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Li Q, Zhou M, Yang Y, Jiang Y, Chen C, Hu E, Chen J, Wang D. Penta-1,4-dien-3-one and quinoxaline conjugates as potential anticancer agents via inhibiting EphB3/SRC/AKT axis. Life Sci 2025; 368:123510. [PMID: 40021052 DOI: 10.1016/j.lfs.2025.123510] [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: 10/10/2024] [Revised: 02/21/2025] [Accepted: 02/25/2025] [Indexed: 03/03/2025]
Abstract
Overexpression of EphB3 has been documented across various cancers and essential for cell proliferation, survive and metastasis, making it a valuable therapeutic target. In this study, a series of novel penta-1,4-dien-3-one and quinoxaline conjugates were designed and synthesized using pharmacophore fusion strategies to explore potential EphB3 inhibitors. CCK-8 experiments revealed significant anti-cancer activity of most newly synthesized compounds against hepatocellular carcinoma (HCC). Among them, compound W8 displaying the highest inhibitory activity against MHCC97H (IC50 = 1.87 μM), which arrests MHCC97H cells in the G0/G1 phase and induces apoptosis. Furthermore, compound W8 suppresses tumor growth in an MHCC97H xenograft model in vivo by suppressing phosphorylation level of EphB3 and down-regulating the SRC-AKT signaling pathway, leading to a dose-dependent reduction in tumor volumes and weights, with a 40 mg/kg dose achieving decreases of 68.4 % and 65.3 %, respectively. Given its ability to modulate EphB3 signaling, W8 represents a promising lead compound for further drug development, particularly for cancers characterized by EphB3 overexpression, and may offer new opportunities for targeted therapy in precision oncology.
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Affiliation(s)
- Qing Li
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 550014 Guiyang, PR China; Natural Products Research Center of Guizhou Province, 550014 Guiyang, PR China
| | - Mei Zhou
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 550014 Guiyang, PR China; Natural Products Research Center of Guizhou Province, 550014 Guiyang, PR China
| | - Ying Yang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 550014 Guiyang, PR China; Natural Products Research Center of Guizhou Province, 550014 Guiyang, PR China
| | - Yangming Jiang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 550014 Guiyang, PR China; Natural Products Research Center of Guizhou Province, 550014 Guiyang, PR China
| | - Chao Chen
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 550014 Guiyang, PR China; Natural Products Research Center of Guizhou Province, 550014 Guiyang, PR China
| | - Enming Hu
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 550014 Guiyang, PR China; Natural Products Research Center of Guizhou Province, 550014 Guiyang, PR China
| | - Jialin Chen
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 550014 Guiyang, PR China; Natural Products Research Center of Guizhou Province, 550014 Guiyang, PR China
| | - Daoping Wang
- State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 550014 Guiyang, PR China; Natural Products Research Center of Guizhou Province, 550014 Guiyang, PR China.
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Wang G, Xu G, Fan Y, Wang G, Xu J, Zhang N, Chen J, Chen H, Li Z, Cao X, Zhao Y. EPHA5 promotes cell proliferation and inhibits apoptosis in Follicular Thyroid Cancer via the STAT3 signaling pathway. Oncogenesis 2025; 14:12. [PMID: 40263257 PMCID: PMC12015243 DOI: 10.1038/s41389-025-00556-3] [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: 05/28/2024] [Revised: 03/14/2025] [Accepted: 04/04/2025] [Indexed: 04/24/2025] Open
Abstract
Follicular thyroid carcinoma (FTC) is a common endocrine malignancy characterized by a higher propensity for invasion and metastasis compared to papillary thyroid carcinoma (PTC). Ephrin type A receptor 5 (EPHA5) is a crucial receptor tyrosine kinase involved in orchestrating diverse physiological processes, including apoptosis and proliferation. However, the mechanism of EPHA5 in FTC remains unclear. This study identified significant overexpression of EPHA5 in FTC. In vitro experiments showed that increased expression of EPHA5 promotes proliferation and inhibits apoptosis in FTC. Furthermore, EPHA5 activates the STAT3 signaling pathway. To explore the interaction between EPHA5 and the STAT3 signaling pathway, we used SH-4-54 (a STAT3-specific inhibitor). Interestingly, the influence of EPHA5 on proliferation and apoptosis was reduced upon combination with SH-4-54. In summary, this study unveils the involvement of the EPHA5-STAT3 signaling pathway in FTC and implies that the function of EPHA5 in FTC may partly depend on the STAT3 signaling pathway.
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Affiliation(s)
- Guorong Wang
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Gaoran Xu
- Department of Thyroid and Breast Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yanan Fan
- Department of Thyroid and Breast Surgery, The Central Hospital of Ezhou, Ezhou, China
| | - Guangzhi Wang
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
| | - Jingchao Xu
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Ning Zhang
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Junzhu Chen
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Huanjie Chen
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Zhoufan Li
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Xianwang Cao
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China
| | - Yongfu Zhao
- Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, 116023, China.
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Velasco-Sampedro EA, Sánchez-Vicente C, Caloca MJ. β2-Chimaerin Deficiency Favors Polyp Growth in the Colon of Apc Min/+ Mice. Molecules 2025; 30:824. [PMID: 40005135 PMCID: PMC11858732 DOI: 10.3390/molecules30040824] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2024] [Revised: 02/05/2025] [Accepted: 02/07/2025] [Indexed: 02/27/2025] Open
Abstract
A Rho-GTPases are pivotal regulators of key cellular processes implicated in colorectal cancer (CRC) progression, yet the roles of their regulatory proteins, particularly GTPase-activating proteins (GAPs), remain poorly understood. This study focuses on β2-chimaerin, a Rac1-specific GAP, in Apc-driven tumorigenesis using the ApcMin/+ mouse model. We demonstrate that β2-chimaerin deficiency selectively promotes the growth of colonic polyps without influencing small intestinal polyp formation. Mechanistically, β2-chimaerin loss is associated with enhanced ERK phosphorylation, while canonical Wnt/β-catenin and E-cadherin pathways remain unaffected, suggesting its specific involvement in modulating proliferative signaling in the colon. Consistent with its tumor-suppressive role, bioinformatics analyses reveal that low β2-chimaerin expression correlates with poor prognosis in CRC patients. This study expands the understanding of Rho-GTPase regulatory mechanisms in intestinal tumorigenesis, providing a basis for future therapeutic strategies targeting Rho-GTPase pathways in CRC.
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Affiliation(s)
| | | | - María J. Caloca
- Instituto de Biomedicina y Genética Molecular (IBGM), CSIC-UVA, 47003 Valladolid, Spain (C.S.-V.)
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Liu M, Charek JG, Vicetti Miguel RD, Cherpes TL. Ephrin-Eph signaling: an important regulator of epithelial integrity and barrier function. Tissue Barriers 2025:2462855. [PMID: 39921660 DOI: 10.1080/21688370.2025.2462855] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2024] [Revised: 01/20/2025] [Accepted: 01/29/2025] [Indexed: 02/10/2025] Open
Abstract
Eph receptor-interacting proteins (ephrin) ligands and their erythropoietin-producing human hepatocellular (Eph) receptors elicit bidirectional signals that regulate cell migration, angiogenesis, neuronal plasticity, and other developmental processes in the embryo. In adulthood, ephrin-Eph signaling regulates numerous homeostatic events, including epithelial cell proliferation and differentiation. Epithelial surfaces, including those of skin and vagina, are lined by layers of stratified squamous epithelium (SSE) that protect against mechanical stress and microbial pathogen invasion. Ephrin-Eph signaling is known to promote cutaneous epithelial barrier function by regulating the expression of specialized cell-cell adhesion junctions termed desmosomes, but the role of this signaling system in maintaining epithelial integrity and barrier function in the vagina is less explored. This review summarizes current understanding of ephrin-Eph signaling that regulates desmosome expression and barrier function in the skin and considers evidence that suggests ephrin-Eph signaling similarly regulates these processes in vaginal SSE.
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Affiliation(s)
- Mohan Liu
- Comparative Biomedical Sciences Graduate Program, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA
- Department of Otolaryngology - Head and Neck Surgery, The Ohio State University, Columbus, OH, USA
| | - Joseph G Charek
- Department of Otolaryngology - Head and Neck Surgery, The Ohio State University, Columbus, OH, USA
| | - Rodolfo D Vicetti Miguel
- Department of Otolaryngology - Head and Neck Surgery, The Ohio State University, Columbus, OH, USA
| | - Thomas L Cherpes
- Department of Otolaryngology - Head and Neck Surgery, The Ohio State University, Columbus, OH, USA
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5
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Gofur MR, Ogawa K. EphB2, EphB4, and ephrin-B1 expression and localization in postnatal developing epididymis in mice. Dev Dyn 2024. [PMID: 39390685 DOI: 10.1002/dvdy.752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Revised: 08/29/2024] [Accepted: 09/02/2024] [Indexed: 10/12/2024] Open
Abstract
BACKGROUND Eph receptors and ephrin ligands, the transmembrane proteins, function as a mechanism of communication between cells. Therefore, we intended to explore the expression array of EphB2 and EphB4 receptors and ephrin-B1 ligand in postnatal developing mouse epididymis during 1 day to 8 weeks using RT-PCR amplification and immunofluorescence staining. RESULTS RT-PCR analysis indicated that the expression levels of EphB2, EphB4, and ephrin-B1 in the epididymis declined with the advancement of age during the initial phases of postnatal development and stayed relatively near to adult levels until 4 weeks. We discovered that the predominant compartments expressing EphB2/B4 and ephrin-B1 emerged in the excurrent duct epithelia of postnatal developing epididymis until 3 weeks. Consequently, even before spermatozoa reach the excurrent duct in epididymis, at the age of 3 weeks, the epididymal excurrent duct system exhibits characteristics similar to those of an adult in terms of expression of EphB2/B4 and ephrin-B1. Moreover, ephrin-B1 was expressed in epididymal epithelial cells throughout the development and EphB4 was expressed only in early postnatal stages while basal cells expressed EphB4 throughout the postnatal development. CONCLUSION The study represents the first expression analysis of ephrin-B1, EphB2, and EphB4 in the normal mouse epididymis during the postnatal development.
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Affiliation(s)
- Md Royhan Gofur
- Department of Veterinary and Animal Sciences, University of Rajshahi, Rajshahi, Bangladesh
| | - Kazushige Ogawa
- Laboratory of Veterinary Anatomy, Graduate School of Veterinary Science, Osaka Metropolitan University, Izumisano, Osaka, Japan
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6
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Nishida M, Sato A, Shimizu A, Rahman N, Wada A, Kageyama S, Ogita H. EphA-Mediated Regulation of Stomatin Expression in Prostate Cancer Cells. Cancer Med 2024; 13:e70276. [PMID: 39377541 PMCID: PMC11459579 DOI: 10.1002/cam4.70276] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 09/13/2024] [Accepted: 09/20/2024] [Indexed: 10/09/2024] Open
Abstract
BACKGROUND AND AIMS Tumor growth and progression are affected by interactions between tumor cells and stromal cells within the tumor microenvironment. We previously showed that the expression of an integral membrane protein, called stomatin, was increased in cancer cells following their association with stromal cells. Additionally, stomatin impaired the Akt signaling pathway to suppress tumor growth. However, it remains unclear how stomatin expression is regulated. To explore this, we examined the cell surface molecules that can transduce the intercellular communication signals between cancer cells and stromal cells. RESULTS Among these molecules, EphA3 and EphA7 receptors and their ligand ephrin-A5 were found to be expressed in prostate cancer cells, but not in prostate stromal cells. Cell-to-cell contact of prostate cancer cells through the EphA-ephrin-A interaction suppressed stomatin expression, while knockdown of EphA3/7 or ephrin-A5 increased stomatin expression. This increase contributed to an inhibition of prostate cancer cell proliferation. Intracellularly, the binding of ephrin-A to EphA attenuated extracellular signaling-regulated kinase (ERK) activation that promoted stomatin expression. Furthermore, ELK1 and ELK4, which are Ets family transcription factors phosphorylated by ERK, were involved in the induction of stomatin expression. We also found that higher Gleason score prostate cancer tissue samples had increased activation of EphA, while the stomatin expression and activated ERK and ELK levels were all low. In the mouse xenograft tumor samples generated by implantation of prostate cancer cells, EphA3 phosphorylation was attenuated and the ERK-ELK signaling and stomatin expression were enhanced in the area where stromal cells infiltrated the tumor. CONCLUSION The EphA-mediated signaling suppresses the ERK-ELK pathway, leading to the reduction of stomatin expression that affects prostate cancer malignancy.
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Affiliation(s)
- Masanari Nishida
- Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular BiologyShiga University of Medical ScienceOtsuJapan
- Department of UrologyShiga University of Medical ScienceOtsuJapan
| | - Akira Sato
- Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular BiologyShiga University of Medical ScienceOtsuJapan
| | - Akio Shimizu
- Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular BiologyShiga University of Medical ScienceOtsuJapan
| | - Nor Idayu A. Rahman
- Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular BiologyShiga University of Medical ScienceOtsuJapan
| | - Akinori Wada
- Department of UrologyShiga University of Medical ScienceOtsuJapan
| | - Susumu Kageyama
- Department of UrologyShiga University of Medical ScienceOtsuJapan
| | - Hisakazu Ogita
- Division of Molecular Medical Biochemistry, Department of Biochemistry and Molecular BiologyShiga University of Medical ScienceOtsuJapan
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7
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Liu D, van der Zalm AP, Koster J, Bootsma S, Oyarce C, van Laarhoven HWM, Bijlsma MF. Predictive biomarkers for response to TGF- β inhibition in resensitizing chemo(radiated) esophageal adenocarcinoma. Pharmacol Res 2024; 207:107315. [PMID: 39059615 DOI: 10.1016/j.phrs.2024.107315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 06/26/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024]
Abstract
Epithelial-mesenchymal transition (EMT) has been identified as a driver of therapy resistance, particularly in esophageal adenocarcinoma (EAC), where transforming growth factor beta (TGF-β) can induce this process. Inhibitors of TGF-β may counteract the occurrence of mesenchymal, resistant tumor cell populations following chemo(radio)therapy and improve treatment outcomes in EAC. Here, we aimed to identify predictive biomarkers for the response to TGF-β targeting. In vitro approximations of neoadjuvant treatment were applied to publicly available primary EAC cell lines. TGF-β inhibitors fresolimumab and A83-01 were employed to inhibit EMT, and mesenchymal markers were quantified via flow cytometry to assess efficacy. Our results demonstrated a robust induction of mesenchymal cell states following chemoradiation, with TGF-β inhibition leading to variable reductions in mesenchymal markers. The cell lines were clustered into responders and non-responders. Genomic expression profiles were obtained through RNA-seq analysis. Differentially expressed gene (DEG) analysis identified 10 positively- and 23 negatively-associated hub genes, which were bioinformatically identified. Furthermore, the correlation of DEGs with response to TGF-β inhibition was examined using public pharmacogenomic databases, revealing 9 positively associated and 11 negatively associated DEGs. Among these, ERBB2, EFNB1, and TNS4 were the most promising candidates. Our findings reveal a distinct gene expression pattern associated with the response to TGF-β inhibition in chemo(radiated) EAC. The identified DEGs and predictive markers may assist patient selection in clinical studies investigating TGF-β targeting.
