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1
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Heidari Z, Naeimzadeh Y, Fallahi J, Savardashtaki A, Razban V, Khajeh S. The Role of Tissue Factor In Signaling Pathways of Pathological Conditions and Angiogenesis. Curr Mol Med 2024; 24:1135-1151. [PMID: 37817529 DOI: 10.2174/0115665240258746230919165935] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 07/10/2023] [Accepted: 07/27/2023] [Indexed: 10/12/2023]
Abstract
Tissue factor (TF) is an integral transmembrane protein associated with the extrinsic coagulation pathway. TF gene expression is regulated in response to inflammatory cytokines, bacterial lipopolysaccharides, and mechanical injuries. TF activity may be affected by phosphorylation of its cytoplasmic domain and alternative splicing. TF acts as the primary initiator of physiological hemostasis, which prevents local bleeding at the injury site. However, aberrant expression of TF, accompanied by the severity of diseases and infections under various pathological conditions, triggers multiple signaling pathways that support thrombosis, angiogenesis, inflammation, and metastasis. Protease-activated receptors (PARs) are central in the downstream signaling pathways of TF. In this study, we have reviewed the TF signaling pathways in different pathological conditions, such as wound injury, asthma, cardiovascular diseases (CVDs), viral infections, cancer and pathological angiogenesis. Angiogenic activities of TF are critical in the repair of wound injuries and aggressive behavior of tumors, which are mainly performed by the actions of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor-1 (HIF1-α). Pro-inflammatory effects of TF have been reported in asthma, CVDs and viral infections, including COVID-19, which result in tissue hypertrophy, inflammation, and thrombosis. TF-FVII induces angiogenesis via clotting-dependent and -independent mechanisms. Clottingdependent angiogenesis is induced via the generation of thrombin and cross-linked fibrin network, which facilitate vessel infiltration and also act as a reservoir for endothelial cells (ECs) growth factors. Expression of TF in tumor cells and ECs triggers clotting-independent angiogenesis through induction of VEGF, urokinase-type plasminogen activator (uPAR), early growth response 1 (EGR1), IL8, and cysteine-rich angiogenic inducer 61 (Cyr61).
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Affiliation(s)
- Zahra Heidari
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Yasaman Naeimzadeh
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Jafar Fallahi
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Amir Savardashtaki
- Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
- Infertility Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Vahid Razban
- Department of Molecular Medicine, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sahar Khajeh
- Bone and Joint Diseases Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
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2
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Ren Z, Xue Y, Liu L, Zhang X, Pei J, Zhang Y, Wang Y, Yu K. Tissue factor overexpression in triple-negative breast cancer promotes immune evasion by impeding T-cell infiltration and effector function. Cancer Lett 2023; 565:216221. [PMID: 37192729 DOI: 10.1016/j.canlet.2023.216221] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/27/2023] [Accepted: 05/08/2023] [Indexed: 05/18/2023]
Abstract
Triple-negative breast cancer (TNBC) remains a most deadly human malignancy with limited response to chemotherapy, targeted therapy and immunotherapy. Tumor immunoenvironment plays an increasingly important role in therapy outcome. Tissue factor (TF) is the target of the FDA-approved ADC Tivdak. HuSC1-39 is the parent antibody of MRG004A, a clinical stage TF-ADC (NCT04843709). Here, we employed HuSC1-39 (termed "anti-TF") to investigate the role of TF in regulating immune-tolerance in TNBC. We found that patients with aberrant TF expression had a poor prognosis and low immune effector cell infiltration, characterizing as "cold tumor". In the 4T1 TNBC syngeneic mouse model, knockout of tumor cell TF inhibited tumor growth and increased tumor infiltration of effector T cell, which was not dependent on the clotting inhibition. In an immune-reconstituted M-NSG mouse model of TNBC, anti-TF inhibited tumor growth, which was further enhanced by a dual-targeting anti-TF&TGFβR fusion protein. There were diminished P-AKT and P-ERK signaling and profound tumor cell death in treated tumors. Transcriptome analyses and immunohistochemistry revealed a dramatically improved tumor immunoenvironment including the increase of effector T cells, decrease of Treg cells and the transformation of tumor into "hot tumor". Moreover, employing qPCR analysis and T cell culture, we further demonstrated that TF expression in tumor cells is sufficient to block the synthesis and secretion of T cell-recruiting chemokine CXCL9/10/11. Treatment of TF-high TNBC cells with anti-TF or TF-knockout all stimulated CXCL9/10/11 production, promoted T cell migration and effector function. Thus, we have identified a new mechanism of TF in TNBC tumor progression and therapy resistance.
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Affiliation(s)
- Zhiqiang Ren
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Yinyin Xue
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Liang Liu
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Xuesai Zhang
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Jinpeng Pei
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Yu Zhang
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Yue Wang
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China
| | - Ker Yu
- Department of Pharmacology, Fudan University School of Pharmacy, Shanghai, 201203, China.
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3
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Newcomer MM, Dorayappan KDP, Wagner V, Suarez AA, Calo CA, Kalmar EL, Maxwell GL, O'Malley D, Cohn DE, Tweedle MF, Selvendiran K. Tissue factor as a novel diagnostic target for early detection of ovarian cancer using ultrasound microbubbles. Gynecol Oncol 2023; 173:138-150. [PMID: 37178671 DOI: 10.1016/j.ygyno.2023.04.008] [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: 07/22/2022] [Revised: 03/29/2023] [Accepted: 04/12/2023] [Indexed: 05/15/2023]
Abstract
INTRODUCTION Ovarian cancer (OC) is the deadliest gynecologic malignancy, with an overall 5-year survival rate of less than 30%. The existing paradigm for OC detection involves a serum marker, CA125, and ultrasound examination, neither of which is sufficiently specific for OC. This study addresses this deficiency through the use of a targeted ultrasound microbubble directed against tissue factor (TF). METHODS TF expression was examined in both OC cell lines and patient-derived tumor samples via western blotting and IHC. In vivo microbubble ultrasound imaging was analyzed using high grade serous ovarian carcinoma orthotopic mouse models. RESULTS While TF expression has previously been described on angiogenic, tumor-associated vascular endothelial cells (VECs) of several tumor types, this is first study to show TF expression on both murine and patient-derived ovarian tumor-associated VECs. Biotinylated anti-TF antibody was conjugated to streptavidin-coated microbubbles and in vitro binding assays were performed to assess the binding efficacy of these agents. TF-targeted microbubbles successfully bound to TF-expressing OC cells, as well as an in vitro model of angiogenic endothelium. In vivo, these microbubbles bound to the tumor-associated VECs of a clinically relevant orthotopic OC mouse model. CONCLUSION Development of a TF-targeted microbubble capable of successfully detecting ovarian tumor neovasculature could have significant implications towards increasing the number of early-stage OC diagnoses. This preclinical study shows potential for translation to clinical use, which could ultimately help increase the number of early OC detections and decrease the mortality associated with this disease.
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Affiliation(s)
- Meghan M Newcomer
- Division of Anatomy, College of Medicine, The Ohio State University, Columbus, OH, USA; Department of Anatomy, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
| | - Kalpana Deepa Priya Dorayappan
- Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Vincent Wagner
- Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Adrian A Suarez
- Department of Pathology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Corinne A Calo
- Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Eileen L Kalmar
- Division of Anatomy, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - G Larry Maxwell
- Inova Women's Service Line and the Inova Schar Cancer Institute, Falls Church, VA, USA
| | - David O'Malley
- Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - David E Cohn
- Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Michael F Tweedle
- Department of Radiology, Comprehensive Cancer Center, The Ohio State University, USA
| | - Karuppaiyah Selvendiran
- Division of Gynecologic Oncology, Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA..
