of three types of oral squamous carcinoma cells, with the most evident effect occurring in Tca8113 cells. Also, in the Tca8113 cells, WWOX overexpression significantly inhibited colony formation, and induced apoptosis and cell cycle arrest. Microarray analysis, reverse transcription-quantitative polymerase chain reaction and western blotting methods detected that WWOX overexpression contributed to the differential expression of the genes involved in mediating the extracellular-signal regulated protein kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway. These results suggest that the tumor-suppressor function of the WWOX gene may be associated with the modulation of the ERK/MAPK signaling pathway, thus providing a novel target for OSCC therapy.
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Affiliation(s)
- Wei Yang
- School of Laboratory Medicine, Beihua University, Jilin City, Jilin 132013, P.R. China
| | - Xiao-Ming Wang
- Department of Pathology, Jilin Province People's Hospital, Changchun, Jilin 132001, P.R. China
| | - Hong-Yan Yuan
- Department of Immunology, College of Basic Medical Science, Jilin University, Changchun, Jilin 132001, P.R. China
| | - Zhi-Hui Liu
- Department of Stomatology, Taizhou Municipal Hospital, Taizhou, Zhejiang 318000, P.R. China
| | - Shuang Gao
- School of Laboratory Medicine, Beihua University, Jilin City, Jilin 132013, P.R. China
| | - Liang Peng
- School of Laboratory Medicine, Beihua University, Jilin City, Jilin 132013, P.R. China
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25
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Luz FAC, Brígido PC, Moraes AS, Silva MJB. Aberrant Splicing in Cancer: Mediators of Malignant Progression through an Imperfect Splice Program Shift. Oncology 2016; 92:3-13. [PMID: 27794578 DOI: 10.1159/000450650] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Accepted: 08/30/2016] [Indexed: 01/07/2023]
Abstract
Although the efforts to understand the genetic basis of cancer allowed advances in diagnosis and therapy, little is known about other molecular bases. Splicing is a key event in gene expression, controlling the excision of introns decoded inside genes and being responsible for 80% of the proteome amplification through events of alternative splicing. Growing data from the last decade point to deregulation of splicing events as crucial in carcinogenesis and tumor progression. Several alterations in splicing events were observed in cancer, caused by either missexpression of or detrimental mutations in some splicing factors, and appear to be critical in carcinogenesis and key events during tumor progression. Notwithstanding, it is difficult to determine whether it is a cause or consequence of cancer and/or tumorigenesis. Most reviews focus on the generated isoforms of deregulated splicing pattern, while others mainly summarize deregulated splicing factors observed in cancer. In this review, events associated with carcinogenesis and tumor progression mainly, and epithelial-to-mesenchymal transition, which is also implicated in alternative splicing regulation, will be progressively discussed in the light of a new perspective, suggesting that splicing deregulation mediates cell reprogramming in tumor progression by an imperfect shift of the splice program.
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Affiliation(s)
- Felipe Andrés Cordero Luz
- Laboratório de Osteoimunologia e Imunologia dos Tumores, Instituto de Ciências Biomédicas (ICBIM), Universidade Federal de Uberlândia (UFU), Uberlândia, Brazil
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26
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Woodby B, Scott M, Bodily J. The Interaction Between Human Papillomaviruses and the Stromal Microenvironment. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2016; 144:169-238. [PMID: 27865458 PMCID: PMC5727914 DOI: 10.1016/bs.pmbts.2016.09.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Human papillomaviruses (HPVs) are small, double-stranded DNA viruses that replicate in stratified squamous epithelia and cause a variety of malignancies. Current efforts in HPV biology are focused on understanding the virus-host interactions that enable HPV to persist for years or decades in the tissue. The importance of interactions between tumor cells and the stromal microenvironment has become increasingly apparent in recent years, but how stromal interactions impact the normal, benign life cycle of HPVs, or progression of lesions to cancer is less understood. Furthermore, how productively replicating HPV impacts cells in the stromal environment is also unclear. Here we bring together some of the relevant literature on keratinocyte-stromal interactions and their impacts on HPV biology, focusing on stromal fibroblasts, immune cells, and endothelial cells. We discuss how HPV oncogenes in infected cells manipulate other cells in their environment, and, conversely, how neighboring cells may impact the efficiency or course of HPV infection.