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Affiliation(s)
- Dajia Liu
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Amber P van der Zalm
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Jan Koster
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands
| | - Sanne Bootsma
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Amsterdam UMC location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Cesar Oyarce
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands
| | - Hanneke W M van Laarhoven
- Amsterdam UMC location University of Amsterdam, Department of Medical Oncology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands
| | - Maarten F Bijlsma
- Amsterdam UMC Location University of Amsterdam, Center for Experimental and Molecular Medicine, Laboratory of Experimental Oncology and Radiobiology, Meibergdreef 9, Amsterdam 1105 AZ, the Netherlands; Cancer Center Amsterdam, Cancer Biology, Amsterdam, the Netherlands; Oncode Institute, Amsterdam, the Netherlands.
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Guo X, Yang Y, Tang J, Xiang J. Ephs in cancer progression: complexity and context-dependent nature in signaling, angiogenesis and immunity. Cell Commun Signal 2024; 22:299. [PMID: 38811954 PMCID: PMC11137953 DOI: 10.1186/s12964-024-01580-3] [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: 01/07/2024] [Accepted: 03/23/2024] [Indexed: 05/31/2024] Open
Abstract
Eph receptors constitute the largest family of receptor tyrosine kinases, comprising 14 distinct members classified into two subgroups: EphAs and EphBs.. Despite their essential functions in normal physiological processes, accumulating evidence suggests that the involvement of the Eph family in cancer is characterized by a dual and often contradictory nature. Research indicates that Eph/ephrin bidirectional signaling influences cell-cell communication, subsequently regulating cell migration, adhesion, differentiation and proliferation. The contradictory functionalities may arise from the diversity of Eph signaling pathways and the heterogeneity of different cancer microenvironment. In this review, we aim to discuss the dual role of the Eph receptors in tumor development, attempting to elucidate the paradoxical functionality through an exploration of Eph receptor signaling pathways, angiogenesis, immune responses, and more. Our objective is to provide a comprehensive understanding of the molecular mechanisms underlying tumor development. Additionally, we will explore the evolving landscape of utilizing Eph receptors as potential targets for tumor therapy and diagnostic tools.
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Affiliation(s)
- Xiaoting Guo
- Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, the Second Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China
- Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, China
- NHC Key Laboratory of Carcinogenesis and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Yanyi Yang
- Health Management Center, the Second Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Jingqun Tang
- Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, the Second Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
- Department of Thoracic Surgery, the Second Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
| | - Juanjuan Xiang
- Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, the Second Xiangya Hospital, Central South University, Changsha, 410013, Hunan, China.
- Cancer Research Institute, School of Basic Medical Science, Central South University, Changsha, Hunan, China.
- NHC Key Laboratory of Carcinogenesis and the Key Laboratory of Carcinogenesis and Cancer Invasion of the Chinese Ministry of Education, Xiangya Hospital, Central South University, Changsha, Hunan, China.
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Scarini JF, Gonçalves MWA, de Lima-Souza RA, Lavareze L, de Carvalho Kimura T, Yang CC, Altemani A, Mariano FV, Soares HP, Fillmore GC, Egal ESA. Potential role of the Eph/ephrin system in colorectal cancer: emerging druggable molecular targets. Front Oncol 2024; 14:1275330. [PMID: 38651144 PMCID: PMC11033724 DOI: 10.3389/fonc.2024.1275330] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 03/19/2024] [Indexed: 04/25/2024] Open
Abstract
The Eph/ephrin system regulates many developmental processes and adult tissue homeostasis. In colorectal cancer (CRC), it is involved in different processes including tumorigenesis, tumor angiogenesis, metastasis development, and cancer stem cell regeneration. However, conflicting data regarding Eph receptors in CRC, especially in its putative role as an oncogene or a suppressor gene, make the precise role of Eph-ephrin interaction confusing in CRC development. In this review, we provide an overview of the literature and highlight evidence that collaborates with these ambiguous roles of the Eph/ephrin system in CRC, as well as the molecular findings that represent promising therapeutic targets.
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Affiliation(s)
- João Figueira Scarini
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Moisés Willian Aparecido Gonçalves
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Reydson Alcides de Lima-Souza
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Luccas Lavareze
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Talita de Carvalho Kimura
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Department of Oral Diagnosis, Piracicaba Dental School, University of Campinas (UNICAMP), Piracicaba, São Paulo, Brazil
| | - Ching-Chu Yang
- Department of Pathology, School of Medicine, University of Utah (UU), Salt Lake City, UT, United States
| | - Albina Altemani
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Fernanda Viviane Mariano
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
| | - Heloisa Prado Soares
- Division of Oncology, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah (UU), Salt Lake City, UT, United States
| | - Gary Chris Fillmore
- Biorepository and Molecular Pathology, Huntsman Cancer Institute, University of Utah (UU), Salt Lake City, UT, United States
| | - Erika Said Abu Egal
- Department of Pathology, Faculty of Medical Sciences, University of Campinas (UNICAMP), Campinas, São Paulo, Brazil
- Biorepository and Molecular Pathology, Huntsman Cancer Institute, University of Utah (UU), Salt Lake City, UT, United States
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10
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Gao X, Zhang R, He Y, Wang X, Bao W, Feng X, Chai J, Wang J. EphB3 protein is a potential ancillary diagnostic biomarker for thyroid cancers. Ann Diagn Pathol 2024; 69:152262. [PMID: 38150866 DOI: 10.1016/j.anndiagpath.2023.152262] [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: 11/30/2023] [Revised: 12/21/2023] [Accepted: 12/21/2023] [Indexed: 12/29/2023]
Abstract
OBJECTIVE To investigate the expression of ephrin type B receptor 3 (EphB3) in thyroid tumors and its usage as an ancillary diagnostic biomarker for thyroid tumors. METHODS Formalin-fixed and paraffin-embedded (FFPE) tissue samples (78 cases) and FNAC samples (57 cases) were assessed with the EphB3 antibody using immunohistochemistry. PTC and other thyroid follicular tumors were compared regarding their EphB3 expression. Sanger sequencing was used to assess for the presence of a BRAF V600E mutation. RESULTS EphB3 was positive in 81.8 % (27/33) of papillary thyroid carcinoma (PTC), 83.3 % (5/6) of medullary thyroid carcinoma (MTC), 25 % (1/4) of hyperplastic/adenomatoid nodule (HN), 14.3 % (1/7) of follicular adenoma (FA), and negative in follicular tumors of uncertain malignant potential (FT-UMP) (0/13), noninvasive follicular neoplasm with papillary-like nuclear features (NIFTP) (0/7), thyroid follicular carcinoma (TFC) (0/4), Hashimoto's thyroiditis (0/4), and normal thyroid follicular tissues (0/33). In cellular blocks, EphB3 was positive in 87.1 % (20/23) of PTC, 75 % (3/4) of MTC, 20 % (2/10) of HN, and negative in atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) (0/20) and normal thyroid follicular cells (0/10). CONCLUSION EphB3 is expressed in the majority of PTC, but less so in benign follicular nodules. EphB3 expression in fine needle aspiration cytology (FNAC) specimens can be used as a diagnostic tool to differentiate thyroid cancer from other follicular lesions in its differential diagnosis, especially AUS/FLUS and PTC.
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Affiliation(s)
- Xinyue Gao
- Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China
| | - Rusong Zhang
- Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China
| | - Yan He
- Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China
| | - Xuan Wang
- Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China
| | - Wei Bao
- Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China
| | - Xiao Feng
- Department of Pathology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
| | - Jiaxin Chai
- Department of Pathology Eastern Theater Air Force Hospital, No. 1 Nanjing Ma Lu Jie, Nanjing 120002, China
| | - Jiandong Wang
- Department of Pathology, Jinling Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing 210002, China.
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11
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Ebrahim T, Ebrahim AS, Kandouz M. Diversity of Intercellular Communication Modes: A Cancer Biology Perspective. Cells 2024; 13:495. [PMID: 38534339 PMCID: PMC10969453 DOI: 10.3390/cells13060495] [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: 01/05/2024] [Revised: 02/27/2024] [Accepted: 03/10/2024] [Indexed: 03/28/2024] Open
Abstract
From the moment a cell is on the path to malignant transformation, its interaction with other cells from the microenvironment becomes altered. The flow of molecular information is at the heart of the cellular and systemic fate in tumors, and various processes participate in conveying key molecular information from or to certain cancer cells. For instance, the loss of tight junction molecules is part of the signal sent to cancer cells so that they are no longer bound to the primary tumors and are thus free to travel and metastasize. Upon the targeting of a single cell by a therapeutic drug, gap junctions are able to communicate death information to by-standing cells. The discovery of the importance of novel modes of cell-cell communication such as different types of extracellular vesicles or tunneling nanotubes is changing the way scientists look at these processes. However, are they all actively involved in different contexts at the same time or are they recruited to fulfill specific tasks? What does the multiplicity of modes mean for the overall progression of the disease? Here, we extend an open invitation to think about the overall significance of these questions, rather than engage in an elusive attempt at a systematic repertory of the mechanisms at play.
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Affiliation(s)
- Thanzeela Ebrahim
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48202, USA
| | - Abdul Shukkur Ebrahim
- Department of Ophthalmology, Visual and Anatomical Sciences, Wayne State University School of Medicine, Detroit, MI 48202, USA
| | - Mustapha Kandouz
- Department of Pathology, Wayne State University School of Medicine, Detroit, MI 48202, USA
- Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48202, USA
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12
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Kandouz M. Cell Death, by Any Other Name…. Cells 2024; 13:325. [PMID: 38391938 PMCID: PMC10886887 DOI: 10.3390/cells13040325] [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: 12/31/2023] [Revised: 02/04/2024] [Accepted: 02/06/2024] [Indexed: 02/24/2024] Open
Abstract
Studies trying to understand cell death, this ultimate biological process, can be traced back to a century ago. Yet, unlike many other fashionable research interests, research on cell death is more alive than ever. New modes of cell death are discovered in specific contexts, as are new molecular pathways. But what is "cell death", really? This question has not found a definitive answer yet. Nevertheless, part of the answer is irreversibility, whereby cells can no longer recover from stress or injury. Here, we identify the most distinctive features of different modes of cell death, focusing on the executive final stages. In addition to the final stages, these modes can differ in their triggering stimulus, thus referring to the initial stages. Within this framework, we use a few illustrative examples to examine how intercellular communication factors in the demise of cells. First, we discuss the interplay between cell-cell communication and cell death during a few steps in the early development of multicellular organisms. Next, we will discuss this interplay in a fully developed and functional tissue, the gut, which is among the most rapidly renewing tissues in the body and, therefore, makes extensive use of cell death. Furthermore, we will discuss how the balance between cell death and communication is modified during a pathological condition, i.e., colon tumorigenesis, and how it could shed light on resistance to cancer therapy. Finally, we briefly review data on the role of cell-cell communication modes in the propagation of cell death signals and how this has been considered as a potential therapeutic approach. Far from vainly trying to provide a comprehensive review, we launch an invitation to ponder over the significance of cell death diversity and how it provides multiple opportunities for the contribution of various modes of intercellular communication.
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Affiliation(s)
- Mustapha Kandouz
- Department of Pathology, School of Medicine, Wayne State University, 540 East Canfield Avenue, Detroit, MI 48201, USA;
- Karmanos Cancer Institute, Wayne State University, Detroit, MI 48201, USA
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13
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Abstract
Evidence implicating Eph receptor tyrosine kinases and their ephrin ligands (that together make up the 'Eph system') in cancer development and progression has been accumulating since the discovery of the first Eph receptor approximately 35 years ago. Advances in the past decade and a half have considerably increased the understanding of Eph receptor-ephrin signalling mechanisms in cancer and have uncovered intriguing new roles in cancer progression and drug resistance. This Review focuses mainly on these more recent developments. I provide an update on the different mechanisms of Eph receptor-ephrin-mediated cell-cell communication and cell autonomous signalling, as well as on the interplay of the Eph system with other signalling systems. I further discuss recent advances in elucidating how the Eph system controls tumour expansion, invasiveness and metastasis, supports cancer stem cells, and drives therapy resistance. In addition to functioning within cancer cells, the Eph system also mediates the reciprocal communication between cancer cells and cells of the tumour microenvironment. The involvement of the Eph system in tumour angiogenesis is well established, but recent findings also demonstrate roles in immune cells, cancer-associated fibroblasts and the extracellular matrix. Lastly, I discuss strategies under evaluation for therapeutic targeting of Eph receptors-ephrins in cancer and conclude with an outlook on promising future research directions.
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Affiliation(s)
- Elena B Pasquale
- Cancer Center, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA.
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14
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Guan LY, Lin SZ, Chen PC, Lv JQ, Li B, Feng XQ. Interfacial Organization and Forces Arising from Epithelial-Cancerous Monolayer Interactions. ACS NANO 2023; 17:24668-24684. [PMID: 38091551 DOI: 10.1021/acsnano.3c03990] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2023]
Abstract
The interfacial interactions between epithelia and cancer cells have profound relevance for tumor development and metastasis. Through monolayer confrontation of MCF10A (nontumorigenic human breast epithelial cells) and MDA-MB-231 (human epithelial breast cancer cells) cells, we investigate the epithelial-cancerous interfacial interactions at the tissue level. We show that the monolayer interaction leads to competitive interfacial morphodynamics and drives an intricate spatial organization of MCF10A cells into multicellular finger-like structures, which further branch into multiple subfinger-like structures. These hierarchical interfacial structures penetrate the cancer monolayer and can spontaneously segregate or even envelop cancer cell clusters, consistent with our theoretical prediction. By tracking the substrate displacements via embedded fluorescent nanobeads and implementing nanomechanical modeling that combines atomic force microscopy and finite element simulations, we computed mechanical force patterns, including traction forces and monolayer stresses, caused by the monolayer interaction. It is found that the heterogeneous mechanical forces accumulated in the monolayers are able to squeeze cancer cells, leading to three-dimensional interfacial bulges or cell extrusion, initiating the p53 apoptosis signaling pathways of cancer cells. We reveal that intercellular E-cadherin and P-cadherin of epithelial cells differentially regulate the interfacial organization including migration speed, directionality, spatial correlation, F-actin alignment, and subcellular protrusions of MCF10A cells; whereas E-cadherin governs interfacial geometry that is relevant to force localization and cancer cell extrusion, P-cadherin maintains interfacial integrity that enables long-range force transmission. Our findings suggest that the collaborative molecular and mechanical behaviors are crucial for preventing epithelial tissues from undergoing tumor invasion.