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de Bono JS, Harris JR, Burm SM, Vanderstichele A, Houtkamp MA, Aarass S, Riisnaes R, Figueiredo I, Nava Rodrigues D, Christova R, Olbrecht S, Niessen HWM, Ruuls SR, Schuurhuis DH, Lammerts van Bueren JJ, Breij ECW, Vergote I. Systematic study of tissue factor expression in solid tumors. Cancer Rep (Hoboken) 2023; 6:e1699. [PMID: 36806722 PMCID: PMC9940005 DOI: 10.1002/cnr2.1699] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 07/19/2022] [Accepted: 07/31/2022] [Indexed: 11/08/2022] Open
Abstract
BACKGROUND Elevated tissue factor (TF) expression, although restricted in normal tissue, has been reported in multiple solid cancers, and expression has been associated with poor prognosis. This manuscript compares TF expression across various solid tumor types via immunohistochemistry in a single study, which has not been performed previously. AIMS To increase insight in the prevalence and cellular localization of TF expression across solid cancer types, we performed a detailed and systematic analysis of TF expression in tumor tissue obtained from patients with ovarian, esophageal, bladder, cervical, endometrial, pancreatic, prostate, colon, breast, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (HNSCC), and glioblastoma. The spatial and temporal variation of TF expression was analyzed over time and upon disease progression in patient-matched biopsies taken at different timepoints. In addition, TF expression in patient-matched primary tumor and metastatic lesions was also analyzed. METHODS AND RESULTS TF expression was detected via immunohistochemistry (IHC) using a validated TF-specific antibody. TF was expressed in all cancer types tested, with highest prevalence in pancreatic cancer, cervical cancer, colon cancer, glioblastoma, HNSCC, and NSCLC, and lowest in breast cancer. Staining was predominantly membranous in pancreatic, cervical, and HNSCC, and cytoplasmic in glioblastoma and bladder cancer. In general, expression was consistent between biopsies obtained from the same patient over time, although variability was observed for individual patients. NSCLC biopsies of primary tumor and matched lymph node metastases showed no clear difference in TF expression overall, although individual patient changes were observed. CONCLUSION This study shows that TF is expressed across a broad range of solid cancer types, and expression is present upon tumor dissemination and over the course of treatment.
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Affiliation(s)
| | | | | | - Adriaan Vanderstichele
- Department of Gynaecology and Obstetrics, Division of Gynaecologic OncologyUniversity Hospitals Leuven, Leuven Cancer InstituteLeuvenBelgium
| | | | - Saida Aarass
- GenmabPlainsboroNew JerseyUSA
- GenmabUtrechtThe Netherlands
| | - Ruth Riisnaes
- The Institute of Cancer ResearchRoyal Cancer HospitalLondonUK
| | - Ines Figueiredo
- The Institute of Cancer ResearchRoyal Cancer HospitalLondonUK
| | | | | | - Siel Olbrecht
- Department of Gynaecology and Obstetrics, Division of Gynaecologic OncologyUniversity Hospitals Leuven, Leuven Cancer InstituteLeuvenBelgium
| | | | | | | | | | | | - Ignace Vergote
- Department of Gynaecology and Obstetrics, Division of Gynaecologic OncologyUniversity Hospitals Leuven, Leuven Cancer InstituteLeuvenBelgium
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Proteins Found in the Triple-Negative Breast Cancer Secretome and Their Therapeutic Potential. Int J Mol Sci 2023; 24:ijms24032100. [PMID: 36768435 PMCID: PMC9916912 DOI: 10.3390/ijms24032100] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/15/2023] [Accepted: 01/17/2023] [Indexed: 01/24/2023] Open
Abstract
The cancer secretome comprises factors secreted by tumors, including cytokines, growth factors, proteins from the extracellular matrix (ECM), proteases and protease inhibitors, membrane and extracellular vesicle proteins, peptide hormones, and metabolic proteins. Secreted proteins provide an avenue for communication with other tumor cells and stromal cells, and these in turn promote tumor growth and progression. Breast cancer is the most commonly diagnosed cancer in women in the US and worldwide. Triple-negative breast cancer (TNBC) is characterized by its aggressiveness and its lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2, making it unable to be treated with therapies targeting these protein markers, and leaving patients to rely on standard chemotherapy. In order to develop more effective therapies against TNBC, researchers are searching for targetable molecules specific to TNBC. Proteins in the TNBC secretome are involved in wide-ranging cancer-promoting processes, including tumor growth, angiogenesis, inflammation, the EMT, drug resistance, invasion, and development of the premetastatic niche. In this review, we catalog the currently known proteins in the secretome of TNBC tumors and correlate these secreted molecules with potential therapeutic opportunities to facilitate translational research.
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Strasenburg W, Jóźwicki J, Durślewicz J, Kuffel B, Kulczyk MP, Kowalewski A, Grzanka D, Drewa T, Adamowicz J. Tumor Cell-Induced Platelet Aggregation as an Emerging Therapeutic Target for Cancer Therapy. Front Oncol 2022; 12:909767. [PMID: 35814405 PMCID: PMC9259835 DOI: 10.3389/fonc.2022.909767] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Tumor cells have the ability to induce platelet activation and aggregation. This has been documented to be involved in tumor progression in several types of cancers, such as lung, colon, breast, pancreatic, ovarian, and brain. During the process, platelets protect circulating tumor cells from the deleterious effects of shear forces, shield tumor cells from the immune system, and provide growth factors, facilitating metastatic spread and tumor growth at the original site as well as at the site of metastasis. Herein, we present a wider view on the induction of platelet aggregation by specific factors primarily developed by cancer, including coagulation factors, adhesion receptors, growth factors, cysteine proteases, matrix metalloproteinases, glycoproteins, soluble mediators, and selectins. These factors may be presented on the surface of tumor cells as well as in their microenvironment, and some may trigger more than just one simple receptor-ligand mechanism. For a better understanding, we briefly discuss the physiological role of the factors in the platelet activation process, and subsequently, we provide scientific evidence and discuss their potential role in the progression of specific cancers. Targeting tumor cell-induced platelet aggregation (TCIPA) by antiplatelet drugs may open ways to develop new treatment modalities. On the one hand, it may affect patients' prognosis by enhancing known therapies in advanced-stage tumors. On the other hand, the use of drugs that are mostly easily accessible and widely used in general practice may be an opportunity to propose an unparalleled antitumor prophylaxis. In this review, we present the recent discoveries of mechanisms by which cancer cells activate platelets, and discuss new platelet-targeted therapeutic strategies.
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Affiliation(s)
- Wiktoria Strasenburg
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Jakub Jóźwicki
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Justyna Durślewicz
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Błażej Kuffel
- Department of General and Oncological Urology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Martyna Parol Kulczyk
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Adam Kowalewski
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Dariusz Grzanka
- Department of Clinical Pathomorphology, Faculty of Medicine, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, Toruń, Poland
| | - Tomasz Drewa
- Department of General and Oncological Urology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
| | - Jan Adamowicz
- Department of General and Oncological Urology, Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, Toruń, Poland
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Zarychta E, Ruszkowska-Ciastek B. Cooperation between Angiogenesis, Vasculogenesis, Chemotaxis, and Coagulation in Breast Cancer Metastases Development: Pathophysiological Point of View. Biomedicines 2022; 10:biomedicines10020300. [PMID: 35203510 PMCID: PMC8869468 DOI: 10.3390/biomedicines10020300] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/20/2022] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Breast cancer is one of the main causes of morbidity and mortality in women. Early breast cancer has a relatively good prognosis, in contrast to metastatic disease with rather poor outcomes. Metastasis formation in distant organs is a complex process requiring cooperation of numerous cells, growth factors, cytokines, and chemokines. Tumor growth, invasion, and finally systemic spread are driven by processes of angiogenesis, vasculogenesis, chemotaxis, and coagulation. This review summarizes their role in development of distant metastases in breast cancer, as well as explains the essential processes occurring throughout these actions. Abstract With almost 2.3 million new cases and 685 thousand fatal events in 2020 alone, breast cancer remains one of the main causes of morbidity and mortality in women worldwide. Despite the increasing prevalence of the disease in recent years, the number of deaths has dropped—this is mostly the result of better diagnostic and therapeutic opportunities, allowing to recognize and treat breast cancer earlier and more efficiently. However, metastatic disease still remains a therapeutic challenge. As mechanisms of tumor spread are being explored, new drugs can be implemented in clinical practice, improving the outcomes in patients with advanced disease. Formation of metastases is a complex process, which involves activation of angiogenesis, vasculogenesis, chemotaxis, and coagulation. The actions, which occur during metastatic spread are interrelated and complementary. This review summarizes their importance and mutual connections in formation of secondary tumors in breast cancer.