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Affiliation(s)
- B Woodby
- Louisiana State University Health Sciences Center, Shreveport, LA, United States
| | - M Scott
- Louisiana State University Health Sciences Center, Shreveport, LA, United States
| | - J Bodily
- Louisiana State University Health Sciences Center, Shreveport, LA, United States.
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27
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Li J, Luo M, Wang Y, Shang B, Dong L. Celecoxib suppresses fibroblast growth factor-2 expression in pancreatic ductal adenocarcinoma PANC-1 cells. Oncol Rep 2016; 36:1345-52. [DOI: 10.3892/or.2016.4924] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2016] [Accepted: 03/16/2016] [Indexed: 11/05/2022] Open
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28
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Gnatenko D, Kopantsev E, Sverdlov E. Role of fibroblast growth factors in pancreatic cancer. ACTA ACUST UNITED AC 2016; 62:622-629. [DOI: 10.18097/pbmc20166206622] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Fibroblast growth factors belong to a family of growth factors that are involved in various processes in organism and have a wide range of biological functions. Specifically for pancreas, FGFs are important during both organogenesis and carcinogenesis. One of the main characteristic of pancreatic cancer, is it close interaction between cancer and stromal cells via different factors, including FGF. Pathological changes in FGF/FGFR signaling pathway is a complex process. The remodeling effects and stimulation of tumor growth are mostly depend not only on types of receptors, but also from their isoforms. FGF/FGFR signaling pathway is a perspective specific marker for cancer progression, and a potential drug target, which can be used for treatment of pancreatic cancer.
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Affiliation(s)
- D.A. Gnatenko
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - E.P. Kopantsev
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
| | - E.D. Sverdlov
- Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Moscow, Russia
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29
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AMMENDOLA MICHELE, SACCO ROSARIO, MARECH ILARIA, SAMMARCO GIUSEPPE, ZUCCALÀ VALERIA, LUPOSELLA MARIA, PATRUNO ROSA, GIORDANO MARCELLA, RUGGIERI EUSTACHIO, ZIZZO NICOLA, GADALETA COSMODAMIANO, RANIERI GIROLAMO. Microvascular density and endothelial area correlate with Ki-67 proliferative index in surgically-treated pancreatic ductal adenocarcinoma patients. Oncol Lett 2015; 10:967-971. [PMID: 26622606 PMCID: PMC4509049 DOI: 10.3892/ol.2015.3286] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Accepted: 04/09/2015] [Indexed: 12/14/2022] Open
Abstract
Previous experimental and clinical data have indicated that tumour cell proliferation is associated with angiogenesis; in addition, an increased microvascular density (MVD) of tumours has been associated with poor prognosis in solid and haematological malignancies. However, limited data exists regarding the association between tumour cell proliferation and angiogenesis in primary tumour tissue from pancreatic ductal adenocarcinoma (PDAC) patients; therefore, the present study aimed to investigate this association. A series of 31 PDAC patients with stage Tumour (T)2-3 Node (N)0-1 Metastasis (M)0 were recruited into the present study and subsequently underwent surgery. PDAC tissue and adjacent normal tissue (ANT), resected during surgery, were evaluated using immunohistochemistry and image analysis methods to determine MVD, endothelial area (EA) and Ki-67 expression, which is an indicator of cell proliferation rate. The results demonstrated a correlation between the above parameters with each other as well as the main clinico-pathological features of PDAC. Significant differences were identified in MVD, EA and Ki-67 proliferation index between PDAC and ANT. It was demonstrated that MVD, EA and Ki-67 proliferation index were significantly correlated with each other in tumour tissue (r=0.69-0.81; P=0.001-0.003). However, no other significant correlations were identified. These data therefore suggested that angiogenesis and cell proliferation rate were significantly increased in PDAC compared with ANT, which provides a biological basis for the potential use of novel combinations of angiogenesis inhibitors and anti-proliferative chemotherapeutic drugs in the treatment of PDAC.