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Affiliation(s)
- Liu-Yuan Guan
- Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China
| | - Shao-Zhen Lin
- Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China
| | - Peng-Cheng Chen
- Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China
| | - Jian-Qing Lv
- Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China
| | - Bo Li
- Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China
| | - Xi-Qiao Feng
- Institute of Biomechanics and Medical Engineering, Applied Mechanics Laboratory, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, China
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15
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Kundu S, Nunes L, Adler J, Mathot L, Stoimenov I, Sjöblom T. Recurring EPHB1 mutations in human cancers alter receptor signalling and compartmentalisation of colorectal cancer cells. Cell Commun Signal 2023; 21:354. [PMID: 38102712 PMCID: PMC10722860 DOI: 10.1186/s12964-023-01378-9] [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: 08/25/2023] [Accepted: 11/01/2023] [Indexed: 12/17/2023] Open
Abstract
BACKGROUND Ephrin (EPH) receptors have been implicated in tumorigenesis and metastasis, but the functional understanding of mutations observed in human cancers is limited. We previously demonstrated reduced cell compartmentalisation for somatic EPHB1 mutations found in metastatic colorectal cancer cases. We therefore integrated pan-cancer and pan-EPH mutational data to prioritise recurrent EPHB1 mutations for functional studies to understand their contribution to cancer development and metastasis. METHODS Here, 79,151 somatic mutations in 9,898 samples of 33 different tumour types were analysed with a bioinformatic pipeline to find 3D-mutated cluster pairs and hotspot mutations in EPH receptors. From these, 15 recurring EPHB1 mutations were stably expressed in colorectal cancer followed by confocal microscopy based in vitro compartmentalisation assays and phospho-proteome analysis. RESULTS The 3D-protein structure-based bioinformatics analysis resulted in 63% EPHB1 mutants with compartmentalisation phenotypes vs 43% for hotspot mutations. Whereas the ligand-binding domain mutations C61Y, R90C, and R170W, the fibronectin domain mutation R351L, and the kinase domain mutation D762N displayed reduced to strongly compromised cell compartmentalisation, the kinase domain mutations R743W and G821R enhanced this phenotype. While mutants with reduced compartmentalisation also had reduced ligand induced receptor phosphorylation, the enhanced compartmentalisation was not linked to receptor phosphorylation level. Phosphoproteome mapping pinpointed the PI3K pathway and PIK3C2B phosphorylation in cells harbouring mutants with reduced compartmentalisation. CONCLUSIONS This is the first integrative study of pan-cancer EPH receptor mutations followed by in vitro validation, a robust way to identify cancer-causing mutations, uncovering EPHB1 mutation phenotypes and demonstrating the utility of protein structure-based mutation analysis in characterization of novel cancer genes. Video Abstract.
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Affiliation(s)
- Snehangshu Kundu
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Luís Nunes
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Jeremy Adler
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Lucy Mathot
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Ivaylo Stoimenov
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Tobias Sjöblom
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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16
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Kim Y, Ahmed S, Miller WT. Colorectal cancer-associated mutations impair EphB1 kinase function. J Biol Chem 2023; 299:105115. [PMID: 37527777 PMCID: PMC10463257 DOI: 10.1016/j.jbc.2023.105115] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 07/24/2023] [Accepted: 07/25/2023] [Indexed: 08/03/2023] Open
Abstract
Erythropoietin-producing hepatoma (Eph) receptor tyrosine kinases regulate the migration and adhesion of cells that are required for many developmental processes and adult tissue homeostasis. In the intestinal epithelium, Eph signaling controls the positioning of cell types along the crypt-villus axis. Eph activity can suppress the progression of colorectal cancer (CRC). The most frequently mutated Eph receptor in metastatic CRC is EphB1. However, the functional effects of EphB1 mutations are mostly unknown. We expressed and purified the kinase domains of WT and five cancer-associated mutant EphB1 and developed assays to assess the functional effects of the mutations. Using purified proteins, we determined that CRC-associated mutations reduce the activity and stability of the folded structure of EphB1. By mammalian cell expression, we determined that CRC-associated mutant EphB1 receptors inhibit signal transducer and activator of transcription 3 and extracellular signal-regulated kinases 1 and 2 signaling. In contrast to the WT, the mutant EphB1 receptors are unable to suppress the migration of human CRC cells. The CRC-associated mutations also impair cell compartmentalization in an assay in which EphB1-expressing cells are cocultured with ligand (ephrin B1)-expressing cells. These results suggest that somatic mutations impair the kinase-dependent tumor suppressor function of EphB1 in CRC.
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Affiliation(s)
- Yunyoung Kim
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA
| | - Sultan Ahmed
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA
| | - W Todd Miller
- Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA; Department of Veterans Affairs Medical Center, Northport, New York, USA.
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17
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Weeden CE, Hill W, Lim EL, Grönroos E, Swanton C. Impact of risk factors on early cancer evolution. Cell 2023; 186:1541-1563. [PMID: 37059064 DOI: 10.1016/j.cell.2023.03.013] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 01/31/2023] [Accepted: 03/14/2023] [Indexed: 04/16/2023]
Abstract
Recent identification of oncogenic cells within healthy tissues and the prevalence of indolent cancers found incidentally at autopsies reveal a greater complexity in tumor initiation than previously appreciated. The human body contains roughly 40 trillion cells of 200 different types that are organized within a complex three-dimensional matrix, necessitating exquisite mechanisms to restrain aberrant outgrowth of malignant cells that have the capacity to kill the host. Understanding how this defense is overcome to trigger tumorigenesis and why cancer is so extraordinarily rare at the cellular level is vital to future prevention therapies. In this review, we discuss how early initiated cells are protected from further tumorigenesis and the non-mutagenic pathways by which cancer risk factors promote tumor growth. By nature, the absence of permanent genomic alterations potentially renders these tumor-promoting mechanisms clinically targetable. Finally, we consider existing strategies for early cancer interception with perspectives on the next steps for molecular cancer prevention.
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Affiliation(s)
- Clare E Weeden
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - William Hill
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Emilia L Lim
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute, London, UK
| | - Eva Grönroos
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Charles Swanton
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Center of Excellence, University College London Cancer Institute, London, UK; Department of Oncology, University College London Hospitals, London, UK.
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18
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Eph Receptors in Cancer. Biomedicines 2023; 11:biomedicines11020315. [PMID: 36830852 PMCID: PMC9953285 DOI: 10.3390/biomedicines11020315] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2022] [Revised: 01/13/2023] [Accepted: 01/20/2023] [Indexed: 01/24/2023] Open
Abstract
Eph receptor tyrosine kinases play critical functions during development, in the formation of tissue and organ borders, and the vascular and neural systems. Uniquely among tyrosine kinases, their activities are controlled by binding to membrane-bound ligands, called ephrins. Ephs and ephrins generally have a low expression in adults, functioning mainly in tissue homeostasis and plasticity, but are often overexpressed in cancers, where they are especially associated with undifferentiated or progenitor cells, and with tumour development, vasculature, and invasion. Mutations in Eph receptors also occur in various tumour types and are suspected to promote tumourigenesis. Ephs and ephrins have the capacity to operate as both tumour promoters and tumour suppressors, depending on the circumstances. They have been demonstrated to impact tumour cell proliferation, migration, and invasion in vitro, as well as tumour development, angiogenesis, and metastases in vivo, making them potential therapeutic targets. However, successful development of therapies will require detailed understanding of the opposing roles of Ephs in various cancers. In this review, we discuss the variations in Eph expression and functions in a variety of malignancies. We also describe the multiple strategies that are currently available to target them in tumours, including preclinical and clinical development.
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19
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Venkitachalam S, Babu D, Ravillah D, Katabathula RM, Joseph P, Singh S, Udhayakumar B, Miao Y, Martinez-Uribe O, Hogue JA, Kresak AM, Dawson D, LaFramboise T, Willis JE, Chak A, Garman KS, Blum AE, Varadan V, Guda K. The Ephrin B2 Receptor Tyrosine Kinase Is a Regulator of Proto-oncogene MYC and Molecular Programs Central to Barrett's Neoplasia. Gastroenterology 2022; 163:1228-1241. [PMID: 35870513 PMCID: PMC9613614 DOI: 10.1053/j.gastro.2022.07.045] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 06/20/2022] [Accepted: 07/12/2022] [Indexed: 01/12/2023]
Abstract
BACKGROUND & AIMS Mechanisms contributing to the onset and progression of Barrett's (BE)-associated esophageal adenocarcinoma (EAC) remain elusive. Here, we interrogated the major signaling pathways deregulated early in the development of Barrett's neoplasia. METHODS Whole-transcriptome RNA sequencing analysis was performed in primary BE, EAC, normal esophageal squamous, and gastric biopsy tissues (n = 89). Select pathway components were confirmed by quantitative polymerase chain reaction in an independent cohort of premalignant and malignant biopsy tissues (n = 885). Functional impact of selected pathway was interrogated using transcriptomic, proteomic, and pharmacogenetic analyses in mammalian esophageal organotypic and patient-derived BE/EAC cell line models, in vitro and/or in vivo. RESULTS The vast majority of primary BE/EAC tissues and cell line models showed hyperactivation of EphB2 signaling. Transcriptomic/proteomic analyses identified EphB2 as an endogenous binding partner of MYC binding protein 2, and an upstream regulator of c-MYC. Knockdown of EphB2 significantly impeded the viability/proliferation of EAC and BE cells in vitro/in vivo. Activation of EphB2 in normal esophageal squamous 3-dimensional organotypes disrupted epithelial maturation and promoted columnar differentiation programs, notably including MYC. EphB2 and MYC showed selective induction in esophageal submucosal glands with acinar ductal metaplasia, and in a porcine model of BE-like esophageal submucosal gland spheroids. Clinically approved inhibitors of MEK, a protein kinase that regulates MYC, effectively suppressed EAC tumor growth in vivo. CONCLUSIONS The EphB2 signaling is frequently hyperactivated across the BE-EAC continuum. EphB2 is an upstream regulator of MYC, and activation of EphB2-MYC axis likely precedes BE development. Targeting EphB2/MYC could be a promising therapeutic strategy for this often refractory and aggressive cancer.
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Affiliation(s)
- Srividya Venkitachalam
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Deepak Babu
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Durgadevi Ravillah
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Ramachandra M Katabathula
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Peronne Joseph
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Salendra Singh
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Bhavatharini Udhayakumar
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Yanling Miao
- Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Omar Martinez-Uribe
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - Joyce A Hogue
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - Adam M Kresak
- Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Dawn Dawson
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Thomas LaFramboise
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Joseph E Willis
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Amitabh Chak
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio
| | - Katherine S Garman
- Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina
| | - Andrew E Blum
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio; Division of Gastroenterology, Northeast Ohio Veteran Affairs Healthcare System, Cleveland, Ohio
| | - Vinay Varadan
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
| | - Kishore Guda
- Division of General Medical Sciences-Oncology, Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio.
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20
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Takeichi M. Cell sorting in vitro and in vivo: How are cadherins involved? Semin Cell Dev Biol 2022; 147:2-11. [PMID: 36376196 DOI: 10.1016/j.semcdb.2022.11.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 11/07/2022] [Accepted: 11/07/2022] [Indexed: 11/13/2022]
Abstract
Animal tissues are composed of heterogenous cells, and their sorting into different compartments of the tissue is a pivotal process for organogenesis. Cells accomplish sorting by themselves-it is well known that singly dispersed cells can self-organize into tissue-like structures in vitro. Cell sorting is regulated by both biochemical and physical mechanisms. Adhesive proteins connect cells together, selecting particular partners through their specific binding properties, while physical forces, such as cell-cortical tension, control the cohesiveness between cells and in turn cell assembly patterns in mechanical ways. These processes cooperate in determining the overall cell sorting behavior. This article focuses on the 'cadherin' family of adhesion molecules as a biochemical component of cell-cell interactions, addressing how they regulate cell sorting by themselves or by cooperating with other factors. New ideas beyond the classical models of cell sorting are also discussed.
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21
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Zhang H, Cui Z, Pan T, Hu H, He R, Yi M, Sun W, Gao R, Wang H, Ma X, Peng Q, Feng X, Liang S, Du Y, Wang C. RNF186/EPHB2 Axis Is Essential in Regulating TNF Signaling for Colorectal Tumorigenesis in Colorectal Epithelial Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2022; 209:1796-1805. [PMID: 36130827 PMCID: PMC9553791 DOI: 10.4049/jimmunol.2200229] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Accepted: 08/08/2022] [Indexed: 01/04/2023]
Abstract
The receptor tyrosine kinase EPHB2 (EPH receptor B2) is highly expressed in many human cancer types, especially in gastrointestinal cancers, such as colorectal cancer. Several coding mutations of the EPHB2 gene have been identified in many cancer types, suggesting that EPHB2 plays a critical role in carcinogenesis. However, the exact functional mechanism of EPHB2 in carcinogenesis remains unknown. In this study, we find that EPHB2 is required for TNF-induced signaling activation and proinflammatory cytokine production in colorectal epithelial cells. Mechanistically, after TNF stimulation, EPHB2 is ubiquitinated by its E3 ligase RNF186. Then, ubiquitinated EPHB2 recruits and further phosphorylates TAB2 at nine tyrosine sites, which is a critical step for the binding between TAB2 and TAK1. Due to defects in TNF signaling in RNF186-knockout colorectal epithelial cells, the phenotype of colitis-propelled colorectal cancer model in RNF186-knockout mice is significantly reduced compared with that in wild-type control mice. Moreover, we find that a genetic mutation in EPHB2 identified in a family with colorectal cancer is a gain-of-function mutation that promoted TNF signaling activation compared with wild-type EPHB2. We provide evidence that the EPHB2-RNF186-TAB2-TAK1 signaling cascade plays an essential role in TNF-mediated signal transduction in colorectal epithelial cells and the carcinogenesis of colorectal cancer, which may provide potential targets for the treatment of colorectal cancer.