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Nassar E, Hassan N, El-Ghonaimy EA, Hassan H, Abdullah MS, Rottke TV, Kiesel L, Greve B, Ibrahim SA, Götte M. Syndecan-1 Promotes Angiogenesis in Triple-Negative Breast Cancer through the Prognostically Relevant Tissue Factor Pathway and Additional Angiogenic Routes. Cancers (Basel) 2021; 13:cancers13102318. [PMID: 34066023 PMCID: PMC8150756 DOI: 10.3390/cancers13102318] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Revised: 05/07/2021] [Accepted: 05/07/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Triple-negative breast cancer is an aggressive subtype of breast cancer characterized by tumor angiogenesis and poor patient survival. Here, we analyzed the function of the cell surface molecule Syndecan-1 in tumor angiogenesis in a 3D cell culture system. As a novel finding, we demonstrate that downregulation of Syndecan-1 reduces angiogenesis by decreasing the amount of angiogenesis factors of the tissue factor pathway. Furthermore, we show that the components of this pathway are associated with the prognosis of breast cancer patients. Our study identifies Syndecan-1 and the tissue factor pathway as novel potential therapeutic targets in the aggressive triple-negative subtype of breast cancer, for which no targeted therapies are currently available. Abstract Triple-negative breast cancer (TNBC) is characterized by increased angiogenesis, metastasis, and poor survival. Dysregulation of the cell surface heparan sulfate proteoglycan and signaling co-receptor Syndecan-1 is linked to poor prognosis. To study its role in angiogenesis, we silenced Syndecan-1 in TNBC cell lines using a 3D human umbilical vein endothelial cell (HUVEC) co-culture system. Syndecan-1 siRNA depletion in SUM-149, MDA-MB-468, and MDA-MB-231 cells decreased HUVEC tubule network formation. Angiogenesis array revealed reduced VEGF-A and tissue factor (TF) in the Syndecan-1-silenced secretome. qPCR independently confirmed altered expression of F3, F7, F2R/PAR1, F2RL1/PAR2, VEGF-A, EDN1, IGFBP1, and IGFBP2 in SUM-149, MDA-MB-231, and MDA-MB-468 cells. ELISA revealed reduced secreted endothelin-1 (SUM-149, MDA-MB-468) and TF (all cell lines) upon Syndecan-1 depletion, while TF pathway inhibitor treatment impaired angiogenesis. Survival analysis of 3951 patients demonstrated that high expression of F3 and F7 are associated with better relapse-free survival, whereas poor survival was observed in TNBC and p53 mutant basal breast cancer (F3) and in ER-negative and HER2-positive breast cancer (F2R, F2RL1). STRING protein network analysis revealed associations of Syndecan-1 with VEGF-A and IGFBP1, further associated with the TF and ET-1 pathways. Our study suggests that TNBC Syndecan-1 regulates angiogenesis via the TF and additional angiogenic pathways and marks its constituents as novel prognostic markers and therapeutic targets.
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Affiliation(s)
- Eyyad Nassar
- Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, D11, 48149 Münster, Germany; (E.N.); (N.H.); (E.A.E.-G.); (T.V.R.); (L.K.)
| | - Nourhan Hassan
- Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, D11, 48149 Münster, Germany; (E.N.); (N.H.); (E.A.E.-G.); (T.V.R.); (L.K.)
- Biotechnology/Biomolecular Chemistry Program, Faculty of Science, Cairo University, 12613 Giza, Egypt;
| | - Eslam A. El-Ghonaimy
- Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, D11, 48149 Münster, Germany; (E.N.); (N.H.); (E.A.E.-G.); (T.V.R.); (L.K.)
- Department of Zoology, Faculty of Science, Cairo University, 12613 Giza, Egypt;
| | - Hebatallah Hassan
- Department of Zoology, Faculty of Science, Cairo University, 12613 Giza, Egypt;
| | - Mahmoud Salah Abdullah
- Biotechnology/Biomolecular Chemistry Program, Faculty of Science, Cairo University, 12613 Giza, Egypt;
| | - Theresa V. Rottke
- Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, D11, 48149 Münster, Germany; (E.N.); (N.H.); (E.A.E.-G.); (T.V.R.); (L.K.)
| | - Ludwig Kiesel
- Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, D11, 48149 Münster, Germany; (E.N.); (N.H.); (E.A.E.-G.); (T.V.R.); (L.K.)
| | - Burkhard Greve
- Department of Radiotherapy and Radiooncology, University Hospital Münster, 48149 Münster, Germany;
| | - Sherif Abdelaziz Ibrahim
- Department of Zoology, Faculty of Science, Cairo University, 12613 Giza, Egypt;
- Correspondence: (S.A.I.); (M.G.)
| | - Martin Götte
- Department of Gynecology and Obstetrics, Münster University Hospital, Albert-Schweitzer-Campus 1, D11, 48149 Münster, Germany; (E.N.); (N.H.); (E.A.E.-G.); (T.V.R.); (L.K.)
- Correspondence: (S.A.I.); (M.G.)
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Mendoza-Almanza G, Burciaga-Hernández L, Maldonado V, Melendez-Zajgla J, Olmos J. Role of platelets and breast cancer stem cells in metastasis. World J Stem Cells 2020; 12:1237-1254. [PMID: 33312396 PMCID: PMC7705471 DOI: 10.4252/wjsc.v12.i11.1237] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/23/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
The high mortality rate of breast cancer is mainly caused by the metastatic ability of cancer cells, resistance to chemotherapy and radiotherapy, and tumor regression capacity. In recent years, it has been shown that the presence of breast cancer stem cells is closely associated with the migration and metastatic ability of cancer cells, as well as with their resistance to chemotherapy and radiotherapy. The tumor microenvironment is one of the main molecular factors involved in cancer and metastatic processes development, in this sense it is interesting to study the role of platelets, one of the main communicator cells in the human body which are activated by the signals they receive from the microenvironment and can generate more than one response. Platelets can ingest and release RNA, proteins, cytokines and growth factors. After the platelets interact with the tumor microenvironment, they are called "tumor-educated platelets." Tumor-educated platelets transport material from the tumor microenvironment to sites adjacent to the tumor, thus helping to create microenvironments conducive for the development of primary and metastatic tumors. It has been observed that the clone capable of carrying out the metastatic process is a cancer cell with stem cell characteristics. Cancer stem cells go through a series of processes, including epithelial-mesenchymal transition, intravasation into blood vessels, movement through blood vessels, extravasation at the site of the establishment of a metastatic focus, and site colonization. Tumor-educated platelets support all these processes.
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Affiliation(s)
| | | | - Vilma Maldonado
- Laboratorio de Epigenética, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Melendez-Zajgla
- Génómica funcional del cáncer, Instituto Nacional de Medicina Genómica, Ciudad de México 14610, Mexico
| | - Jorge Olmos
- Biotecnología Marina, Centro de Investigación Científica y de Estudios Superiores de Ensenada, Ensenada 22860, Mexico
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10
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Kong D, Hughes CJ, Ford HL. Cellular Plasticity in Breast Cancer Progression and Therapy. Front Mol Biosci 2020; 7:72. [PMID: 32391382 PMCID: PMC7194153 DOI: 10.3389/fmolb.2020.00072] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2020] [Accepted: 03/31/2020] [Indexed: 12/24/2022] Open
Abstract
With the exception of non-melanoma skin cancer, breast cancer is the most frequently diagnosed malignant disease among women, with the majority of mortality being attributable to metastatic disease. Thus, even with improved early screening and more targeted treatments which may enable better detection and control of early disease progression, metastatic disease remains a significant problem. While targeted therapies exist for breast cancer patients with particular subtypes of the disease (Her2+ and ER/PR+), even in these subtypes the therapies are often not efficacious once the patient's tumor metastasizes. Increases in stemness or epithelial-to-mesenchymal transition (EMT) in primary breast cancer cells lead to enhanced plasticity, enabling tumor progression, therapeutic resistance, and distant metastatic spread. Numerous signaling pathways, including MAPK, PI3K, STAT3, Wnt, Hedgehog, and Notch, amongst others, play a critical role in maintaining cell plasticity in breast cancer. Understanding the cellular and molecular mechanisms that regulate breast cancer cell plasticity is essential for understanding the biology of breast cancer progression and for developing novel and more effective therapeutic strategies for targeting metastatic disease. In this review we summarize relevant literature on mechanisms associated with breast cancer plasticity, tumor progression, and drug resistance.
