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1
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Josefsson EC. Platelets and megakaryocytes in cancer. J Thromb Haemost 2025; 23:804-816. [PMID: 39742972 DOI: 10.1016/j.jtha.2024.12.016] [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: 10/06/2024] [Revised: 12/03/2024] [Accepted: 12/16/2024] [Indexed: 01/04/2025]
Abstract
Platelets have important roles in hemostasis but also actively participate in cancer metastasis and inflammatory processes. They are produced by large precursor cells, the megakaryocytes, residing mainly in the bone marrow. Clinically, elevated platelet counts and/or increased platelet-to-lymphocyte ratio are being explored as biomarkers of metastatic disease and to predict survival or response to therapy in certain cancers. Multiple mechanisms have been put forward on how platelets promote hematogenous metastasis stemming mainly from murine experimental models. Research is now beginning to explore the potential roles of megakaryocytes in solid cancer, myeloma, and lymphoma. Here, we review mechanisms on how platelets and megakaryocytes contribute to cancer progression and metastasis but also discuss potential cancer-suppressing functions mainly related to the regulation of vascular intratumor integrity. Recent developments in cancer immune checkpoint therapy are reviewed with a focus on the potential roles of platelets. Moreover, we review studies exploring platelets for targeted drug delivery systems in cancer therapy.
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Affiliation(s)
- Emma C Josefsson
- Region Västra Götaland, Sahlgrenska University Hospital, Department of Clinical Chemistry, Gothenburg, Sweden; Department of Laboratory Medicine, Institute of Biomedicine, The University of Gothenburg, Gothenburg, Sweden.
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2
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Wang X, Zhang X, Zhang C, Qi L, Liu J. Plasma von Willebrand factor levels in patients with cancer: A meta‑analysis. Oncol Lett 2024; 28:399. [PMID: 38979552 PMCID: PMC11228924 DOI: 10.3892/ol.2024.14532] [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: 02/06/2024] [Accepted: 06/17/2024] [Indexed: 07/10/2024] Open
Abstract
von Willebrand Factor (VWF) is well recognized for being dysregulated in various malignancies and has emerged as a potential biomarker for cancer detection. The present meta-analysis aimed to elucidate the association between plasma VWF and the incidence and metastasis of cancer. For this purpose, a comprehensive search was conducted across multiple databases from their inception until March 3, 2023. This culminated in the selection of 15 original studies on various types of cancer, including a collective sample of 1,403 individuals. The standardized mean difference (SMD) and 95% confidence intervals (CIs) were employed as statistical parameters to determine the association between plasma VWF and the incidence and metastasis of cancer. These were estimated using a random-effects model. The pooled data revealed that the plasma VWF levels of patients with cancer were significantly elevated compared with those of healthy controls (SMD, 0.98; 95% CI, 0.59-1.36), and a significant association was observed between plasma VWF levels and cancer metastasis (SMD, 0.69; 95% CI, 0.33-1.06). The symmetry of the Begg's funnel plots indicated that no significant bias was present in the analyses of VWF in cancer and its metastasis. In summary, the results of the present meta-analysis support the hypothesis that increased plasma VWF levels may serve as a biomarker for cancer and metastatic progression.