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Affiliation(s)
- Huazhi Zhang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Zhihui Cui
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ting Pan
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China;,Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; and
| | - Huijun Hu
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ruirui He
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China;,Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; and
| | - Ming Yi
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China;,Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; and
| | - Wanwei Sun
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ru Gao
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Heping Wang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaojian Ma
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Qianwen Peng
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xiong Feng
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | | | - Yanyun Du
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China;,Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; and
| | - Chenhui Wang
- The Key Laboratory for Human Disease Gene Study of Sichuan Province and the Department of Laboratory Medicine, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, China;,Research Unit for Blindness Prevention of the Chinese Academy of Medical Sciences (2019RU026), Sichuan Academy of Medical Sciences and Sichuan Provincial People’s Hospital, Chengdu, Sichuan, China; and
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22
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Suzuki Y, Okabayashi K, Hasegawa H, Tsuruta M, Seishima R, Tokuda T, Kitagawa Y. Role of EphB2/ephrin‑B1 signalling in the development and progression of obesity‑associated colorectal cancer. Oncol Lett 2022; 24:316. [PMID: 35949596 PMCID: PMC9353875 DOI: 10.3892/ol.2022.13436] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 06/29/2022] [Indexed: 11/17/2022] Open
Abstract
Obesity is a major problem worldwide and has been associated with colorectal cancer development, among other diseases. Ephrin receptors and ligands play an important role in the turnover of the intestinal mucosa and intestinal crypt compartmentalization. It has been hypothesised that obesity-induced inflammation affects ephrin signals, leading to carcinogenesis. Therefore, the aim of the present study was to assess the relationship between Eph-ephrin B signalling, obesity and obesity-associated colorectal cancer. An azoxymethane-induced obesity-associated cancer KKAy mouse model developed in our prior study was used. A total of 46 patients with consecutive colorectal cancer and 48 tumours were analysed. Immunohistological analyses were performed in mouse and human samples, and immunoreactive scores (IRS) were determined. KKAy mice were significantly more prone to cancer development compared with control C57/BL mice (2/15 in C57/BL vs. 10/10 in KKAy; P<0.001). TUNEL assay revealed a lower number of apoptotic cells in normal mucosa of KKAy mice (8.8% in C57/BL vs. 3.2% in KKAy; P<0.001) and obese patients (9.2% with BMI <25 vs. 3.6% with BMI ≥25; P=0.021). Immunohistological analysis revealed that ephrin-B1 was downregulated in normal mucosa from KKAy mice and obese patients (IRS, 2.86 with BMI <25 vs. 6.00 with BMI ≥25; P=0.002). Moreover, EphB2 was downregulated in tumours from KKAy mice and obese patients (IRS, 6.58 with BMI <25 vs. 3.83 with BMI ≥25; P<0.001). The distribution of infiltrated macrophages corresponded to the MCP-1 expression pattern in KKAy mice, and the number of macrophages was also significantly higher in those mice (36.3 in C57/BL vs. 120.0 in KKAy; P=0.029). The findings suggested that obesity results in disruption of EphB2/ephrin-B1 signalling, promoting colorectal cancer development and progression.
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Affiliation(s)
- Yoshiyuki Suzuki
- Department of Surgery, Keio University School of Medicine, Tokyo 1608582, Japan
| | - Koji Okabayashi
- Department of Surgery, Keio University School of Medicine, Tokyo 1608582, Japan
| | - Hirotoshi Hasegawa
- Department of Surgery, Keio University School of Medicine, Tokyo 1608582, Japan
| | - Masashi Tsuruta
- Department of Surgery, Keio University School of Medicine, Tokyo 1608582, Japan
| | - Ryo Seishima
- Department of Surgery, Keio University School of Medicine, Tokyo 1608582, Japan
| | - Toshiki Tokuda
- Department of Surgery, Keio University School of Medicine, Tokyo 1608582, Japan
| | - Yuko Kitagawa
- Department of Surgery, Keio University School of Medicine, Tokyo 1608582, Japan
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23
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Kakarla M, ChallaSivaKanaka S, Dufficy MF, Gil V, Filipovich Y, Vickman R, Crawford SE, Hayward SW, Franco OE. Ephrin B Activate Src Family Kinases in Fibroblasts Inducing Stromal Remodeling in Prostate Cancer. Cancers (Basel) 2022; 14:2336. [PMID: 35565468 PMCID: PMC9102363 DOI: 10.3390/cancers14092336] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 04/29/2022] [Accepted: 05/06/2022] [Indexed: 12/14/2022] Open
Abstract
Through stromal-epithelial interactions, carcinoma associated fibroblasts (CAF) play a critical role in tumor growth and progression. Activation of erythrophoyetin-producing human hepatocellular (Eph) receptors has been implicated in cancer. Eph receptor interactions with Ephrin ligands lead to bidirectional signals in the recipient and effector cells. The consequences of continuous reverse Ephrin signaling activation in fibroblasts on prostate cancer (PCa) is unknown. When compared to benign prostate fibroblast, CAF displayed higher expression of Ephrin B1, B2, and B3 ligands (EFNB1, EFNB2, and EFNB3). In this study, we found that continuous activation of EFNB1 and EFNB3 in a benign human prostate stromal cell line (BHPrS1) increased the expression of CAF markers and induced a CAF phenotype. BHPrS1EFNB1 and BHPrS1EFNB3 displayed a pro-tumorigenic secretome with multiple effects on neovascularization, collagen deposition, and cancer cell proliferation, overall increasing tumorigenicity of a premalignant prostate epithelial cell line BPH1 and PCa cell line LNCaP, both in vitro and in vivo. Inhibition of Src family kinases (SFK) in BHPrS1EFNB1 and BHPrS1EFNB3 suppressed EFNB-induced ɑ-SMA (Alpha-smooth muscle actin) and TN-C (Tenascin-C) in vitro. Our study suggests that acquisition of CAF characteristics via SFK activation in response to increased EFNB ligands could promote carcinogenesis via modulation of TME in PCa.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Omar E. Franco
- Department of Surgery, NorthShore University HealthSystem, Research Institute, 1001 University Place, Chicago, IL 60201, USA; (M.K.); (S.C.); (M.F.D.); (V.G.); (Y.F.); (R.V.); (S.E.C.); (S.W.H.)
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24
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Liu W, Yu C, Li J, Fang J. The Roles of EphB2 in Cancer. Front Cell Dev Biol 2022; 10:788587. [PMID: 35223830 PMCID: PMC8866850 DOI: 10.3389/fcell.2022.788587] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2021] [Accepted: 01/17/2022] [Indexed: 11/13/2022] Open
Abstract
The erythropoietin-producing hepatocellular carcinoma (Eph) receptors and their Eph receptor-interacting (ephrin) ligands together constitute a vital cell communication system with diverse roles. Experimental evidence revealed Eph receptor bidirectional signaling with both tumor-promoting and tumor-suppressing activities in different cancer types and surrounding environment. Eph receptor B2 (EphB2), an important member of the Eph receptor family, has been proved to be aberrantly expressed in many cancer types, such as colorectal cancer, gastric cancer and hepatocellular carcinoma, resulting in tumor occurrence and progression. However, there are no reviews focusing on the dual roles of EphB2 in cancer. Thus, in this paper we systematically summarize and discuss the roles of EphB2 in cancer. Firstly, we review the main biological features and the related signaling regulatory mechanisms of EphB2, and then we summarize the roles of EphB2 in cancer through current studies. Finally, we put forward our viewpoint on the future prospects of cancer research focusing on EphB2, especially with regard to the effects of EphB2 on tumor immunity.
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Affiliation(s)
- Wei Liu
- Department of Geriatrics, The First Affiliated Hospital of Nanchang University, Nanchang, China
- Second Clinical Medical College, Nanchang University, Nanchang, China
| | - Chengpeng Yu
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jianfeng Li
- Department of General Surgery, The First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Jiwei Fang
- Department of Geriatrics, The First Affiliated Hospital of Nanchang University, Nanchang, China
- *Correspondence: Jiwei Fang,
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25
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Wilkinson DG. Interplay of Eph-Ephrin Signalling and Cadherin Function in Cell Segregation and Boundary Formation. Front Cell Dev Biol 2021; 9:784039. [PMID: 34869386 PMCID: PMC8633894 DOI: 10.3389/fcell.2021.784039] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 10/25/2021] [Indexed: 11/13/2022] Open
Abstract
The segregation of distinct cell populations to form sharp boundaries is crucial for stabilising tissue organisation, for example during hindbrain segmentation in craniofacial development. Two types of mechanisms have been found to underlie cell segregation: differential adhesion mediated by cadherins, and Eph receptor and ephrin signalling at the heterotypic interface which regulates cell adhesion, cortical tension and repulsion. An interplay occurs between these mechanisms since cadherins have been found to contribute to Eph-ephrin-mediated cell segregation. This may reflect that Eph receptor activation acts through multiple pathways to decrease cadherin-mediated adhesion which can drive cell segregation. However, Eph receptors mainly drive cell segregation through increased heterotypic tension or repulsion. Cadherins contribute to cell segregation by antagonising homotypic tension within each cell population. This suppression of homotypic tension increases the difference with heterotypic tension triggered by Eph receptor activation, and it is this differential tension that drives cell segregation and border sharpening.
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26
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Modeling Intestinal Stem Cell Function with Organoids. Int J Mol Sci 2021; 22:ijms222010912. [PMID: 34681571 PMCID: PMC8535974 DOI: 10.3390/ijms222010912] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 10/06/2021] [Accepted: 10/07/2021] [Indexed: 12/11/2022] Open
Abstract
Intestinal epithelial cells (IECs) are crucial for the digestive process and nutrient absorption. The intestinal epithelium is composed of the different cell types of the small intestine (mainly, enterocytes, goblet cells, Paneth cells, enteroendocrine cells, and tuft cells). The small intestine is characterized by the presence of crypt-villus units that are in a state of homeostatic cell turnover. Organoid technology enables an efficient expansion of intestinal epithelial tissue in vitro. Thus, organoids hold great promise for use in medical research and in the development of new treatments. At present, the cholinergic system involved in IECs and intestinal stem cells (ISCs) are attracting a great deal of attention. Thus, understanding the biological processes triggered by epithelial cholinergic activation by acetylcholine (ACh), which is produced and released from neuronal and/or non-neuronal tissue, is of key importance. Cholinergic signaling via ACh receptors plays a pivotal role in IEC growth and differentiation. Here, we discuss current views on neuronal innervation and non-neuronal control of the small intestinal crypts and their impact on ISC proliferation, differentiation, and maintenance. Since technology using intestinal organoid culture systems is advancing, we also outline an organoid-based organ replacement approach for intestinal diseases.
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27
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Sato A, Rahman NIA, Shimizu A, Ogita H. Cell-to-cell contact-mediated regulation of tumor behavior in the tumor microenvironment. Cancer Sci 2021; 112:4005-4012. [PMID: 34420253 PMCID: PMC8486192 DOI: 10.1111/cas.15114] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/15/2021] [Accepted: 08/17/2021] [Indexed: 02/06/2023] Open
Abstract
Tumor growth and progression are complex processes mediated by mutual interactions between cancer cells and their surrounding stroma that include diverse cell types and acellular components, which form the tumor microenvironment. In this environment, direct intercellular communications play important roles in the regulation of the biological behaviors of tumors. However, the underlying molecular mechanisms are insufficiently defined. We used an in vitro coculture system to identify genes that were specifically expressed at higher levels in cancer cells associated with stromal cells. Major examples included epithelial membrane protein 1 (EMP1) and stomatin, which positively and negatively regulate tumor progression, respectively. EMP1 promotes tumor cell migration and metastasis via activation of the small GTPase Rac1, while stomatin strongly suppresses cell proliferation and induces apoptosis of cancer cells via inhibition of Akt signaling. Here we highlight important aspects of EMP1, stomatin, and their family members in cancer biology. Furthermore, we consider the molecules that participate in intercellular communications and signaling transduction between cancer cells and stromal cells, which may affect the phenotypes of cancer cells in the tumor microenvironment.
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Affiliation(s)
- Akira Sato
- Division of Molecular Medical BiochemistryDepartment of Biochemistry and Molecular BiologyShiga University of Medical ScienceOtsuJapan
| | - Nor Idayu A. Rahman
- Division of Molecular Medical BiochemistryDepartment of Biochemistry and Molecular BiologyShiga University of Medical ScienceOtsuJapan
| | - Akio Shimizu
- Division of Molecular Medical BiochemistryDepartment of Biochemistry and Molecular BiologyShiga University of Medical ScienceOtsuJapan
| | - Hisakazu Ogita
- Division of Molecular Medical BiochemistryDepartment of Biochemistry and Molecular BiologyShiga University of Medical ScienceOtsuJapan
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28
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Shim G, Devenport D, Cohen DJ. Overriding native cell coordination enhances external programming of collective cell migration. Proc Natl Acad Sci U S A 2021; 118:e2101352118. [PMID: 34272284 PMCID: PMC8307614 DOI: 10.1073/pnas.2101352118] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
As collective cell migration is essential in biological processes spanning development, healing, and cancer progression, methods to externally program cell migration are of great value. However, problems can arise if the external commands compete with strong, preexisting collective behaviors in the tissue or system. We investigate this problem by applying a potent external migratory cue-electrical stimulation and electrotaxis-to primary mouse skin monolayers where we can tune cell-cell adhesion strength to modulate endogenous collectivity. Monolayers with high cell-cell adhesion showed strong natural coordination and resisted electrotactic control, with this conflict actively damaging the leading edge of the tissue. However, reducing preexisting coordination in the tissue by specifically inhibiting E-cadherin-dependent cell-cell adhesion, either by disrupting the formation of cell-cell junctions with E-cadherin-specific antibodies or rapidly dismantling E-cadherin junctions with calcium chelators, significantly improved controllability. Finally, we applied this paradigm of weakening existing coordination to improve control and demonstrate accelerated wound closure in vitro. These results are in keeping with those from diverse, noncellular systems and confirm that endogenous collectivity should be considered as a key quantitative design variable when optimizing external control of collective migration.
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Affiliation(s)
- Gawoon Shim
- Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ 08540
| | - Danelle Devenport
- Department of Molecular Biology, Princeton University, Princeton, NJ 08540
| | - Daniel J Cohen
- Department of Mechanical and Aerospace Engineering, Princeton University, Princeton, NJ 08540;
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29
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Yu JC, Balaghi N, Erdemci-Tandogan G, Castle V, Fernandez-Gonzalez R. Myosin cables control the timing of tissue internalization in the Drosophila embryo. Cells Dev 2021; 168:203721. [PMID: 34271226 DOI: 10.1016/j.cdev.2021.203721] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 07/05/2021] [Accepted: 07/07/2021] [Indexed: 11/25/2022]
Abstract
Compartment boundaries prevent cell mixing during animal development. In the early Drosophila embryo, the mesectoderm is a group of glial precursors that separate ectoderm and mesoderm, forming the ventral midline. Mesectoderm cells undergo one round of oriented divisions during axis elongation and are eventually internalized 6 h later. Using spinning disk confocal microscopy and image analysis, we found that after dividing, mesectoderm cells reversed their planar polarity. The polarity factor Bazooka was redistributed to mesectoderm-mesectoderm cell interfaces, and the molecular motor non-muscle Myosin II and its upstream activator Rho-kinase (Rok) accumulated at mesectoderm-ectoderm (ME) interfaces, forming supracellular cables flanking the mesectoderm on either side of the tissue. Laser ablation revealed the presence of increased tension at ME cables, where Myosin was stabilized, as shown by fluorescence recovery after photobleaching. We used laser nanosurgery to reduce tension at the ME boundary, and we found that Myosin fluorescence decreased rapidly, suggesting a role for tension in ME boundary maintenance. Mathematical modelling predicted that increased tension at the ME boundary was necessary to prevent the premature establishment of contacts between the two ectodermal sheets on opposite sides of the mesectoderm, thus controlling the timing of mesectoderm internalization. We validated the model in vivo: Myosin inhibition disrupted the linearity of the ME boundary and resulted in early internalization of the mesectoderm. Our results suggest that the redistribution of Rok polarizes Myosin and Bazooka within the mesectoderm to establish tissue boundaries, and that ME boundaries control the timely internalization of the mesectoderm as embryos develop.