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Affiliation(s)
- Deguang Kong
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Department of General Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Connor J. Hughes
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Heide L. Ford
- Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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11
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Algarni A, Greenman J, Madden LA. Procoagulant tumor microvesicles attach to endothelial cells on biochips under microfluidic flow. BIOMICROFLUIDICS 2019; 13:064124. [PMID: 31832122 PMCID: PMC6897561 DOI: 10.1063/1.5123462] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 11/22/2019] [Indexed: 05/11/2023]
Abstract
Tumor patients are at a high risk of venous thromboembolism (VTE), and the mechanism by which this occurs may involve tumor-derived microvesicles (MVs). Previously, it has been shown that tumor MVs become attached to endothelial cells in static conditions. To investigate whether this process occurs under physiologically relevant flow rates, tumor MVs were perfused across a microfluidic device coated with growing human umbilical vein endothelial cells (HUVECs). Cell lines were screened for their ability to form tumor spheroids, and two cell lines, ES-2 and U87, were selected; spheroids formed were transferred to a microfluidic chip, and a second endothelial cell biochip was coated with HUVECs and the two chips were linked. Media flowed through the spheroid chip to the endothelial chip, and procoagulant activity (PCA) of the tumor media was determined by a one-stage prothrombin time assay. Tumor MVs were also quantified by flow cytometry before and after interaction with HUVECs. Confocal images showed that HUVECs acquired fluorescence from MV attachment. Labeled MVs were proportionally lost from MV rich media with time when flowed over HUVECs and were not observed on a control chip. The loss of MV was accompanied by a proportional reduction in PCA. Flow cytometry, confocal microscopy, and live flow imagery captured under pulsatile flow confirmed an association between tumor MVs and HUVECs. Tumor MVs attached to endothelial cells under physiological flow rates, which may be relevant to the VTE pathways in cancer patients.
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Affiliation(s)
| | | | - Leigh A. Madden
- Author to whom correspondence should be addressed:. Tel.: 441482466031
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12
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Das K, Paul S, Singh A, Ghosh A, Roy A, Ansari SA, Prasad R, Mukherjee A, Sen P. Triple-negative breast cancer-derived microvesicles transfer microRNA221 to the recipient cells and thereby promote epithelial-to-mesenchymal transition. J Biol Chem 2019; 294:13681-13696. [PMID: 31341019 DOI: 10.1074/jbc.ra119.008619] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 07/08/2019] [Indexed: 12/15/2022] Open
Abstract
The triple-negative phenotype is the most prevalent form of human breast cancer worldwide and is characterized by poor survival, high aggressiveness, and recurrence. Microvesicles (MV) are shredded plasma membrane components and critically mediate cell-cell communication, but can also induce cancer proliferation and metastasis. Previous studies have revealed that protease-activated receptor 2 (PAR2) contributes significantly to human triple-negative breast cancer (TNBC) progression by releasing nano-size MV and promoting cell proliferation, migration, and invasion. MV isolated from highly aggressive human TNBC cells impart metastatic potential to nonmetastatic cells. Over-expression of microRNA221 (miR221) has also been reported to enhance the metastatic potential of human TNBC, but miR221's relationship to PAR2-induced MV is unclear. Here, using isolated MV, immunoblotting, quantitative RT-PCR, FACS analysis, and enzymatic assays, we show that miR221 is translocated via human TNBC-derived MV, which upon fusion with recipient cells, enhance their proliferation, survival, and metastasis both in vitro and in vivo by inducing the epithelial-to-mesenchymal transition (EMT). Administration of anti-miR221 significantly impaired MV-induced expression of the mesenchymal markers Snail, Slug, N-cadherin, and vimentin in the recipient cells, whereas restoring expression of the epithelial marker E-cadherin. We also demonstrate that MV-associated miR221 targets phosphatase and tensin homolog (PTEN) in the recipient cells, followed by AKT Ser/Thr kinase (AKT)/NF-κB activation, which promotes EMT. Moreover, elevated miR221 levels in MV derived from human TNBC patients' blood could induce cell proliferation and metastasis in recipient cells. In summary, miR221 transfer from TNBC cells via PAR2-derived MV induces EMT and enhances the malignant potential of recipient cells.
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Affiliation(s)
- Kaushik Das
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata 700032, India
| | - Subhojit Paul
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata 700032, India
| | - Arpana Singh
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata 700032, India
| | - Arnab Ghosh
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata 700032, India
| | - Abhishek Roy
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata 700032, India
| | | | - Ramesh Prasad
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata 700032, India
| | - Ashis Mukherjee
- A Unit of Himadri Memorial Cancer Welfare Trust, Netaji Subhash Chandra Bose Cancer Research Institute, Kolkata 700016, India
| | - Prosenjit Sen
- School of Biological Sciences, Indian Association for the Cultivation of Science, Kolkata 700032, India
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13
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Formisano L, Jansen VM, Marciano R, Bianco R. From Biology to Therapy: Improvements of Therapeutic Options in Lung Cancer. Anticancer Agents Med Chem 2019; 18:1235-1240. [PMID: 28901258 DOI: 10.2174/1871520617666170912123416] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Revised: 07/12/2017] [Accepted: 08/25/2017] [Indexed: 12/14/2022]
Abstract
Lung cancer is the leading cause of cancer-related mortality around the world, despite effective chemotherapeutic agents, the prognosis has remained poor for a long time. The discovery of molecular changes that drive lung cancer has led to a dramatic shift in the therapeutic landscape of this disease. In "in vitro" and "in vivo" models of NSCLC (Non-Small Cell Lung Cancer), angiogenesis blockade has demonstrated an excellent anti-tumor activity, thus, a number of anti-angiogenic drugs have been approved by regulatory authorities for use in clinical practice. Much more interesting is the discovery of EGFR (Epithelial Growth Factor Receptor) mutations that predict sensitivity to the anti-EGFR Tyrosine Kinase Inhibitors (TKIs), a class of drugs that has shown to significantly improve survival when compared with standard chemotherapy in the first-line treatment of metastatic NSCLC. Nevertheless, after an initial response, resistance often occurs and prognosis becomes dismal. Biomolecular studies on cell line models have led to the discovery of mutations (e.g., T790M) that confer resistance to anti-EGFR inhibitors. Fortunately, drugs that are able to circumvent this mechanism of resistance have been developed and have been recently approved for clinical use. The discovery of robust intratumor lymphocyte infiltration in NSCLC has paved the way to several strategies able to restore the immune response. Thus, agents interfering with PD-1/PD-L1 (Programmed Death) pathways make up a significant portion of the armamentarium of cancer therapies for NSCLC. In all the above-mentioned situations, the basis of the success in treating NSCLC has started from understanding of the mutational landscape of the tumor.
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Affiliation(s)
- Luigi Formisano
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Italy
| | - Valerie M Jansen
- Department of Medicine, Division of Hematology-Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, United States
| | - Roberta Marciano
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Italy
| | - Roberto Bianco
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Italy
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14
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Prophylactic Versus Therapeutic Mastectomy: A Contemporary Analysis of the ACS-NSQIP Database. Clin Breast Cancer 2019; 19:e428-e432. [DOI: 10.1016/j.clbc.2019.01.008] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2019] [Accepted: 01/22/2019] [Indexed: 11/19/2022]
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15
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Østerud B, Bouchard BA. Detection of tissue factor in platelets: why is it so troublesome? Platelets 2019; 30:957-961. [DOI: 10.1080/09537104.2019.1624708] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Bjarne Østerud
- K.G. Jebsen Thrombosis Research Center (TREC), Deparment of Medical Biology, UiT The Artic University of Norway, Tromsø, Norway
| | - Beth A. Bouchard
- Department of Biochemistry, Larner College of Medicine at the University of Vermont, Burlington, VT, USA
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16
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Falanga A, Marchetti M. Hemostatic biomarkers in cancer progression. Thromb Res 2018; 164 Suppl 1:S54-S61. [PMID: 29703485 DOI: 10.1016/j.thromres.2018.01.017] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Revised: 01/08/2018] [Accepted: 01/10/2018] [Indexed: 02/06/2023]
Abstract
Malignant disease is characterized by a hemostatic imbalance, usually shifted towards a procoagulant direction, and a high incidence of thrombotic complications. The mechanisms of hemostasis that are critically involved in thrombosis are also implicated in tumor progression, angiogenesis, and metastatic spread. As there is a close relationship between cancer and the clotting system, circulating biomarkers of activation of various hemostasis compartments (i.e. coagulation, fibrinolysis, platelets, endothelium, and other blood cells) have been extensively studied to predict cancer outcomes along with predicting the thrombotic risk. In this review, we will summarize the results of published studies and will focus on ongoing research and future directions of clotting activation bioproducts as biomarkers of cancer disease and progression.