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Affiliation(s)
- Xitan Wang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
- Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Xiaoyu Zhang
- Department of Medical Physiology, School of Basic Medical Sciences, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Chaonan Zhang
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
- Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
| | - Li Qi
- Department of Infectious Diseases, Affiliated Hospital of Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
| | - Ju Liu
- School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong 261053, P.R. China
- Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250014, P.R. China
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3
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Radisky ES. Extracellular proteolysis in cancer: Proteases, substrates, and mechanisms in tumor progression and metastasis. J Biol Chem 2024; 300:107347. [PMID: 38718867 PMCID: PMC11170211 DOI: 10.1016/j.jbc.2024.107347] [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: 02/09/2024] [Revised: 04/08/2024] [Accepted: 04/25/2024] [Indexed: 06/02/2024] Open
Abstract
A vast ensemble of extracellular proteins influences the development and progression of cancer, shaped and reshaped by a complex network of extracellular proteases. These proteases, belonging to the distinct classes of metalloproteases, serine proteases, cysteine proteases, and aspartic proteases, play a critical role in cancer. They often become dysregulated in cancer, with increases in pathological protease activity frequently driven by the loss of normal latency controls, diminished regulation by endogenous protease inhibitors, and changes in localization. Dysregulated proteases accelerate tumor progression and metastasis by degrading protein barriers within the extracellular matrix (ECM), stimulating tumor growth, reactivating dormant tumor cells, facilitating tumor cell escape from immune surveillance, and shifting stromal cells toward cancer-promoting behaviors through the precise proteolysis of specific substrates to alter their functions. These crucial substrates include ECM proteins and proteoglycans, soluble proteins secreted by tumor and stromal cells, and extracellular domains of cell surface proteins, including membrane receptors and adhesion proteins. The complexity of the extracellular protease web presents a significant challenge to untangle. Nevertheless, technological strides in proteomics, chemical biology, and the development of new probes and reagents are enabling progress and advancing our understanding of the pivotal importance of extracellular proteolysis in cancer.
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Affiliation(s)
- Evette S Radisky
- Department of Cancer Biology, Mayo Clinic Comprehensive Cancer Center, Jacksonville, Florida, USA.
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4
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Ryan AT, Kim M, Lim K. Immune Cell Migration to Cancer. Cells 2024; 13:844. [PMID: 38786066 PMCID: PMC11120175 DOI: 10.3390/cells13100844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2024] [Revised: 04/27/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024] Open
Abstract
Immune cell migration is required for the development of an effective and robust immune response. This elegant process is regulated by both cellular and environmental factors, with variables such as immune cell state, anatomical location, and disease state that govern differences in migration patterns. In all cases, a major factor is the expression of cell surface receptors and their cognate ligands. Rapid adaptation to environmental conditions partly depends on intrinsic cellular immune factors that affect a cell's ability to adjust to new environment. In this review, we discuss both myeloid and lymphoid cells and outline key determinants that govern immune cell migration, including molecules required for immune cell adhesion, modes of migration, chemotaxis, and specific chemokine signaling. Furthermore, we summarize tumor-specific elements that contribute to immune cell trafficking to cancer, while also exploring microenvironment factors that can alter these cellular dynamics within the tumor in both a pro and antitumor fashion. Specifically, we highlight the importance of the secretome in these later aspects. This review considers a myriad of factors that impact immune cell trajectory in cancer. We aim to highlight the immunotherapeutic targets that can be harnessed to achieve controlled immune trafficking to and within tumors.
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Affiliation(s)
- Allison T. Ryan
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (A.T.R.); (M.K.)
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA
| | - Minsoo Kim
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (A.T.R.); (M.K.)
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA
| | - Kihong Lim
- Department of Microbiology and Immunology, University of Rochester, Rochester, NY 14642, USA; (A.T.R.); (M.K.)
- David H. Smith Center for Vaccine Biology and Immunology, University of Rochester, Rochester, NY 14642, USA
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5
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Falanga A, Lorusso D, Colombo N, Cormio G, Cosmi B, Scandurra G, Zanagnolo V, Marietta M. Gynecological Cancer and Venous Thromboembolism: A Narrative Review to Increase Awareness and Improve Risk Assessment and Prevention. Cancers (Basel) 2024; 16:1769. [PMID: 38730721 PMCID: PMC11083004 DOI: 10.3390/cancers16091769] [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: 02/14/2024] [Revised: 04/24/2024] [Accepted: 04/24/2024] [Indexed: 05/13/2024] Open
Abstract
The prevention and appropriate management of venous thromboembolism in cancer patients is of paramount importance. However, the literature data report an underestimation of this major problem in patients with gynecological cancers, with an inconsistent venous thromboembolism risk assessment and prophylaxis in this patient setting. This narrative review provides a comprehensive overview of the available evidence regarding the management of venous thromboembolism in cancer patients, focusing on the specific context of gynecological tumors, exploring the literature discussing risk factors, risk assessment, and pharmacological prophylaxis. We found that the current understanding and management of venous thromboembolism in gynecological malignancy is largely based on studies on solid cancers in general. Hence, further, larger, and well-designed research in this area is needed.