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Affiliation(s)
- Jessica C Yu
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Negar Balaghi
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Gonca Erdemci-Tandogan
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Veronica Castle
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada
| | - Rodrigo Fernandez-Gonzalez
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON M5S 3G9, Canada; Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON M5G 1M1, Canada; Department of Cell and Systems Biology, University of Toronto, Toronto, ON M5S 3G5, Canada; Developmental and Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
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30
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Takahashi T, Shiraishi A, Murata J, Matsubara S, Nakaoka S, Kirimoto S, Osawa M. Muscarinic receptor M3 contributes to intestinal stem cell maintenance via EphB/ephrin-B signaling. Life Sci Alliance 2021; 4:4/9/e202000962. [PMID: 34244422 PMCID: PMC8321669 DOI: 10.26508/lsa.202000962] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 06/30/2021] [Accepted: 07/01/2021] [Indexed: 12/31/2022] Open
Abstract
Acetylcholine (ACh) signaling through activation of nicotinic and muscarinic ACh receptors regulates expression of specific genes that mediate and sustain proliferation, differentiation, and homeostasis in the intestinal crypts. This signaling plays a pivotal role in the regulation of intestinal stem cell function, but the details have not been clarified. Here, we performed experiments using type 3 muscarinic acetylcholine receptor (M3) knockout mice and their intestinal organoids and report that endogenous ACh affects the size of the intestinal stem niche via M3 signaling. RNA sequencing of crypts identified up-regulation of the EphB/ephrin-B signaling pathway. Furthermore, using an MEK inhibitor (U0126), we found that mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling, which is downstream of EphB/ephrin-B signaling, is activated in M3-deficient crypts. Collectively, M3, EphB/ephrin-B, and the MAPK/ERK signaling cascade work together to maintain the homeostasis of intestinal epithelial cell growth and differentiation following modifications of the cholinergic intestinal niche.
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Affiliation(s)
- Toshio Takahashi
- Suntory Foundation for Life Sciences, Bioorganic Research Institute, Kyoto, Japan
| | - Akira Shiraishi
- Suntory Foundation for Life Sciences, Bioorganic Research Institute, Kyoto, Japan
| | - Jun Murata
- Suntory Foundation for Life Sciences, Bioorganic Research Institute, Kyoto, Japan
| | - Shin Matsubara
- Suntory Foundation for Life Sciences, Bioorganic Research Institute, Kyoto, Japan
| | | | | | - Masatake Osawa
- Department of Regenerative Medicine and Applied Biomedical Sciences, Graduate School of Medicine, Gifu University, Gifu, Japan.,Center for Highly Advanced Integration of Nano and Life Sciences, Gifu University (G-CHAIN), Gifu, Japan
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31
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Hill W, Zaragkoulias A, Salvador-Barbero B, Parfitt GJ, Alatsatianos M, Padilha A, Porazinski S, Woolley TE, Morton JP, Sansom OJ, Hogan C. EPHA2-dependent outcompetition of KRASG12D mutant cells by wild-type neighbors in the adult pancreas. Curr Biol 2021; 31:2550-2560.e5. [PMID: 33891893 PMCID: PMC8231095 DOI: 10.1016/j.cub.2021.03.094] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2020] [Revised: 02/15/2021] [Accepted: 03/29/2021] [Indexed: 12/22/2022]
Abstract
As we age, our tissues are repeatedly challenged by mutational insult, yet cancer occurrence is a relatively rare event. Cells carrying cancer-causing genetic mutations compete with normal neighbors for space and survival in tissues. However, the mechanisms underlying mutant-normal competition in adult tissues and the relevance of this process to cancer remain incompletely understood. Here, we investigate how the adult pancreas maintains tissue health in vivo following sporadic expression of oncogenic Kras (KrasG12D), the key driver mutation in human pancreatic cancer. We find that when present in tissues in low numbers, KrasG12D mutant cells are outcompeted and cleared from exocrine and endocrine compartments in vivo. Using quantitative 3D tissue imaging, we show that before being cleared, KrasG12D cells lose cell volume, pack into round clusters, and E-cadherin-based cell-cell adhesions decrease at boundaries with normal neighbors. We identify EphA2 receptor as an essential signal in the clearance of KrasG12D cells from exocrine and endocrine tissues in vivo. In the absence of functional EphA2, KrasG12D cells do not alter cell volume or shape, E-cadherin-based cell-cell adhesions increase and KrasG12D cells are retained in tissues. The retention of KRasG12D cells leads to the early appearance of premalignant pancreatic intraepithelial neoplasia (PanINs) in tissues. Our data show that adult pancreas tissues remodel to clear KrasG12D cells and maintain tissue health. This study provides evidence to support a conserved functional role of EphA2 in Ras-driven cell competition in epithelial tissues and suggests that EphA2 is a novel tumor suppressor in pancreatic cancer.
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Affiliation(s)
- William Hill
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
| | - Andreas Zaragkoulias
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
| | - Beatriz Salvador-Barbero
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
| | - Geraint J Parfitt
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK; School of Optometry & Vision Sciences, Cardiff University, Maindy Road, Cardiff CF24 4HQ, UK
| | - Markella Alatsatianos
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
| | - Ana Padilha
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK
| | - Sean Porazinski
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK; Faculty of Medicine, St Vincent's Clinical School, University of New South Wales, Sydney, Australia
| | - Thomas E Woolley
- School of Mathematics, Cardiff University, Senghennydd Road, Cardiff CF24 4AG, UK
| | - Jennifer P Morton
- CRUK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
| | - Owen J Sansom
- CRUK Beatson Institute, Glasgow G61 1BD, UK; Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK
| | - Catherine Hogan
- European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff CF24 4HQ, UK.
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32
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Malijauskaite S, Connolly S, Newport D, McGourty K. Gradients in the in vivo intestinal stem cell compartment and their in vitro recapitulation in mimetic platforms. Cytokine Growth Factor Rev 2021; 60:76-88. [PMID: 33858768 DOI: 10.1016/j.cytogfr.2021.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Accepted: 03/05/2021] [Indexed: 02/07/2023]
Abstract
Intestinal tissue, and specifically its mucosal layer, is a complex and gradient-rich environment. Gradients of soluble factor (BMP, Noggin, Notch, Hedgehog, and Wnt), insoluble extracellular matrix proteins (laminins, collagens, fibronectin, and their cognate receptors), stromal stiffness, oxygenation, and sheer stress induced by luminal fluid flow at the crypt-villus axis controls and supports healthy intestinal tissue homeostasis. However, due to current technological challenges, very few of these features have so far been included in in vitro intestinal tissue mimetic platforms. In this review, the tightly defined and dynamic microenvironment of the intestinal tissue is presented in detail. Additionally, the authors introduce the current state-of-the-art intestinal tissue mimetic platforms, as well as the design drawbacks and challenges they face while attempting to capture the complexity of the intestinal tissue's physiology. Finally, the compositions of an "idealized" mimetic system is presented to guide future developmental efforts.
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Affiliation(s)
- Sigita Malijauskaite
- Dept. of Chemical Sciences, University of Limerick, Limerick, Ireland; Bernal Institute, University of Limerick, Limerick, Ireland.
| | - Sinead Connolly
- Bernal Institute, University of Limerick, Limerick, Ireland; School of Engineering, University of Limerick, Limerick, Ireland.
| | - David Newport
- Bernal Institute, University of Limerick, Limerick, Ireland; Health Research Institute (HRI), University of Limerick, Limerick, Ireland; School of Engineering, University of Limerick, Limerick, Ireland.
| | - Kieran McGourty
- Dept. of Chemical Sciences, University of Limerick, Limerick, Ireland; Bernal Institute, University of Limerick, Limerick, Ireland; Health Research Institute (HRI), University of Limerick, Limerick, Ireland.
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33
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Chemosensitization of HT29 and HT29-5FU Cell Lines by a Combination of a Multi-Tyrosine Kinase Inhibitor and 5FU Downregulates ABCC1 and Inhibits PIK3CA in Light of Their Importance in Saudi Colorectal Cancer. Molecules 2021; 26:molecules26020334. [PMID: 33440689 PMCID: PMC7827067 DOI: 10.3390/molecules26020334] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 12/30/2020] [Accepted: 01/07/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) remains one of the main causes of death worldwide and in Saudi Arabia. The toxicity and the development of resistance against 5 fluorouracil 5FU pose increasing therapeutic difficulties, which necessitates the development of personalized drugs and drug combinations. Objectives: First, to determine the most important kinases and kinase pathways, and the amount of ABC transporters and KRAS in samples taken from Saudi CRC patients. Second, to investigate the chemosensitizing effect of LY294002 and HAA2020 and their combinations with 5FU on HT29, HT29-5FU, HCT116, and HCT116-5FU CRC cells, their effect on the three ABC transporters, cell cycle, and apoptosis, in light of the important kinase pathways resulting from the first part of this study. Methods: The PamChip® peptide micro-array profiling was used to determine the level of kinase and targets in the Saudi CRC samples. Next, RT-PCR, MTT cytotoxicity, Western blotting, perturbation of cell cycle, annexin V, and immunofluorescence assays were used to investigate the effect on CRC, MRC5, and HUVEC cells. Results: The kinase activity profiling highlighted the importance of the PI3K/AKT, MAPK, and the growth factors pathways in the Saudi CRC samples. PIK3CA was the most overexpressed, and it was associated with increased level of mutated KRAS and the three ABC transporters, especially ABCC1 in the Saudi samples. Next, combining HAA2020 with 5FU exhibited the best synergistic and resistance-reversal effect in the four CRC cells, and the highest selectivity indices compared to MRC5 and HUVEC normal cells. Additionally, HAA2020 with 5FU exerted significant inhibition of ABCC1 in the four CRC cells, and inhibition of PIK3CA/AKT/MAPK7/ERK in HT29 and HT29-5FU cells. The combination also inhibited EGFR, increased the preG1/S cell cycle phases, apoptosis, and caspase 8 in HT29 cells, while it increased the G1 phase, p21/p27, and apoptosis in HT29-5FU cells. Conclusion: We have combined the PamChip kinase profiling of Saudi CRC samples with in vitro drug combination studies in four CRC cells, highlighting the importance of targeting PIK3CA and ABCC1 for Saudi CRC patients, especially given that the overexpression of PIK3CA mutations was previously linked with the lack of activity for the anti-EGFRs as first line treatment for CRC patients. The combination of HAA2020 and 5FU has selectively sensitized the four CRC cells to 5FU and could be further studied.
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Anderton M, van der Meulen E, Blumenthal MJ, Schäfer G. The Role of the Eph Receptor Family in Tumorigenesis. Cancers (Basel) 2021; 13:cancers13020206. [PMID: 33430066 PMCID: PMC7826860 DOI: 10.3390/cancers13020206] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 12/22/2020] [Accepted: 12/28/2020] [Indexed: 01/20/2023] Open
Abstract
Simple Summary The Eph receptor family is implicated in both tumour promotion and suppression, depending on the tissue-specific context of available receptor interactions with ligands, adaptor proteins and triggered downstream signalling pathways. This complex interplay has not only consequences for tumorigenesis but also offers a basis from which new cancer-targeting strategies can be developed. This review comprehensively summarises the current knowledge of Eph receptor implications in oncogenesis in a tissue- and receptor-specific manner, with the aim to develop a better understanding of Eph signalling pathways for potential targeting in novel cancer therapies. Abstract The Eph receptor tyrosine kinase family, activated by binding to their cognate ephrin ligands, are important components of signalling pathways involved in animal development. More recently, they have received significant interest due to their involvement in oncogenesis. In most cases, their expression is altered, affecting the likes of cell proliferation and migration. Depending on the context, Eph receptors have the potential to act as both tumour promoters and suppressors in a number of cancers, such as breast cancer, colorectal cancer, lung cancer, prostate cancer, brain cancer and Kaposi’s sarcoma (KS), the latter being intrinsically linked to EphA2 as this is the receptor used for endothelial cell entry by the Kaposi’s sarcoma-associated herpesvirus (KSHV). In addition, EphA2 deregulation is associated with KS, indicating that it has a dual role in this case. Associations between EphA2 sequence variation and KSHV infection/KS progression have been detected, but further work is required to formally establish the links between EphA2 signalling and KS oncogenesis. This review consolidates the available literature of the role of the Eph receptor family, and particularly EphA2, in tumorigenesis, with the aim to develop a better understanding of Eph signalling pathways for potential targeting in novel cancer therapies.
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Affiliation(s)
- Meg Anderton
- International Centre for Genetic Engineering and Biotechnology (ICGEB) Cape Town, Observatory, Cape Town 7925, South Africa; (M.A.); (E.v.d.M.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa
| | - Emma van der Meulen
- International Centre for Genetic Engineering and Biotechnology (ICGEB) Cape Town, Observatory, Cape Town 7925, South Africa; (M.A.); (E.v.d.M.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa
| | - Melissa J. Blumenthal
- International Centre for Genetic Engineering and Biotechnology (ICGEB) Cape Town, Observatory, Cape Town 7925, South Africa; (M.A.); (E.v.d.M.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa
- Correspondence: (M.J.B.); (G.S.); Tel.: +27-21-4047630 (M.J.B.)
| | - Georgia Schäfer
- International Centre for Genetic Engineering and Biotechnology (ICGEB) Cape Town, Observatory, Cape Town 7925, South Africa; (M.A.); (E.v.d.M.)
- Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa
- Division of Medical Biochemistry and Structural Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, University of Cape Town, Observatory, Cape Town 7925, South Africa
- Correspondence: (M.J.B.); (G.S.); Tel.: +27-21-4047630 (M.J.B.)