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Affiliation(s)
- Anna Falanga
- Division of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy.
| | - Marina Marchetti
- Division of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, Bergamo, Italy
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17
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Hernandez R, England CG, Yang Y, Valdovinos HF, Liu B, Wong HC, Barnhart TE, Cai W. ImmunoPET imaging of tissue factor expression in pancreatic cancer with 89Zr-Df-ALT-836. J Control Release 2017; 264:160-168. [PMID: 28843831 DOI: 10.1016/j.jconrel.2017.08.029] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 08/22/2017] [Indexed: 12/17/2022]
Abstract
Overexpression of tissue factor (TF) has been associated with increased tumor growth, tumor angiogenesis, and metastatic potential in many malignancies, including pancreatic cancer. Additionally, high TF expression was shown to strongly correlate with poor prognoses and decreased survival in pancreatic cancer patients. Herein, we exploited the potential targeting of TF for positron emission tomography (PET) imaging of pancreatic cancer. The TF-targeted tracer was developed through radiolabeling of the anti-human TF monoclonal antibody (ALT-836) with 89Zr. The tracer was characterized by fluorescence microscopy and flow cytometry assays in BXPC-3 and PANC-1 cells, two pancreatic cancer cell lines with high and low TF expression levels, respectively. Non-invasive PET scans were acquired in tumor-bearing mice injected with 89Zr-Df-ALT-836. Additionally, ex vivo biodistribution, blocking, and histological studies were performed to establish the affinity and specificity of 89Zr-Df-ALT-836 for TF in vivo. 89Zr-labeling of Df-ALT-836 was achieved in high yield and good specific activity. Flow cytometry and microscopy studies revealed no detectable difference in TF-binding affinity between ALT-836 and Df-ALT-836 in vitro. Longitudinal PET scans unveiled a lasting and prominent 89Zr-Df-ALT-836 uptake in BXPC-3 tumors (peak at 31.5±6.0%ID/g at 48h post-injection; n=3), which was significantly abrogated (2.3±0.5%ID/g at 48h post-injection; n=3) when mice were pre-injected with a blocking dose (50mg/kg) of unlabeled ALT-836. Ex vivo biodistribution data confirmed the accuracy of the PET results, and histological analysis correlated high tumor uptake with in situ TF expression. Taken together, these results attest to the excellent affinity and TF-specificity of 89Zr-Df-ALT-836. With elevated, persistent, and specific accumulation in TF-positive BXPC-3 tumors, PET imaging using 89Zr-Df-ALT-836 promises to open new avenues for improving future diagnosis, stratification, and treatment response assessment in pancreatic cancer patients.
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Affiliation(s)
- Reinier Hernandez
- Department of Medical Physics, University of Wisconsin - Madison, WI 53705, USA
| | | | - Yunan Yang
- Department of Radiology, University of Wisconsin - Madison, WI 53705, USA
| | - Hector F Valdovinos
- Department of Medical Physics, University of Wisconsin - Madison, WI 53705, USA
| | - Bai Liu
- Altor Bioscience Corporation, Miramar, FL 33025, USA
| | - Hing C Wong
- Altor Bioscience Corporation, Miramar, FL 33025, USA
| | - Todd E Barnhart
- Department of Medical Physics, University of Wisconsin - Madison, WI 53705, USA
| | - Weibo Cai
- Department of Medical Physics, University of Wisconsin - Madison, WI 53705, USA; Department of Radiology, University of Wisconsin - Madison, WI 53705, USA; University of Wisconsin Carbone Cancer Center, Madison, WI 53792, USA.
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18
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Francart ME, Lambert J, Vanwynsberghe AM, Thompson EW, Bourcy M, Polette M, Gilles C. Epithelial-mesenchymal plasticity and circulating tumor cells: Travel companions to metastases. Dev Dyn 2017; 247:432-450. [PMID: 28407379 DOI: 10.1002/dvdy.24506] [Citation(s) in RCA: 83] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2017] [Revised: 03/29/2017] [Accepted: 03/29/2017] [Indexed: 12/11/2022] Open
Abstract
Epithelial-mesenchymal transitions (EMTs) associated with metastatic progression may contribute to the generation of hybrid phenotypes capable of plasticity. This cellular plasticity would provide tumor cells with an increased potential to adapt to the different microenvironments encountered during metastatic spread. Understanding how EMT may functionally equip circulating tumor cells (CTCs) with an enhanced competence to survive in the bloodstream and niche in the colonized organs has thus become a major cancer research axis. We summarize here clinical data with CTC endpoints involving EMT. We then review the work functionally linking EMT programs to CTC biology and deciphering molecular EMT-driven mechanisms supporting their metastatic competence. Developmental Dynamics 247:432-450, 2018. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Marie-Emilie Francart
- GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium
| | - Justine Lambert
- GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium
| | - Aline M Vanwynsberghe
- GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium
| | - Erik W Thompson
- Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology, and Translational Research Institute Brisbane, and University of Melbourne Department of Surgery, St Vincent's Hospital, Melbourne, Australia
| | - Morgane Bourcy
- GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium
| | - Myriam Polette
- Inserm UMR-S 903, University of Reims Champagne-Ardenne, Biopathology Laboratory, CHU of Reims, Reims, France
| | - Christine Gilles
- GIGA-Cancer, Laboratory of Tumor and Development Biology, University of Liège, Liège, Belgium
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19
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Roy A, Ansari SA, Das K, Prasad R, Bhattacharya A, Mallik S, Mukherjee A, Sen P. Coagulation factor VIIa-mediated protease-activated receptor 2 activation leads to β-catenin accumulation via the AKT/GSK3β pathway and contributes to breast cancer progression. J Biol Chem 2017; 292:13688-13701. [PMID: 28522609 DOI: 10.1074/jbc.m116.764670] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2016] [Revised: 05/17/2017] [Indexed: 12/20/2022] Open
Abstract
Cell migration and invasion are very characteristic features of cancer cells that promote metastasis, which is one of the most common causes of mortality among cancer patients. Emerging evidence has shown that coagulation factors can directly mediate cancer-associated complications either by enhancing thrombus formation or by initiating various signaling events leading to metastatic cancer progression. It is well established that, apart from its distinct role in blood coagulation, coagulation factor FVIIa enhances aggressive behaviors of breast cancer cells, but the underlying signaling mechanisms still remain elusive. To this end, we investigated FVIIa's role in the migration and invasiveness of the breast cancer cell line MDA-MB-231. Consistent with previous observations, we observed that FVIIa increased the migratory and invasive potential of these cells. We also provide molecular evidence that protease-activated receptor 2 activation followed by PI3K-AKT activation and GSK3β inactivation is involved in these processes and that β-catenin, a well known tumor-regulatory protein, contributes to this signaling pathway. The pivotal role of β-catenin was further indicated by the up-regulation of its downstream targets cyclin D1, c-Myc, COX-2, MMP-7, MMP-14, and Claudin-1. β-Catenin knockdown almost completely attenuated the FVIIa-induced enhancement of breast cancer migration and invasion. These findings provide a new perspective to counteract the invasive behavior of breast cancer, indicating that blocking PI3K-AKT pathway-dependent β-catenin accumulation may represent a potential therapeutic approach to control breast cancer.