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Affiliation(s)
- Anna Falanga
- Department of Medicine and Surgery, University of Milan-Bicocca, 20900 Monza, Italy; (A.F.); (N.C.)
- Department of Immunohematology and Transfusion Medicine, Hospital Papa Giovanni XXIII, 24127 Bergamo, Italy
| | - Domenica Lorusso
- Fondazione Policlinico Universitario A. Gemelli, Catholic University of Sacred Heart, 00168 Rome, Italy
| | - Nicoletta Colombo
- Department of Medicine and Surgery, University of Milan-Bicocca, 20900 Monza, Italy; (A.F.); (N.C.)
- Gynecologic Oncology Program, European Institute of Oncology, IRCCS, 20141 Milan, Italy
| | - Gennaro Cormio
- Gynecologic Oncology Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
- Department of Interdisciplinary Medicine (DIM), University “A. Moro”, 70124 Bari, Italy
| | - Benilde Cosmi
- Angiology and Blood Coagulation Unit, Department of Medical and Surgical Sciences, University of Bologna, 40126 Bologna, Italy;
- Angiology and Blood Coagulation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Giuseppa Scandurra
- Unità Operativa Oncologia Medica, Ospedale Cannizzaro di Catania, 95126 Catania, Italy;
| | | | - Marco Marietta
- Hematology Unit, Azienda Ospedaliero-Universitaria, 41125 Modena, Italy;
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6
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Shirai Y, Hamura R, Tanji Y, Taniai T, Yanagaki M, Haruki K, Furukawa K, Onda S, Sakamoto T, Gocho T, Ikegami T. The postoperative platelet-to-lymphocyte ratio predicts the outcome of patients undergoing pancreaticoduodenectomy for pancreatic head cancer. Surg Today 2024; 54:247-257. [PMID: 37488354 DOI: 10.1007/s00595-023-02727-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Accepted: 06/22/2023] [Indexed: 07/26/2023]
Abstract
PURPOSE The preoperative platelet-to-lymphocyte ratio (PLR) has been reported as an important prognostic index for pancreatic ductal adenocarcinoma (PDAC); however, the significance of the postoperative (post-op) PLR for this disease has not been elucidated. METHODS We analyzed data on 118 patients who underwent pancreaticoduodenectomy for pancreatic head PDAC, collected from a prospectively maintained database. The post-op PLR was obtained by dividing the platelet count after surgery by the lymphocyte count on post-op day (POD) 14. The patients were divided into two groups according to a post-op PLR of < 310 or ≥ 310. Survival data were analyzed. RESULTS A high post-op PLR was identified as a significant prognostic index on univariate analysis for disease-free survival (DFS) and overall survival (OS). The post-op PLR remained significant, along with tumor differentiation and adjuvant chemotherapy, on multivariate analysis for OS (hazard ratio = 2.077, 95% confidence interval: 1.220-3.537; p = 0.007). The post-op PLR was a significant independent prognostic index for poor DFS, along with tumor differentiation and lymphatic invasion, on multivariate analysis (hazard ratio = 1.678, 95% confidence interval: 1.056-2.667; p = 0.028). CONCLUSIONS The post-op PLR in patients with pancreatic head PDAC was an independent predictor of DFS and OS after elective resection.
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Affiliation(s)
- Yoshihiro Shirai
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan.
- Department of Gastrointestinal Surgery, Saku General Hospital Advanced Care Center, Nagano, 385-0051, Japan.