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Schwarzmueller L, Bril O, Vermeulen L, Léveillé N. Emerging Role and Therapeutic Potential of lncRNAs in Colorectal Cancer. Cancers (Basel) 2020; 12:E3843. [PMID: 33352769 PMCID: PMC7767007 DOI: 10.3390/cancers12123843] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 02/06/2023] Open
Abstract
Maintenance of the intestinal epithelium is dependent on the control of stem cell (SC) proliferation and differentiation. The fine regulation of these cellular processes requires a complex dynamic interplay between several signaling pathways, including Wnt, Notch, Hippo, EGF, Ephrin, and BMP/TGF-β. During the initiation and progression of colorectal cancer (CRC), key events, such as oncogenic mutations, influence these signaling pathways, and tilt the homeostatic balance towards proliferation and dedifferentiation. Therapeutic strategies to specifically target these deregulated signaling pathways are of particular interest. However, systemic blocking or activation of these pathways poses major risks for normal stem cell function and tissue homeostasis. Interestingly, long non-coding RNAs (lncRNAs) have recently emerged as potent regulators of key cellular processes often deregulated in cancer. Because of their exceptional tissue and tumor specificity, these regulatory RNAs represent attractive targets for cancer therapy. Here, we discuss how lncRNAs participate in the maintenance of intestinal homeostasis and how they can contribute to the deregulation of each signaling pathway in CRC. Finally, we describe currently available molecular tools to develop lncRNA-targeted cancer therapies.
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Affiliation(s)
- Laura Schwarzmueller
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Oscar Bril
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Louis Vermeulen
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
| | - Nicolas Léveillé
- Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Cancer Center Amsterdam and Amsterdam Gastroenterology and Metabolism, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands; (L.S.); (O.B.); (L.V.)
- Oncode Institute, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands
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Zhang H, Cui Z, Cheng D, Du Y, Guo X, Gao R, Chen J, Sun W, He R, Ma X, Peng Q, Martin BN, Yan W, Rong Y, Wang C. RNF186 regulates EFNB1 (ephrin B1)-EPHB2-induced autophagy in the colonic epithelial cells for the maintenance of intestinal homeostasis. Autophagy 2020; 17:3030-3047. [PMID: 33280498 DOI: 10.1080/15548627.2020.1851496] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Although genome-wide association studies have identified the gene RNF186 encoding an E3 ubiquitin-protein ligase as conferring susceptibility to ulcerative colitis, the exact function of this protein remains unclear. In the present study, we demonstrate an important role for RNF186 in macroautophagy/autophagy activation in colonic epithelial cells and intestinal homeostasis. Mechanistically, RNF186 acts as an E3 ubiquitin-protein ligase for EPHB2 and regulates the ubiquitination of EPHB2. Upon stimulation by ligand EFNB1 (ephrin B1), EPHB2 is ubiquitinated by RNF186 at Lys892, and further recruits MAP1LC3B for autophagy. Compared to control mice, rnf186-/- and ephb2-/- mice have a more severe phenotype in the DSS-induced colitis model, which is due to a defect in autophagy in colon epithelial cells. More importantly, treatment with ephrin-B1-Fc recombinant protein effectively relieves DSS-induced mouse colitis, which suggests that ephrin-B1-Fc may be a potential therapy for human inflammatory bowel diseases.Abbreviations: ACTB: actin beta; ATG5: autophagy related 5; ATG16L1: autophagy related 16 like 1; ATP: adenosine triphosphate; Cas9: CRISPR associated protein 9; CD: Crohn disease; CQ: chloroquine; Csf2: colony stimulating factor 2; Cxcl1: c-x-c motif chemokine ligand 1; DMSO: dimethyl sulfoxide; DSS: dextran sodium sulfate; EFNB1: ephrin B1; EPHB2: EPH receptor B2; EPHB3: EPH receptor B3; EPHB2K788R: lysine 788 mutated to arginine in EPHB2; EPHB2K892R: lysine 892 mutated to arginine in EPHB2; ER: endoplasmic reticulum; FITC: fluorescein isothiocyanate; GFP: green fluorescent protein; GWAS: genome-wide association studies; HRP: horseradish peroxidase; HSPA5/BiP: heat shock protein family A (Hsp70) member 5; IBD: inflammatory bowel diseases; Il1b: interleukin 1 beta; Il6: interleukin 6; IRGM:immunity related GTPase M; i.p.: intraperitoneally; IPP: inorganic pyrophosphatase; KD: knockdown; KO: knockout; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; NOD2: nucleotide binding oligomerization domain containing 2; PI3K: phosphoinositide 3-kinase; PtdIns3K: class III phosphatidylinositol 3-kinase; RNF186: ring finger protein 186; RNF186A64T: alanine 64 mutated to threonine in RNF186; RNF186R179X: arginine 179 mutated to X in RNF186; RPS6: ribosomal protein S6; Tnf: tumor necrosis factor; SQSTM1: sequestosome 1; Ub: ubiquitin; UBE2D2: ubiquitin conjugating enzyme E2 D2; UBE2H: ubiquitin conjugating enzyme E2 H; UBE2K: ubiquitin conjugating enzyme E2 K; UBE2N: ubiquitin conjugating enzyme E2 N; UC: ulcerative colitis; ULK1:unc-51 like autophagy activating kinase 1; WT: wild type.
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Affiliation(s)
- Huazhi Zhang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Zhihui Cui
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Du Cheng
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Yanyun Du
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaoli Guo
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ru Gao
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Jianwen Chen
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Wanwei Sun
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Ruirui He
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Xiaojian Ma
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Qianwen Peng
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China
| | - Bradley N Martin
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Wei Yan
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology Wuhan, China
| | - Yueguang Rong
- Department of Pathogen Biology, School of Basic Medicine, Huazhong University of Science and Technology, Wuhan, China
| | - Chenhui Wang
- Key Laboratory of Molecular Biophysics of the Ministry of Education, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, China.,Department of Bioinformatics, Wuhan Institute of Biotechnology, Wuhan, China
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Shafraz O, Xie B, Yamada S, Sivasankar S. Mapping transmembrane binding partners for E-cadherin ectodomains. Proc Natl Acad Sci U S A 2020; 117:31157-31165. [PMID: 33229577 PMCID: PMC7733791 DOI: 10.1073/pnas.2010209117] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
We combine proximity labeling and single molecule binding assays to discover transmembrane protein interactions in cells. We first screen for candidate binding partners by tagging the extracellular and cytoplasmic regions of a "bait" protein with BioID biotin ligase and identify proximal proteins that are biotin tagged on both their extracellular and intracellular regions. We then test direct binding interactions between proximal proteins and the bait, using single molecule atomic force microscope binding assays. Using this approach, we identify binding partners for the extracellular region of E-cadherin, an essential cell-cell adhesion protein. We show that the desmosomal proteins desmoglein-2 and desmocollin-3, the focal adhesion protein integrin-α2β1, the receptor tyrosine kinase ligand ephrin-B1, and the classical cadherin P-cadherin, all directly interact with E-cadherin ectodomains. Our data shows that combining extracellular and cytoplasmic proximal tagging with a biophysical binding assay increases the precision with which transmembrane ectodomain interactors can be identified.
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Affiliation(s)
- Omer Shafraz
- Department of Biomedical Engineering, University of California, Davis, CA 95616
| | - Bin Xie
- Biophysics Graduate Group, University of California, Davis, CA 95616
| | - Soichiro Yamada
- Department of Biomedical Engineering, University of California, Davis, CA 95616
| | - Sanjeevi Sivasankar
- Department of Biomedical Engineering, University of California, Davis, CA 95616;
- Biophysics Graduate Group, University of California, Davis, CA 95616
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Janes PW, Vail ME, Ernst M, Scott AM. Eph Receptors in the Immunosuppressive Tumor Microenvironment. Cancer Res 2020; 81:801-805. [PMID: 33177063 DOI: 10.1158/0008-5472.can-20-3047] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/08/2020] [Accepted: 11/06/2020] [Indexed: 11/16/2022]
Abstract
The tumor microenvironment (TME) promotes tumor development via complex intercellular signaling, aiding tumor growth and suppressing immunity. Eph receptors (Eph) and their ephrin ligands control cell interactions during normal development, and reemerge in tumors and the TME, where they are implicated in invasion, metastasis, and angiogenesis. Recent studies also indicate roles for Ephs in suppressing immune responses by controlling tumor interactions with innate and adaptive immune cells within the TME. Accordingly, inhibiting these functions can promote immune response and efficacy of immune checkpoint inhibition. This research highlights Ephs as potential targets to enhance efficacy of immune-based therapies in patients with cancer.
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Affiliation(s)
- Peter W Janes
- Tumour Targeting Program, Olivia Newton-John Cancer Institute/La Trobe University School of Cancer Medicine, Victoria, Melbourne, Australia.
| | - Mary E Vail
- Tumour Targeting Program, Olivia Newton-John Cancer Institute/La Trobe University School of Cancer Medicine, Victoria, Melbourne, Australia
| | - Matthias Ernst
- Cancer and Inflammation Program, Olivia Newton-John Cancer Institute/La Trobe University School of Cancer Medicine, Victoria, Melbourne, Australia
| | - Andrew M Scott
- Tumour Targeting Program, Olivia Newton-John Cancer Institute/La Trobe University School of Cancer Medicine, Victoria, Melbourne, Australia
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Gofur MR, Alam J, Ogawa K. Expression and localisation of ephrin-B1, EphB2, and EphB4 in the mouse testis during postnatal development. Reprod Biol 2020; 20:321-332. [PMID: 32620380 DOI: 10.1016/j.repbio.2020.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 05/28/2020] [Accepted: 06/01/2020] [Indexed: 02/07/2023]
Abstract
The erythropoietin-producing hepatocellular receptor B (EphB) class and ephrin-B ligand have been implicated in boundary formation in various epithelia. We recently found that ephrin-B1 and EphB2/EphB4 exhibit complementary expression in the epithelia along the excurrent duct system in the adult mouse testis. Moreover, the organisation and integrity of the duct system is indispensable for the transport of spermatozoa. Here, we examined ephrin-B1, EphB2 and EphB4 expression in the mouse testis during postnatal development. RT-PCR analysis revealed that the relative expression levels of these molecules decreased with age in early postnatal development, and were similar to those of adults by four weeks of age. Furthermore, immunostaining revealed that the excurrent duct system compartments exhibiting complementary expression of ephrin-B1 and EphB2/EphB4 were formed by two weeks of age. Meanwhile, ephrin-B1 and EphB4 were effective markers for spermatogonia in the neonatal testis due to their negative expression in gonocytes. Alternatively, EphB2 was a suitable marker for assessing completion of the first wave of spermatogenesis in puberty, due to its strong expression in the elongated spermatids of seminiferous tubules. Lastly, ephrin-B1 and EphB4 proved to be markers of both foetal and adult Leydig cells during postnatal development, as they were expressed in CYP17A1-positive cells. This study is the first to investigate the expression of ephrin-B1, EphB2, and EphB4 in normal mouse testes during postnatal development. The expression patterns of ephrin-B and EphBs may represent suitable tools for examining organisation of the excurrent duct system and monitoring reproductive toxicity during postnatal development.
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Affiliation(s)
- Md Royhan Gofur
- Laboratory of Veterinary Anatomy, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano, Osaka 598-8531, Japan
| | - Jahagir Alam
- Laboratory of Veterinary Anatomy, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano, Osaka 598-8531, Japan
| | - Kazushige Ogawa
- Laboratory of Veterinary Anatomy, Graduate School of Life and Environmental Sciences, Osaka Prefecture University, 1-58 Rinku-Ourai-Kita, Izumisano, Osaka 598-8531, Japan.
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Janes PW, Vail ME, Gan HK, Scott AM. Antibody Targeting of Eph Receptors in Cancer. Pharmaceuticals (Basel) 2020; 13:ph13050088. [PMID: 32397088 PMCID: PMC7281212 DOI: 10.3390/ph13050088] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Revised: 04/29/2020] [Accepted: 05/04/2020] [Indexed: 12/20/2022] Open
Abstract
The Eph subfamily of receptor tyrosine kinases mediate cell-cell communication controlling cell and tissue patterning during development. While generally less active in adult tissues, they often re-emerge in cancers, particularly on undifferentiated or progenitor cells in tumors and the tumor microenvironment, associated with tumor initiation, angiogenesis and metastasis. Eph receptors are thus attractive therapeutic targets, and monoclonal antibodies have been commonly developed and tested for anti-cancer activity in preclinical models, and in some cases in the clinic. This review summarizes 20 years of research on various antibody-based approaches to target Eph receptors in tumors and the tumor microenvironment, including their mode of action, tumor specificity, and efficacy in pre-clinical and clinical testing.
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Li C, Lanman NA, Kong Y, He D, Mao F, Farah E, Zhang Y, Liu J, Wang C, Wei Q, Liu X. Inhibition of the erythropoietin-producing receptor EPHB4 antagonizes androgen receptor overexpression and reduces enzalutamide resistance. J Biol Chem 2020; 295:5470-5483. [PMID: 32184358 PMCID: PMC7170517 DOI: 10.1074/jbc.ra119.011385] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 03/03/2020] [Indexed: 12/14/2022] Open
Abstract
Prostate cancer (PCa) cells heavily rely on an active androgen receptor (AR) pathway for their survival. Enzalutamide (MDV3100) is a second-generation antiandrogenic drug that was approved by the Food and Drug Administration in 2012 to treat patients with castration-resistant prostate cancer (CRPC). However, emergence of resistance against this drug is inevitable, and it has been a major challenge to develop interventions that help manage enzalutamide-resistant CRPC. Erythropoietin-producing human hepatocellular (Eph) receptors are targeted by ephrin protein ligands and have a broad range of functions. Increasing evidence indicates that this signaling pathway plays an important role in tumorigenesis. Overexpression of EPH receptor B4 (EPHB4) has been observed in multiple types of cancer, being closely associated with proliferation, invasion, and metastasis of tumors. Here, using RNA-Seq analyses of clinical and preclinical samples, along with several biochemical and molecular methods, we report that enzalutamide-resistant PCa requires an active EPHB4 pathway that supports drug resistance of this tumor type. Using a small kinase inhibitor and RNAi-based gene silencing to disrupt EPHB4 activity, we found that these disruptions re-sensitize enzalutamide-resistant PCa to the drug both in vitro and in vivo Mechanistically, we found that EPHB4 stimulates the AR by inducing proto-oncogene c-Myc (c-Myc) expression. Taken together, these results provide critical insight into the mechanism of enzalutamide resistance in PCa, potentially offering a therapeutic avenue for enhancing the efficacy of enzalutamide to better manage this common malignancy.