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Affiliation(s)
- Abhishek Roy
- From the Department of Biological Chemistry, Indian Association for the Cultivation of Science, Kolkata 700032, India and
| | - Shabbir A Ansari
- From the Department of Biological Chemistry, Indian Association for the Cultivation of Science, Kolkata 700032, India and
| | - Kaushik Das
- From the Department of Biological Chemistry, Indian Association for the Cultivation of Science, Kolkata 700032, India and
| | - Ramesh Prasad
- From the Department of Biological Chemistry, Indian Association for the Cultivation of Science, Kolkata 700032, India and
| | - Anindita Bhattacharya
- From the Department of Biological Chemistry, Indian Association for the Cultivation of Science, Kolkata 700032, India and
| | - Suman Mallik
- From the Department of Biological Chemistry, Indian Association for the Cultivation of Science, Kolkata 700032, India and
| | - Ashis Mukherjee
- Netaji Subhash Chandra Bose Cancer Research Institute, Kolkata 700016, India
| | - Prosenjit Sen
- From the Department of Biological Chemistry, Indian Association for the Cultivation of Science, Kolkata 700032, India and
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20
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Swier N, Versteeg HH. Reciprocal links between venous thromboembolism, coagulation factors and ovarian cancer progression. Thromb Res 2016; 150:8-18. [PMID: 27988375 DOI: 10.1016/j.thromres.2016.12.002] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 11/23/2016] [Accepted: 12/03/2016] [Indexed: 02/06/2023]
Abstract
Ovarian cancer is the most lethal gynecological malignancy, which is due to late presentation. Treating advanced stage ovarian cancer is difficult, and tumor recurrence and chemoresistance frequently occur. In addition, early detection remains a major challenge as there are no early warning signs and no appropriate biomarkers. To reduce mortality rates of ovarian cancer patients, novel drug targets and biomarkers are needed. We postulate that hemostatic keyplayers are of importance when combatting ovarian cancer. The majority of ovarian cancer patients have abnormal hemostatic blood serum marker levels, which indicate an activated coagulation system. This makes patients more prone to experiencing venous thromboembolism (VTE), and the occurrence of VTE in ovarian cancer patients adversely affects survival. Coagulation activation also promotes tumor progression as it influences tumor biology at several stages and the decreased survival rates associated with ovarian cancer-associated thrombosis are more likely due to cancer metastasis rather than to fatal thromboembolic events. In this review, we will discuss; (1) Population studies that address the bidirectional relationship between VTE and ovarian cancer, and the most important risk factors involved; (2) The mechanisms of coagulation factors and platelets that are critically involved in the development of VTE, and the progression of ovarian cancer; (3) Roles and future directions of coagulation factors in ovarian cancer therapy, and in diagnosis and prognosis of ovarian cancer as biomarkers.
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Affiliation(s)
- Nathalie Swier
- Department of Internal Medicine, Thrombosis and Hemostasis Division, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands
| | - Henri H Versteeg
- Department of Internal Medicine, Thrombosis and Hemostasis Division, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands.
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21
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Bourcy M, Suarez-Carmona M, Lambert J, Francart ME, Schroeder H, Delierneux C, Skrypek N, Thompson EW, Jérusalem G, Berx G, Thiry M, Blacher S, Hollier BG, Noël A, Oury C, Polette M, Gilles C. Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells. Cancer Res 2016; 76:4270-82. [DOI: 10.1158/0008-5472.can-15-2263] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2015] [Accepted: 04/26/2016] [Indexed: 11/16/2022]
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22
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Zhang B, Jiang T, Ling L, Cao Z, Zhao J, Tuo Y, She X, Shen S, Jiang X, Hu Y, Pang Z. Enhanced Antitumor Activity of EGFP-EGF1-Conjugated Nanoparticles by a Multitargeting Strategy. ACS APPLIED MATERIALS & INTERFACES 2016; 8:8918-8927. [PMID: 26890991 DOI: 10.1021/acsami.6b00036] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Tumor stromal cells have been increasingly recognized to interact with tumor parenchyma cells and promote tumor growth. Therefore, we speculated that therapeutics delivery to both parenchyma cells and stromal cells simultaneously might treat a tumor more effectively. Tissue factor (TF) was shown to be extensively located in a tumor and was abundantly sited in both tumor parenchyma cells and stromal cells including neo-vascular cells, tumor-associated fibroblasts, and tumor-associated macrophages, indicating it might function as a favorable target for drug delivery to multiple cell types simultaneously. EGFP-EGF1 is a fusion protein derived from factor VII, the natural ligand of TF. It retains the specific TF binding capability but does not cause coagulation. In the present study, a nanoparticle modified with EGFP-EGF1 (ENP) was constructed as a multitargeting drug delivery system. The protein binding experiment showed EGFP-EGF1 could bind well to A549 tumor cells and other stromal cells including neo-vascular cells, tumor-associated fibroblasts, and tumor-associated macrophages. Compared with unmodified nanoparticles (NP), ENP uptake by A549 cells and those stromal cells was significantly enhanced but inhibited by excessive free EGFP-EGF1. In addition, ENP induced more A549 tumor cell apoptosis than Taxol and NP when paclitaxel (PTX) was loaded. In vivo, ENP accumulated more specially in TF-overexpressed A549 tumors by in vivo imaging, mainly regions unoccupied by factor VII and targeted tumor parenchyma cells as well as different types of stromal cells by immunofluorescence staining. Treatment with PTX-loaded ENP (ENP-PTX) significantly reduced the A549 tumor growth in nude mice while NP-PTX- and Taxol-treated mice had lower response to the therapy. Furthermore, H&E and TUNEL staining revealed that ENP-PTX induced more severe tumor necrosis and more extensive cell apoptosis. Altogether, the present study demonstrated that ENP could target multiple key cell types in tumors through TF, which could be utilized to improve the therapeutic effect of anticancer drugs.
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Affiliation(s)
- Bo Zhang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology , Wuhan, Hubei 430022, China
| | - Ting Jiang
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology , Wuhan, Hubei 430022, China
| | - Li Ling
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China
| | - Zhonglian Cao
- Instrumental Analysis Center of School of Pharmacy, Fudan University , 826 Zhangheng Road, Shanghai, 201203, China
| | - Jingjing Zhao
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China
| | - Yanyan Tuo
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China
| | - Xiaojian She
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China
| | - Shun Shen
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China
| | - Xinguo Jiang
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China
| | - Yu Hu
- Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science & Technology , Wuhan, Hubei 430022, China
| | - Zhiqing Pang
- School of Pharmacy, Fudan University, Key Laboratory of Smart Drug Delivery, Ministry of Education, 826 Zhangheng Road, Shanghai, 201203, China
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23
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Wang B, Xiong S, Hua Q, Chen C, Liao H, Chen L, Yao W, Wu D, Tao Z. Tissue factor is strongly expressed in pericarcinomatous tissue in patients with laryngeal carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2015; 8:13719-13724. [PMID: 26722600 PMCID: PMC4680545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 06/11/2015] [Accepted: 09/28/2015] [Indexed: 06/05/2023]
Abstract
OBJECTIVE This study aimed to understand the relationship between tissue factor (TF) and laryngeal carcinoma. METHODS Differences in TF expression between pericarcinomatous and carcinomatous tissues were studied in patients with laryngeal carcinoma; the potential clinical significance of the observed differences is discussed. Immunohistochemical, western blot, and RT-PCR analyses were performed to assess the expression of TF at the protein and mRNA levels, and differences between pericarcinomatous and carcinomatous tissues in patients (n = 20) with laryngeal carcinoma were analyzed. RESULTS Expression of TF was significantly higher in pericarcinomatous tissues than in carcinomatous tissues (P < 0.01); furthermore, the intensity of TF mRNA expression was also significantly stronger in pericarcinomatous than in carcinomatous tissue (P < 0.001). Robust expression of TF was observed in pericarcinomatous tissues but not in carcinomatous tissues. CONCLUSION TF may contribute to the carcinogenesis and development of laryngeal carcinoma and may provide a marker for assessment of the degree of malignancy and the progression of laryngeal carcinoma. TF may also provide a new target for therapeutics for human head and neck cancer.