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Affiliation(s)
- MICHELE AMMENDOLA
- Department of Medical and Surgery Science, Clinical Surgery Unit, University of Catanzaro ‘Magna Graecia’ Medical School, Catanzaro 88100, Italy
- Surgery Unit, National Cancer Research Centre, ‘Giovanni Paolo II’, Bari 70124, Italy
| | - ROSARIO SACCO
- Department of Medical and Surgery Science, Clinical Surgery Unit, University of Catanzaro ‘Magna Graecia’ Medical School, Catanzaro 88100, Italy
| | - ILARIA MARECH
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre, ‘Giovanni Paolo II’, Bari 70124, Italy
| | - GIUSEPPE SAMMARCO
- Department of Medical and Surgery Science, Clinical Surgery Unit, University of Catanzaro ‘Magna Graecia’ Medical School, Catanzaro 88100, Italy
| | - VALERIA ZUCCALÀ
- Department of Health Science, Pathology Unit, University of Catanzaro ‘Magna Graecia’ Medical School, Catanzaro 88100, Italy
| | - MARIA LUPOSELLA
- Department of Medical and Surgery Science, Cardiovascular Disease Unit, University of Catanzaro ‘Magna Graecia’ Medical School, Catanzaro 88100, Italy
| | - ROSA PATRUNO
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre, ‘Giovanni Paolo II’, Bari 70124, Italy
| | - MARCELLA GIORDANO
- Department of Medical and Surgery Science, Clinical Surgery Unit, University of Catanzaro ‘Magna Graecia’ Medical School, Catanzaro 88100, Italy
| | - EUSTACHIO RUGGIERI
- Surgery Unit, National Cancer Research Centre, ‘Giovanni Paolo II’, Bari 70124, Italy
| | - NICOLA ZIZZO
- Chair of Pathology, ‘Aldo Moro’ University of Bari, Bari 70010, Italy
| | - COSMO DAMIANO GADALETA
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre, ‘Giovanni Paolo II’, Bari 70124, Italy
| | - GIROLAMO RANIERI
- Diagnostic and Interventional Radiology Unit with Integrated Section of Translational Medical Oncology, National Cancer Research Centre, ‘Giovanni Paolo II’, Bari 70124, Italy
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30
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Rahmutulla B, Matsushita K, Nomura F. Alternative splicing of DNA damage response genes and gastrointestinal cancers. World J Gastroenterol 2014; 20:17305-17313. [PMID: 25516641 PMCID: PMC4265588 DOI: 10.3748/wjg.v20.i46.17305] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2014] [Revised: 07/18/2014] [Accepted: 09/16/2014] [Indexed: 02/06/2023] Open
Abstract
Alternative splicing, which is a common phenomenon in mammalian genomes, is a fundamental process of gene regulation and contributes to great protein diversity. Alternative splicing events not only occur in the normal gene regulation process but are also closely related to certain diseases including cancer. In this review, we briefly demonstrate the concept of alternative splicing and DNA damage and describe the association of alternative splicing and cancer pathogenesis, focusing on the potential relationship of alternative splicing, DNA damage, and gastrointestinal cancers. We will also discuss whether alternative splicing leads to genetic instability, which is considered to be a driving force for tumorigenesis. Better understanding of the role and mechanism of alternative splicing in tumorigenesis may provide new directions for future cancer studies.
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31
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Cheng C, Hu W, Liu LP, Li J. Fibroblast growth factor receptor 2: a new potential therapeutic target for human cancer. Hum Pathol 2014; 46:339-40. [PMID: 25466307 DOI: 10.1016/j.humpath.2014.10.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2014] [Accepted: 10/03/2014] [Indexed: 10/24/2022]
Affiliation(s)
- Chang Cheng
- Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Wei Hu
- Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Li-Ping Liu
- Department of Pharmacology, The Second Hospital of Anhui Medical University, Hefei 230601, China
| | - Jun Li
- School of Pharmacy, Anhui Medical University, Hefei 230032, China.
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