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Affiliation(s)
- Chaohao Li
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536
| | - Nadia A Lanman
- Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana 47907; Center for Cancer Research, Purdue University, West Lafayette, Indiana 47907
| | - Yifan Kong
- Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907
| | - Daheng He
- Department of Biostatistics, University of Kentucky, Lexington, Kentucky 40536
| | - Fengyi Mao
- Department of Animal Sciences, Purdue University, West Lafayette, Indiana 47907
| | - Elia Farah
- Department of Biochemistry, Purdue University, West Lafayette, Indiana 47907
| | - Yanquan Zhang
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536
| | - Jinghui Liu
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536
| | - Chi Wang
- Department of Biostatistics, University of Kentucky, Lexington, Kentucky 40536; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536
| | - Qiou Wei
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536
| | - Xiaoqi Liu
- Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, Kentucky 40536; Markey Cancer Center, University of Kentucky, Lexington, Kentucky 40536.
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Evaluation of the Anti-Tumor Activity of Small Molecules Targeting Eph/Ephrins in APC min/J Mice. Pharmaceuticals (Basel) 2020; 13:ph13040069. [PMID: 32316101 PMCID: PMC7243115 DOI: 10.3390/ph13040069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 04/12/2020] [Accepted: 04/14/2020] [Indexed: 12/09/2022] Open
Abstract
The Eph receptors are the largest receptors tyrosine kinases (RTKs) family in humans and together with ephrin ligands constitute a complex cellular communication system often dysregulated in many tumors. The role of the Eph-ephrin system in colorectal cancer (CRC) has been investigated and different expression of Eph receptors have been associated with tumor development and progression. In light of this evidence, we investigated if a pharmacological approach aimed at inhibiting Eph/ephrin interaction through small molecules could prevent tumor growth in APC min/J mice. The 8-week treatment with the Eph-ephrin antagonist UniPR129 significantly reduced the number of adenomas in the ileum and decreased the diameter of adenomas in the same region. Overall our data suggested as UniPR129 could be able to slow down the tumor development in APC min/J mice. These results further confirm literature data about Eph kinases as a new valuable target in the intestinal cancer and for the first time showed the feasibility of the Eph-ephrin inhibition as a useful pharmacological approach against the intestinal tumorigenesis. In conclusion this work paves the way for further studies with Eph-ephrin inhibitors in order to confirm the Eph antagonism as innovative pharmacological approach with preventive benefit in the intestinal tumor development.
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Expression Profile and Prognostic Significance of EPHB3 in Colorectal Cancer. Biomolecules 2020; 10:biom10040602. [PMID: 32294981 PMCID: PMC7226026 DOI: 10.3390/biom10040602] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/07/2020] [Accepted: 04/09/2020] [Indexed: 12/14/2022] Open
Abstract
The protein tyrosine kinase Ephrin type-B receptor 3 (EPHB3) is expressed in cells at the base of intestinal crypts, acting as a cellular guide in the maintenance of intestinal crypt architecture. We aimed to investigate the expression profile of EPHB3 in colorectal precancerous lesions and colorectal cancers (CRCs), and assess its prognostic value. EPHB3 expression was higher in CRCs than in normal mucosa and was associated with the intestinal stem cell markers EPHB2, OLFM4, LRIG1, and a proposed cancer stem cell marker, CD44. Enhanced EPHB3 expression significantly declined during the transformation from adenoma to carcinoma and as the tumor invaded into deeper tissue layers. Namely, a substantial reduction of EPHB3 expression was observed in the budding cancer cells at the invasive tumor fronts, which was more extensive than E-cadherin downregulation. In an azoxymethane/dextran sulfate sodium-induced, colitis-associated, CRC model, EPHB3 expression increased along with tumor development. In a large cohort of CRC patients, EPHB3 positivity was observed in 24% of 610 CRCs and was negatively correlated with tumor differentiation, lympho-vascular invasion, and tumor, node, and metastasis stages. EPHB3 was positively associated with microsatellite instability but was associated with neither CpG island methylation, nor with KRAS and BRAF mutations. Notably, EPHB3 positivity was associated with better clinical outcomes, although it was not an independent prognostic marker. Overexpression of EPHB3 in the colon cancer cell line, DLD1, led to decreased cell growth and migration and reduced mitogen-activated protein kinase signaling. Taken together, our data demonstrate the suppressive role of EPHB3 in CRC progression.
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Liu YL, Horning AM, Lieberman B, Kim M, Lin CK, Hung CN, Chou CW, Wang CM, Lin CL, Kirma NB, Liss MA, Vasisht R, Perillo EP, Blocher K, Horng H, Taverna JA, Ruan J, Yankeelov TE, Dunn AK, Huang THM, Yeh HC, Chen CL. Spatial EGFR Dynamics and Metastatic Phenotypes Modulated by Upregulated EphB2 and Src Pathways in Advanced Prostate Cancer. Cancers (Basel) 2019; 11:cancers11121910. [PMID: 31805710 PMCID: PMC6966510 DOI: 10.3390/cancers11121910] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 11/23/2019] [Accepted: 11/26/2019] [Indexed: 12/21/2022] Open
Abstract
Advanced prostate cancer is a very heterogeneous disease reflecting in diverse regulations of oncogenic signaling pathways. Aberrant spatial dynamics of epidermal growth factor receptor (EGFR) promote their dimerization and clustering, leading to constitutive activation in oncogenesis. The EphB2 and Src signaling pathways are associated with the reorganization of the cytoskeleton leading to malignancy, but their roles in regulating EGFR dynamics and activation are scarcely reported. Using single-particle tracking techniques, we found that highly phosphorylated EGFR in the advanced prostate cancer cell line, PC3, was associated with higher EGFR diffusivity, as compared with LNCaP and less aggressive DU145. The increased EGFR activation and biophysical dynamics were consistent with high proliferation, migration, and invasion. After performing single-cell RNA-seq on prostate cancer cell lines and circulating tumor cells from patients, we identified that upregulated gene expression in the EphB2 and Src pathways are associated with advanced malignancy. After dasatinib treatment or siRNA knockdowns of EphB2 or Src, the PC3 cells exhibited significantly lower EGFR dynamics, cell motility, and invasion. Partial inhibitory effects were also found in DU145 cells. The upregulation of parts of the EphB2 and Src pathways also predicts poor prognosis in the prostate cancer patient cohort of The Cancer Genome Atlas. Our results provide evidence that overexpression of the EphB2 and Src signaling pathways regulate EGFR dynamics and cellular aggressiveness in some advanced prostate cancer cells.
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Affiliation(s)
- Yen-Liang Liu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung 404, Taiwan;
- Department of Biomedical Engineering, University of Texas at Austin, 107 W. Dean Keeton, BME Building, Austin, TX 78712, USA; (M.K.); (R.V.); (E.P.P.); (K.B.); (T.E.Y.); (A.K.D.)
| | - Aaron M. Horning
- Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center, 8210 Floyd Curl Drive, Mail code: 8257, San Antonio, TX 78229, USA; (A.M.H.); (C.-K.L.); (C.-N.H.); (C.-W.C.); (C.-M.W.); (C.-L.L.); (N.B.K.); (T.H.-M.H.)
| | - Brandon Lieberman
- Department of Biology, Trinity University, San Antonio, TX 78212, USA;
| | - Mirae Kim
- Department of Biomedical Engineering, University of Texas at Austin, 107 W. Dean Keeton, BME Building, Austin, TX 78712, USA; (M.K.); (R.V.); (E.P.P.); (K.B.); (T.E.Y.); (A.K.D.)
| | - Che-Kuang Lin
- Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center, 8210 Floyd Curl Drive, Mail code: 8257, San Antonio, TX 78229, USA; (A.M.H.); (C.-K.L.); (C.-N.H.); (C.-W.C.); (C.-M.W.); (C.-L.L.); (N.B.K.); (T.H.-M.H.)
| | - Chia-Nung Hung
- Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center, 8210 Floyd Curl Drive, Mail code: 8257, San Antonio, TX 78229, USA; (A.M.H.); (C.-K.L.); (C.-N.H.); (C.-W.C.); (C.-M.W.); (C.-L.L.); (N.B.K.); (T.H.-M.H.)
| | - Chih-Wei Chou
- Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center, 8210 Floyd Curl Drive, Mail code: 8257, San Antonio, TX 78229, USA; (A.M.H.); (C.-K.L.); (C.-N.H.); (C.-W.C.); (C.-M.W.); (C.-L.L.); (N.B.K.); (T.H.-M.H.)
| | - Chiou-Miin Wang
- Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center, 8210 Floyd Curl Drive, Mail code: 8257, San Antonio, TX 78229, USA; (A.M.H.); (C.-K.L.); (C.-N.H.); (C.-W.C.); (C.-M.W.); (C.-L.L.); (N.B.K.); (T.H.-M.H.)
| | - Chun-Lin Lin
- Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center, 8210 Floyd Curl Drive, Mail code: 8257, San Antonio, TX 78229, USA; (A.M.H.); (C.-K.L.); (C.-N.H.); (C.-W.C.); (C.-M.W.); (C.-L.L.); (N.B.K.); (T.H.-M.H.)
| | - Nameer B. Kirma
- Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center, 8210 Floyd Curl Drive, Mail code: 8257, San Antonio, TX 78229, USA; (A.M.H.); (C.-K.L.); (C.-N.H.); (C.-W.C.); (C.-M.W.); (C.-L.L.); (N.B.K.); (T.H.-M.H.)
| | - Michael A. Liss
- Department of Urology, University of Texas Health Science Center, San Antonio, TX 78229, USA;
| | - Rohan Vasisht
- Department of Biomedical Engineering, University of Texas at Austin, 107 W. Dean Keeton, BME Building, Austin, TX 78712, USA; (M.K.); (R.V.); (E.P.P.); (K.B.); (T.E.Y.); (A.K.D.)
| | - Evan P. Perillo
- Department of Biomedical Engineering, University of Texas at Austin, 107 W. Dean Keeton, BME Building, Austin, TX 78712, USA; (M.K.); (R.V.); (E.P.P.); (K.B.); (T.E.Y.); (A.K.D.)
| | - Katherine Blocher
- Department of Biomedical Engineering, University of Texas at Austin, 107 W. Dean Keeton, BME Building, Austin, TX 78712, USA; (M.K.); (R.V.); (E.P.P.); (K.B.); (T.E.Y.); (A.K.D.)
| | - Hannah Horng
- Department of Bioengineering, the University of Maryland, College Park, MD 20742, USA;
| | - Josephine A. Taverna
- Department of Medicine, Mays Cancer Center, University of Texas Health Science Center, San Antonio, TX 78229, USA;
| | - Jianhua Ruan
- Department of Computer Science, University of Texas at San Antonio, San Antonio, TX 78249, USA;
| | - Thomas E. Yankeelov
- Department of Biomedical Engineering, University of Texas at Austin, 107 W. Dean Keeton, BME Building, Austin, TX 78712, USA; (M.K.); (R.V.); (E.P.P.); (K.B.); (T.E.Y.); (A.K.D.)
- Institute for Computational Engineering and Sciences, University of Texas at Austin, Austin, TX 78712, USA
- Department of Diagnostic Medicine, Dell Medical School, University of Texas at Austin, Austin, TX 78712, USA
- Department of Oncology, Dell Medical School, University of Texas at Austin, Austin, TX 78712, USA
- Livestrong Cancer Institutes, University of Texas at Austin, Austin, TX 78712, USA
| | - Andrew K. Dunn
- Department of Biomedical Engineering, University of Texas at Austin, 107 W. Dean Keeton, BME Building, Austin, TX 78712, USA; (M.K.); (R.V.); (E.P.P.); (K.B.); (T.E.Y.); (A.K.D.)
| | - Tim H.-M. Huang
- Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center, 8210 Floyd Curl Drive, Mail code: 8257, San Antonio, TX 78229, USA; (A.M.H.); (C.-K.L.); (C.-N.H.); (C.-W.C.); (C.-M.W.); (C.-L.L.); (N.B.K.); (T.H.-M.H.)
| | - Hsin-Chih Yeh
- Department of Biomedical Engineering, University of Texas at Austin, 107 W. Dean Keeton, BME Building, Austin, TX 78712, USA; (M.K.); (R.V.); (E.P.P.); (K.B.); (T.E.Y.); (A.K.D.)
- Texas Materials Institute, University of Texas at Austin, Austin, TX 78712, USA
- Correspondence: (H.-C.Y.); (C.-L.C.); Tel.: +1-512-471-7931 (H.-C.Y.); +1-210-562-4143 (C.-L.C.); Fax: +1-512-471-0616 (H.-C.Y.); +1-210-562-4161 (C.-L.C.)
| | - Chun-Liang Chen
- Department of Molecular Medicine, Mays Cancer Center, University of Texas Health Science Center, 8210 Floyd Curl Drive, Mail code: 8257, San Antonio, TX 78229, USA; (A.M.H.); (C.-K.L.); (C.-N.H.); (C.-W.C.); (C.-M.W.); (C.-L.L.); (N.B.K.); (T.H.-M.H.)
- Correspondence: (H.-C.Y.); (C.-L.C.); Tel.: +1-512-471-7931 (H.-C.Y.); +1-210-562-4143 (C.-L.C.); Fax: +1-512-471-0616 (H.-C.Y.); +1-210-562-4161 (C.-L.C.)
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DiPrima M, Wang D, Tröster A, Maric D, Terrades-Garcia N, Ha T, Kwak H, Sanchez-Martin D, Kudlinzki D, Schwalbe H, Tosato G. Identification of Eph receptor signaling as a regulator of autophagy and a therapeutic target in colorectal carcinoma. Mol Oncol 2019; 13:2441-2459. [PMID: 31545551 PMCID: PMC6822245 DOI: 10.1002/1878-0261.12576] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 08/02/2019] [Accepted: 09/20/2019] [Indexed: 01/07/2023] Open
Abstract
Advanced colorectal carcinoma is currently incurable, and new therapies are urgently needed. We report that phosphotyrosine‐dependent Eph receptor signaling sustains colorectal carcinoma cell survival, thereby uncovering a survival pathway active in colorectal carcinoma cells. We find that genetic and biochemical inhibition of Eph tyrosine kinase activity or depletion of the Eph ligand EphrinB2 reproducibly induces colorectal carcinoma cell death by autophagy. Spautin and 3‐methyladenine, inhibitors of early steps in the autophagic pathway, significantly reduce autophagy‐mediated cell death that follows inhibition of phosphotyrosine‐dependent Eph signaling in colorectal cancer cells. A small‐molecule inhibitor of the Eph kinase, NVP‐BHG712 or its regioisomer NVP‐Iso, reduces human colorectal cancer cell growth in vitro and tumor growth in mice. Colorectal cancers express the EphrinB ligand and its Eph receptors at significantly higher levels than numerous other cancer types, supporting Eph signaling inhibition as a potential new strategy for the broad treatment of colorectal carcinoma.