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Affiliation(s)
- Bin Wang
- Department of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan UniversityWuhan 430060, China
| | | | - Qingquan Hua
- Department of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan UniversityWuhan 430060, China
| | - Chen Chen
- Department of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan UniversityWuhan 430060, China
| | - Hua Liao
- Department of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan UniversityWuhan 430060, China
| | - Liu Chen
- Department of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan UniversityWuhan 430060, China
| | - Weiqi Yao
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical SciencesWuhan 430071, China
- Wuhan Hamilton Biotechnology Co. LTDWuhan 430075, China
| | - Dongcheng Wu
- Department of Biochemistry and Molecular Biology, Wuhan University School of Basic Medical SciencesWuhan 430071, China
- Wuhan Hamilton Biotechnology Co. LTDWuhan 430075, China
| | - Zezhang Tao
- Department of Otolaryngology Head and Neck Surgery, Renmin Hospital of Wuhan UniversityWuhan 430060, China
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Gbolahan OB, Stankowski-Drengler TJ, Ibraheem A, Engel JM, Onitilo AA. Management of chemotherapy-induced thromboembolism in breast cancer. BREAST CANCER MANAGEMENT 2015. [DOI: 10.2217/bmt.15.10] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Thromboembolic events are common in cancer patients and, apart from contributing to significant morbidity, are regarded as the second leading cause of death in this population. Breast cancer patients are considered low risk for venous thromboembolism; however, the presence of advanced disease and use of chemotherapy and/or other adjunct treatments significantly raises this risk by altering the balance of pro- and anti-coagulant proteins. Low molecular weight heparin is central to the management of venous thromboembolism in this context, whether for prophylaxis, acute management or prevention of recurrences. Risk stratification models need to be incorporated to guide decision making where available.
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Affiliation(s)
- Olumide B Gbolahan
- Morehouse school of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA
| | | | - Abiola Ibraheem
- Morehouse school of Medicine, 720 Westview Drive SW, Atlanta, GA 30310, USA
| | - Jessica M Engel
- Marshfield Clinic Cancer Care at St Michael's, Stevens Point, WI, USA
| | - Adedayo A Onitilo
- Oncology/Hematology Department, Marshfield Clinic Weston Center, Weston, WI, USA
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Che SPY, DeLeonardis C, Shuler ML, Stokol T. Tissue factor-expressing tumor cells can bind to immobilized recombinant tissue factor pathway inhibitor under static and shear conditions in vitro. PLoS One 2015; 10:e0123717. [PMID: 25849335 PMCID: PMC4388665 DOI: 10.1371/journal.pone.0123717] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Accepted: 03/06/2015] [Indexed: 01/10/2023] Open
Abstract
Mammary tumors and malignant breast cancer cell lines over-express the coagulation factor, tissue factor (TF). High expression of TF is associated with a poor prognosis in breast cancer. Tissue factor pathway inhibitor (TFPI), the endogenous inhibitor of TF, is constitutively expressed on the endothelium. We hypothesized that TF-expressing tumor cells can bind to immobilized recombinant TFPI, leading to arrest of the tumor cells under shear in vitro. We evaluated the adhesion of breast cancer cells to immobilized TFPI under static and shear conditions (0.35 – 1.3 dyn/cm2). We found that high-TF-expressing breast cancer cells, MDA-MB-231 (with a TF density of 460,000/cell), but not low TF-expressing MCF-7 (with a TF density of 1,400/cell), adhered to recombinant TFPI, under static and shear conditions. Adhesion of MDA-MB-231 cells to TFPI required activated factor VII (FVIIa), but not FX, and was inhibited by a factor VIIa-blocking anti-TF antibody. Under shear, adhesion to TFPI was dependent on the TFPI-coating concentration, FVIIa concentration and shear stress, with no observed adhesion at shear stresses greater than 1.0 dyn/cm2. This is the first study showing that TF-expressing tumor cells can be captured by immobilized TFPI, a ligand constitutively expressed on the endothelium, under low shear in vitro. Based on our results, we hypothesize that TFPI could be a novel ligand mediating the arrest of TF-expressing tumor cells in high TFPI-expressing vessels under conditions of low shear during metastasis.
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Affiliation(s)
- Sara P. Y. Che
- Department of Biomedical Engineering, College of Engineering, Cornell University, Ithaca, NY, United States of America
| | - Christine DeLeonardis
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States of America
| | - Michael L. Shuler
- Department of Biomedical Engineering, College of Engineering, Cornell University, Ithaca, NY, United States of America
| | - Tracy Stokol
- Department of Population Medicine and Diagnostic Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, United States of America
- * E-mail:
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Lin N, Li C, Wang Z, Zhang J, Ye X, Gao W, Wang A, Jin H, Wei J. A safety study of a novel photosensitizer, sinoporphyrin sodium, for photodynamic therapy in Beagle dogs. Photochem Photobiol Sci 2015; 14:815-32. [DOI: 10.1039/c4pp00463a] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Sinoporphyrin sodium (DVDMS) based photodynamic therapy (PDT) showed skin phototoxicity in Beagle dogs, did not accumulate in blood plasma, and had an effect on the immune organs and the liver.
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Affiliation(s)
- Ni Lin
- New Drug Safety Evaluation Center
- Institute of Materia Medica
- Peking Union Medical College
- Beijing 100050
- China
| | - Chao Li
- Beijing Union-Genius Pharmaceutical Technology Development Co
- Ltd
- Beijing 100050
- China
| | - Zhonghua Wang
- Beijing Union-Genius Pharmaceutical Technology Development Co
- Ltd
- Beijing 100050
- China
| | - Jingxuan Zhang
- Beijing Union-Genius Pharmaceutical Technology Development Co
- Ltd
- Beijing 100050
- China
| | - Xiangfeng Ye
- Beijing Union-Genius Pharmaceutical Technology Development Co
- Ltd
- Beijing 100050
- China
| | - Wenjing Gao
- Beijing Union-Genius Pharmaceutical Technology Development Co
- Ltd
- Beijing 100050
- China
| | - Aiping Wang
- New Drug Safety Evaluation Center
- Institute of Materia Medica
- Peking Union Medical College
- Beijing 100050
- China
| | - Hongtao Jin
- New Drug Safety Evaluation Center
- Institute of Materia Medica
- Peking Union Medical College
- Beijing 100050
- China
| | - Jinfeng Wei
- New Drug Safety Evaluation Center
- Institute of Materia Medica
- Peking Union Medical College
- Beijing 100050
- China
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Abstract
The progression of breast cancer from early-stage to metastatic disease results from a series of events during which malignant cells invade and travel within the bloodstream to distant sites, leading to a clonogenic accumulation of tumor cells in non-breast tissue. While mechanistically complex, an emerging literature supports hemostatic elements as an important patient factor that facilitates the metastatic potential of breast cancer. Hemostatic elements involved include platelets, coagulation, and fibrinolysis. Key steps in breast tumor progression, including cellular transformation, proliferation, tumor cell survival, and angiogenesis, can be mediated by components of the hemostatic system. Thus, the hemostatic system provides potential targets for novel therapeutic approaches to breast cancer therapy with drugs in current use and in development. The present article provides a comprehensive overview of the evidence and mechanisms supporting the roles played by platelets, coagulation activation, and the fibrinolytic system in breast cancer progression.
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Antibody fragment-conjugated polymeric micelles incorporating platinum drugs for targeted therapy of pancreatic cancer. Biomaterials 2014; 39:23-30. [PMID: 25477168 DOI: 10.1016/j.biomaterials.2014.10.069] [Citation(s) in RCA: 99] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 10/20/2014] [Indexed: 12/21/2022]
Abstract
Antibody-mediated therapies including antibody-drug conjugates (ADCs) have shown much potential in cancer treatment by tumor-targeted delivery of cytotoxic drugs. However, there is a limitation of payloads that can be delivered by ADCs. Integration of antibodies to drug-loaded nanocarriers broadens the applicability of antibodies to a wide range of therapeutics. Herein, we developed antibody fragment-installed polymeric micelles via maleimide-thiol conjugation for selectively delivering platinum drugs to pancreatic tumors. By tailoring the surface density of maleimide on the micelles, one tissue factor (TF)-targeting Fab' was conjugated to each carrier. Fab'-installed platinum-loaded micelles exhibited more than 15-fold increased cellular binding within 1 h and rapid cellular internalization compared to non-targeted micelles, leading to superior in vitro cytotoxicity. In vivo, Fab'-installed micelles significantly suppressed the growth of pancreatic tumor xenografts for more than 40 days, outperforming non-targeted micelles and free drugs. These results indicate the potential of Fab'-installed polymeric micelles for efficient drug delivery to solid tumors.
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Lin ZM, Zhao JX, Duan XN, Zhang LB, Ye JM, Xu L, Liu YH. Effects of tissue factor, PAR-2 and MMP-9 expression on human breast cancer cell line MCF-7 invasion. Asian Pac J Cancer Prev 2014; 15:643-6. [PMID: 24568471 DOI: 10.7314/apjcp.2014.15.2.643] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
OBJECTIVE This study aimed to explore the expression of tissue factor (TF), protease activated receptor-2 (PAR-2), and matrix metalloproteinase-9 (MMP-9) in the MCF-7 breast cancer cell line and influence on invasiveness. METHODS Stable MCF-7 cells transfected with TF cDNA and with TF ShRNA were established. TF, PAR-2, and MMP-9 protein expression was analyzed using indirect immunofluorescence and invasiveness was evaluated using a cell invasion test. Effects of an exogenous PAR-2 agonist were also examined. RESULTS TF protein expression significantly differed between the TF cDNA and TF ShRNA groups. MMP-9 protein expression was significantly correlated with TF protein expression, but PAR-2 protein expression was unaffected. The PAR- 2 agonist significantly enhanced MMP-9 expression and slightly increased TF and PAR-2 expression in the TF ShRNA group, but did not significantly affect protein expression in MCF-7 cells transfected with TF cDNA. TF and MMP-9 expression was positively correlated with the invasiveness of tumor cells. CONCLUSION TF, PAR-2, and MMP-9 affect invasiveness of MCF-7 cells. TF may increase MMP-9 expression by activating PAR-2.
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Affiliation(s)
- Zeng-Mao Lin
- Breast Disease Center, Peking University First Hospital, Beijing, China E-mail :
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30
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Han X, Guo B, Li Y, Zhu B. Tissue factor in tumor microenvironment: a systematic review. J Hematol Oncol 2014; 7:54. [PMID: 25084809 PMCID: PMC4237870 DOI: 10.1186/s13045-014-0054-8] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2014] [Accepted: 07/09/2014] [Indexed: 01/01/2023] Open
Abstract
The aberrant hemostasis is a common manifestation of cancer, and venous thromboembolism (VTE) is the second leading cause of cancer patients’ mortality. Tissue factor (TF), comprising of a 47-kDa transmembrane protein that presents in subendothelial tissues and leukocytes and a soluble isoform, have distinct roles in the initiation of extrinsic coagulation cascade and thrombosis. Laboratory and clinical evidence showed the deviant expression of TF in several cancer systems and its tumor-promoting effects. TF contributes to myeloid cell recruitment in tumor stroma, thereby remodeling of tumor microenvironment. Additionally, the number of TF-positive-microparticles (TF+MP) from tumor origins correlates with the VTE rates in cancer patients. In this review, we summarize our current understanding of the TF regulation and roles in tumor progression and clinical complications.
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Zhang B, Wang H, Liao Z, Wang Y, Hu Y, Yang J, Shen S, Chen J, Mei H, Shi W, Hu Y, Pang Z, Jiang X. EGFP–EGF1-conjugated nanoparticles for targeting both neovascular and glioma cells in therapy of brain glioma. Biomaterials 2014; 35:4133-45. [DOI: 10.1016/j.biomaterials.2014.01.071] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2013] [Accepted: 01/26/2014] [Indexed: 10/25/2022]
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Qu B, Liu BR, DU YJ, Chen J, Cheng YQ, Xu W, Wang XH. Wnt/β-catenin signaling pathway may regulate the expression of angiogenic growth factors in hepatocellular carcinoma. Oncol Lett 2014; 7:1175-1178. [PMID: 24944688 PMCID: PMC3961220 DOI: 10.3892/ol.2014.1828] [Citation(s) in RCA: 80] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2013] [Accepted: 12/17/2013] [Indexed: 12/31/2022] Open
Abstract
The Wnt/β-catenin signaling pathway plays a key role during hepatocellular carcinoma (HCC) genesis and development. The present study aimed to investigate the effects of the Wnt/β-catenin signaling pathway on the expression of angiogenic growth factors involved in HCC. The HCC HepG2 cell line was transfected with small interfering RNA (siRNA) against β-catenin. After 72 and 96 h, protein was extracted and the expression levels of β-catenin, matrix metalloproteinase (MMP)-2, MMP-9, vascular endothelial growth factor (VEGF)-A, VEGF-C and basic fibroblast growth factor (bFGF) were detected by western blot analysis. β-catenin protein expression was inhibited at both time points. Notably, MMP-2, MMP-9, VEGF-A, VEGF-C and bFGF protein expression levels decreased at 72 h and then increased at 96 h after transfection. Our results demonstrated that in HCC cells, the Wnt/β-catenin signaling pathway may regulate the protein expression of the angiogenic factors, MMP-2, MMP-9, VEGF-A, VEGF-C and bFGF. These proteins were downstream of β-catenin signaling and were also regulated by other factors. In conclusion, the Wnt/β-catenin signaling pathway may contribute to the regulation of HCC angiogenesis, infiltration and metastasis through regulating the expression of these angiogenic factors.
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Affiliation(s)
- Bo Qu
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Bing-Rong Liu
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Ya-Ju DU
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Jing Chen
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Yan-Qiu Cheng
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Wei Xu
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Xin-Hong Wang
- Department of Gastroenterology, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
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Cesarman-Maus G, Braggio E, Lome-Maldonado C, Morales-Leyte AL, Fonseca R. Absence of tissue factor is characteristic of lymphoid malignancies of both T- and B-cell origin. Thromb Res 2014; 133:606-9. [PMID: 24491425 DOI: 10.1016/j.thromres.2014.01.020] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2013] [Revised: 01/10/2014] [Accepted: 01/14/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND Thrombosis is a marker of poor prognosis in individuals with solid tumors. The expression of tissue factor (TF) on the cell surface membrane of malignant cells is a pivotal molecular link between activation of coagulation, angiogenesis, metastasis, aggressive tumor behavior and poor survival. Interestingly, thrombosis is associated with shortened survival in solid, but not in lymphoid neoplasias. OBJECTIVES We sought to study whether the lack of impact of thrombosis on survival in lymphoid neoplasias could be due to a lack of tumor-derived TF expression. METHODS We analyzed TF gene (F3) expression in lymphoid (N=114), myeloid (N=49) and solid tumor (N=856) cell lines using the publicly available dataset from the Broad-Novartis Cancer Cell Line Encyclopedia (http://www.broadinstitute.org/ccle/home), and in 90 patient-derived lymphoma samples. TF protein expression was studied by immunohistochemistry (IHC). RESULTS In sharp contrast to wide F3 expression in solid tumors (74.2%), F3 was absent in all low and high grade T- and B-cell lymphomas, and in most myeloid tumors, except for select acute myeloid leukemias with monocytic component. IHC confirmed the absence of TF protein in all indolent and high-grade B-cell (0/90) and T-cell (0/20) lymphomas, and acute leukemias (0/11). CONCLUSIONS We show that TF in lymphomas does not derive from the malignant cells, since these do not express either F3 or TF protein. Therefore, it is unlikely that thrombosis in patients with lymphoid neoplasms is secondary to tumor-derived tissue factor.
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Affiliation(s)
| | - Esteban Braggio
- Department of Hematology and Oncology, Mayo Clinic in Arizona, USA
| | - Carmen Lome-Maldonado
- Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, México City, México
| | - Ana Lilia Morales-Leyte
- Department of Pathology, Instituto Nacional de Ciencias Médicas y Nutrición, Salvador Zubirán, México City, México
| | - Rafael Fonseca
- Department of Hematology and Oncology, Mayo Clinic in Arizona, USA
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