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Affiliation(s)
- Michael DiPrima
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), Bethesda, MD, USA
| | - Dunrui Wang
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), Bethesda, MD, USA
| | - Alix Tröster
- Center for Biomolecular Magnetic Resonance, Institute for Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
| | - Dragan Maric
- National Institutes of Neurological Disorders and Stroke, National Institutes of Health (NIH), Bethesda, MD, USA
| | - Nekane Terrades-Garcia
- Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Spain
| | - Taekyu Ha
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), Bethesda, MD, USA
| | - Hyeongil Kwak
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), Bethesda, MD, USA
| | - David Sanchez-Martin
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), Bethesda, MD, USA
| | - Denis Kudlinzki
- Center for Biomolecular Magnetic Resonance, Institute for Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
| | - Harald Schwalbe
- Center for Biomolecular Magnetic Resonance, Institute for Organic Chemistry and Chemical Biology, Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
| | - Giovanna Tosato
- Laboratory of Cellular Oncology, Center for Cancer Research (CCR), National Cancer Institute (NCI), Bethesda, MD, USA
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Mu X, Huang O, Jiang M, Xie Z, Chen D, Zhang X. Prognostic value of ephrin B receptors in breast cancer: An online survival analysis using the microarray data of 3,554 patients. Oncol Lett 2019; 18:742-750. [PMID: 31289549 PMCID: PMC6540016 DOI: 10.3892/ol.2019.10363] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2018] [Accepted: 04/17/2019] [Indexed: 01/19/2023] Open
Abstract
The roles of Ephrin B (EphB) receptors in cancer are relatively unknown as these receptors are associated with complex signaling pathways. A limited number of studies have investigated the association between EphB receptors and prognosis. Using the Kaplan-Meier plotter database, the present study investigated the associations between the mRNA expression levels of five EphB receptors and the outcomes of 3,554 patients with breast cancer who had been followed-up for 20 years. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated to assess the relative risk of survival. The results demonstrated that high mRNA expression levels of EphB2 (HR, 0.74; 95% CI, 0.66-0.84; P=2.1×10-6), EphB4 (HR, 0.82; 95% CI, 0.72-0.93; P=0.0023) and EphB6 (HR, 0.69; 95% CI, 0.61-0.78; P=3×10-9) were significantly associated with improved survival, while a high mRNA expression level of EphB3 (HR, 1.14; 95% CI, 1.01-1.28; P=0.029) was associated with worse survival for patients with breast cancer. High expression levels of all EphB receptors, including EphB1 (HR, 1.4; 95% CI, 1.02-1.94; P=0.039), EphB2 (HR, 1.34; 95% CI, 1.07-1.67; P=0.011), EphB3 (HR, 1.39; 95% CI, 1.11-1.73, P=0.0038), EphB4 (HR, 1.33; 95% CI, 1.06-1.67; P=0.013) and EphB6 (HR, 1.32; 95% CI, 1.05-1.65; P=0.016), were associated with an increased risk of mortality in patients with lymph-node-positive breast cancer. High mRNA expression levels of EphB1 were not associated with survival for all patients with breast cancer (HR, 0.85; 95% CI, 0.72-1.01; P=0.058). The results of the present suggested that EphB receptors may be useful as prognostic biomarkers of breast cancer.
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Affiliation(s)
- Xin Mu
- Department of Urology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Ou Huang
- Comprehensive Breast Health Center, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, P.R. China
| | - Min Jiang
- Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu 215000, P.R. China
| | - Zuoquan Xie
- Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200025, P.R. China
| | - Debo Chen
- Department of Breast Oncology, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
| | - Xi Zhang
- Department of Breast Oncology, The First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China
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Zhang X, Liu S, Wang Y, Hu H, Li L, Wu Y, Cao D, Cai Y, Zhang J, Zhang X. Interleukin‑22 regulates the homeostasis of the intestinal epithelium during inflammation. Int J Mol Med 2019; 43:1657-1668. [PMID: 30816423 PMCID: PMC6414155 DOI: 10.3892/ijmm.2019.4092] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 01/30/2019] [Indexed: 12/13/2022] Open
Abstract
Interleukin‑22 (IL‑22) has both pro‑inflammatory and anti‑inflammatory properties in a number tissues depending on the environment. Epithelial cells usually have a rapid turnover and are fueled by tissue stem cells. However, the question of whether IL‑22 regulates tissue homeostasis through the modulation of stem cells remains unanswered. In this study, we investigated the role of IL‑22 in the homeostasis of intestinal epithelial cells (IECs) during inflammation through a 3D organoid culture system. qPCR was performed to detect the changes in important gene transcriptions, and immunohistochemistry and western blot analysis were carried out to determine protein expression. As a result, we found that the expression of IL‑22 was synchronously altered with the damage of the intestine. IL‑22 treatment promoted cell proliferation and suppressed the cell differentiation of intestinal organoids. Surprisingly, IL‑22 also led to self‑renewal defects of intestinal stem cells (ISCs), thereby eventually resulting in the death of organoids. In examining the underlying mechanisms, we found that IL‑22 activated signal transducer and activator of transcription 3 (Stat3) phosphorylation and suppressed the Wnt and Notch signaling pathways. Importantly, Wnt3a treatment attenuated the organoid defects caused by IL‑22, which consolidated the importance of Wnt pathway at the downstream of IL‑22. Collectively, the findings of this study indicate that IL‑22 regulates the homeostasis of the intestinal epithelium and is critical for the regeneration of the intestine during inflammation. Thus, the data of this study may provide a potential strategy and a basis for the treatment of diseases of intestinal inflammation in clinical practice.
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Affiliation(s)
- Xinyan Zhang
- Hospital and Institute of Obstetrics and Gynecology Affiliated to Fudan University, Shanghai 200011
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241
| | - Shijie Liu
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241
| | - Yueqian Wang
- Shanghai The Fifth People’s Hospital Affiliated to Fudan University, Shanghai 200240
| | - Huiqiong Hu
- Southern Medical University Affiliated Fengxian Hospital, Shanghai 201499
| | - Liang Li
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241
| | - Yibin Wu
- Shanghai The Fifth People’s Hospital Affiliated to Fudan University, Shanghai 200240
| | - Duo Cao
- College of Life Sciences, Northwest University, Xi’an, Shanxi 710069, P.R. China
| | - Yuankun Cai
- Shanghai The Fifth People’s Hospital Affiliated to Fudan University, Shanghai 200240
| | - Jiqin Zhang
- East China Normal University and Shanghai Fengxian District Central Hospital Joint Center for Translational Medicine, Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai 200241
| | - Xueli Zhang
- Southern Medical University Affiliated Fengxian Hospital, Shanghai 201499
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Niethamer TK, Bush JO. Getting direction(s): The Eph/ephrin signaling system in cell positioning. Dev Biol 2019; 447:42-57. [PMID: 29360434 PMCID: PMC6066467 DOI: 10.1016/j.ydbio.2018.01.012] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2017] [Revised: 12/21/2017] [Accepted: 01/18/2018] [Indexed: 12/16/2022]
Abstract
In vertebrates, the Eph/ephrin family of signaling molecules is a large group of membrane-bound proteins that signal through a myriad of mechanisms and effectors to play diverse roles in almost every tissue and organ system. Though Eph/ephrin signaling has functions in diverse biological processes, one core developmental function is in the regulation of cell position and tissue morphology by regulating cell migration and guidance, cell segregation, and boundary formation. Often, the role of Eph/ephrin signaling is to translate patterning information into physical movement of cells and changes in morphology that define tissue and organ systems. In this review, we focus on recent advances in the regulation of these processes, and our evolving understanding of the in vivo signaling mechanisms utilized in distinct developmental contexts.
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Affiliation(s)
- Terren K Niethamer
- Department of Cell and Tissue Biology, Program in Craniofacial Biology, and Institute of Human Genetics, University of California at San Francisco, San Francisco, CA 94143, USA
| | - Jeffrey O Bush
- Department of Cell and Tissue Biology, Program in Craniofacial Biology, and Institute of Human Genetics, University of California at San Francisco, San Francisco, CA 94143, USA.
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Lu Y, Li Y, Wang Z, Xie S, Wang Q, Lei X, Ruan Y, Li J. Downregulation of RGMA by HIF-1A/miR-210-3p axis promotes cell proliferation in oral squamous cell carcinoma. Biomed Pharmacother 2019; 112:108608. [PMID: 30798120 DOI: 10.1016/j.biopha.2019.108608] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 01/16/2019] [Accepted: 01/23/2019] [Indexed: 12/15/2022] Open
Abstract
Repulsive guidance molecules comprise a group of proteins that play an important role in carcinogenesis through interactions with their receptors, but their function in oral squamous cell carcinoma (OSCC) is unclear. Here, we investigated the potential role of the RGM family members in oral cancer pathogenesis. Our study showed that only RGMA was significantly downregulated in the OSCC tissues analyzed by TCGA and validated this finding in OSCC cells. The decreased expression of RGMA was strongly associated with the T stage and with poor prognosis. The ectopic expression of RGMA significantly inhibited the proliferation of OSCC cells both in vitro and in vivo. Moreover, we confirmed that RGMA was a target of miR-210-3p in OSCC and miR-210-3p overexpression contributed to the acceleration of OSCC growth. Further experiments revealed that HIF1A specifically interacted with the promoter of miR-210-3p and enhanced its expression. In summary, our research indicates that RGMA is regulated by the HIF1A/miR-210-3p axis and inhibits OSCC cell proliferation; thus, in the future, the development of therapies that target the HIF1A/miR-210-3p/RGMA axis may aid in the treatment of aggressive cancers.
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Affiliation(s)
- Yingjuan Lu
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China; Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Yingru Li
- Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, the Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510120, China; Department of Gastroenterology, Hernia and Abdominal Wall Surgery, The sixth affiliated Hospital, Sun Yat_Sen University, Guangzhou, 510120, China
| | - Zhangsong Wang
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China; Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Shule Xie
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China; Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Qing Wang
- Department of Dentistry, Weifang Peoples' Hospital, Weifang, 261000, Shandong Province, China
| | - Xinyuan Lei
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China; Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China
| | - Yi Ruan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China; Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
| | - Jinsong Li
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China; Department of Oral & Maxillofacial Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, 510120, China.
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50
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Pérez-González C, Alert R, Blanch-Mercader C, Gómez-González M, Kolodziej T, Bazellieres E, Casademunt J, Trepat X. Active wetting of epithelial tissues. NATURE PHYSICS 2019; 15:79-88. [PMID: 31537984 PMCID: PMC6753015 DOI: 10.1038/s41567-018-0279-5] [Citation(s) in RCA: 116] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Development, regeneration and cancer involve drastic transitions in tissue morphology. In analogy with the behavior of inert fluids, some of these transitions have been interpreted as wetting transitions. The validity and scope of this analogy are unclear, however, because the active cellular forces that drive tissue wetting have been neither measured nor theoretically accounted for. Here we show that the transition between two-dimensional epithelial monolayers and three-dimensional spheroidal aggregates can be understood as an active wetting transition whose physics differs fundamentally from that of passive wetting phenomena. By combining an active polar fluid model with measurements of physical forces as a function of tissue size, contractility, cell-cell and cell-substrate adhesion, and substrate stiffness, we show that the wetting transition results from the competition between traction forces and contractile intercellular stresses. This competition defines a new intrinsic lengthscale that gives rise to a critical size for the wetting transition in tissues, a striking feature that has no counterpart in classical wetting. Finally, we show that active shape fluctuations are dynamically amplified during tissue dewetting. Overall, we conclude that tissue spreading constitutes a prominent example of active wetting - a novel physical scenario that may explain morphological transitions during tissue morphogenesis and tumor progression.
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Affiliation(s)
- Carlos Pérez-González
- Institute for Bioengineering of Catalonia, The Barcelona Institute
for Science and Technology (BIST), Barcelona 08028, Spain
- Facultat de Medicina, University of Barcelona, 08028 Barcelona,
Spain
| | - Ricard Alert
- Departament de Física de la Matèria Condensada,
Facultat de Física, University of Barcelona, 08028 Barcelona, Spain
- University of Barcelona Institute of Complex Systems (UBICS), 08028
Barcelona, Spain
| | - Carles Blanch-Mercader
- Laboratoire Physico Chimie Curie, Institut Curie, PSL Research
University - Sorbonne Universités, UPMC CNRS, UMR 168, 26 rue d’Ulm,
F-75248 Paris Cedex 05, France
- Department of Biochemistry and NCCR Chemical Biology, Sciences II,
University of Geneva, Quai Ernest-Ansermet 30, Geneva, CH-1211, Switzerland
| | - Manuel Gómez-González
- Institute for Bioengineering of Catalonia, The Barcelona Institute
for Science and Technology (BIST), Barcelona 08028, Spain
| | - Tomasz Kolodziej
- Faculty of Physics, Astronomy and Applied Computer Science,
Jagiellonian University in Kraków, 30-348 Kraków, Poland
| | - Elsa Bazellieres
- Institute for Bioengineering of Catalonia, The Barcelona Institute
for Science and Technology (BIST), Barcelona 08028, Spain
| | - Jaume Casademunt
- Departament de Física de la Matèria Condensada,
Facultat de Física, University of Barcelona, 08028 Barcelona, Spain
- University of Barcelona Institute of Complex Systems (UBICS), 08028
Barcelona, Spain
- Corresponding authors: Jaume Casademunt, PhD, Professor of
Physics, Depertment of Condensed Matter Physics (University of Barcelona -
UBICS), Martí i Franquès, 1, 08028, Barcelona, Spain, (+34) 934
021 188, ; Xavier Trepat, PhD, ICREA
Research Professor, Institute for Bioengineering of Catalonia, Ed. Hèlix,
Baldiri i Reixac, 15-21, 08028, Barcelona, Spain, (+34) 934 020 265,
| | - Xavier Trepat
- Institute for Bioengineering of Catalonia, The Barcelona Institute
for Science and Technology (BIST), Barcelona 08028, Spain
- Facultat de Medicina, University of Barcelona, 08028 Barcelona,
Spain
- Institució Catalana de Recerca i Estudis Avançats
(ICREA), Barcelona, Spain
- Centro de Investigación Biomédica en Red en
Bioingeniería, Biomateriales y Nanomedicina, 08028, Spain
- Corresponding authors: Jaume Casademunt, PhD, Professor of
Physics, Depertment of Condensed Matter Physics (University of Barcelona -
UBICS), Martí i Franquès, 1, 08028, Barcelona, Spain, (+34) 934
021 188, ; Xavier Trepat, PhD, ICREA
Research Professor, Institute for Bioengineering of Catalonia, Ed. Hèlix,
Baldiri i Reixac, 15-21, 08028, Barcelona, Spain, (+34) 934 020 265,
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