| | - Ryoga Hamura
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
- Department of Gastrointestinal Surgery, Saku General Hospital Advanced Care Center, Nagano, 385-0051, Japan
| | - Yoshiaki Tanji
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Tomohiko Taniai
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Mitsuru Yanagaki
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Koichiro Haruki
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Kenei Furukawa
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Shinji Onda
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
- Department of Gastrointestinal Surgery, Saku General Hospital Advanced Care Center, Nagano, 385-0051, Japan
| | - Taro Sakamoto
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Takeshi Gocho
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
| | - Toru Ikegami
- Division of Hepatobiliary and Pancreas Surgery, Department of Surgery, The Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-Ku, Tokyo, 105-8461, Japan
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7
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Najafi S, Asemani Y, Majidpoor J, Mahmoudi R, Aghaei-Zarch SM, Mortezaee K. Tumor-educated platelets. Clin Chim Acta 2024; 552:117690. [PMID: 38056548 DOI: 10.1016/j.cca.2023.117690] [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: 10/15/2023] [Revised: 11/29/2023] [Accepted: 12/02/2023] [Indexed: 12/08/2023]
Abstract
Beyond traditional roles in homeostasis and coagulation, growing evidence suggests that platelets also reflect malignant transformation in cancer. Platelets are present in the tumor microenvironment where they interact with cancer cells. This interaction results in direct and indirect "education" as evident by platelet alterations in adhesion molecules, glycoproteins, nucleic acids, proteins and various receptors. Subsequently, these tumor-educated platelets (TEPs) circulate throughout the body and play pivotal roles in promotion of tumor growth and dissemination. Accordingly, platelet status can be considered a unique blood-based biomarker that can potentially predict prognosis and therapeutic success. Recently, liquid biopsies including TEPs have received much attention as safe, minimally invasive and sensitive alternatives for patient management. Herein, we provide an overview of TEPs and explore their benefits and limitations in cancer.
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Affiliation(s)
- Sajad Najafi
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Cellular and Molecular Biology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Yahya Asemani
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Jamal Majidpoor
- Department of Anatomy, School of Medicine, Infectious Diseases Research Center, Gonabad University of Medical Sciences, Gonabad, Iran
| | - Reza Mahmoudi
- Department of Toxicology and Pharmacology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran
| | - Seyed Mohsen Aghaei-Zarch
- Department of Medical Genetics, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Keywan Mortezaee
- Department of Anatomy, School of Medicine, Kurdistan University of Medical Sciences, Sanandaj, Iran.
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8
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Wieder R. Awakening of Dormant Breast Cancer Cells in the Bone Marrow. Cancers (Basel) 2023; 15:cancers15113021. [PMID: 37296983 DOI: 10.3390/cancers15113021] [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: 02/26/2023] [Revised: 05/23/2023] [Accepted: 05/26/2023] [Indexed: 06/12/2023] Open
Abstract
Up to 40% of patients with breast cancer (BC) have metastatic cells in the bone marrow (BM) at the initial diagnosis of localized disease. Despite definitive systemic adjuvant therapy, these cells survive in the BM microenvironment, enter a dormant state and recur stochastically for more than 20 years. Once they begin to proliferate, recurrent macrometastases are not curable, and patients generally succumb to their disease. Many potential mechanisms for initiating recurrence have been proposed, but no definitive predictive data have been generated. This manuscript reviews the proposed mechanisms that maintain BC cell dormancy in the BM microenvironment and discusses the data supporting specific mechanisms for recurrence. It addresses the well-described mechanisms of secretory senescence, inflammation, aging, adipogenic BM conversion, autophagy, systemic effects of trauma and surgery, sympathetic signaling, transient angiogenic bursts, hypercoagulable states, osteoclast activation, and epigenetic modifications of dormant cells. This review addresses proposed approaches for either eliminating micrometastases or maintaining a dormant state.
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Affiliation(s)
- Robert Wieder
- Rutgers New Jersey Medical School and the Cancer Institute of New Jersey, 185 South Orange Avenue, MSB F671, Newark, NJ 07103, USA
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9
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Li H, Jiang W, Zhang SR, Li PC, Li TJ, Jin W, Xu HX, Yu XJ, Liu L. The platelet pannexin 1-IL-1β axis orchestrates pancreatic ductal adenocarcinoma invasion and metastasis. Oncogene 2023; 42:1453-1465. [PMID: 36922676 PMCID: PMC10015141 DOI: 10.1038/s41388-023-02647-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 02/14/2023] [Accepted: 02/22/2023] [Indexed: 03/17/2023]
Abstract
We aimed to investigate the protumor mechanisms of platelets in pancreatic ductal adenocarcinoma (PDAC). Serum samples were collected from 656 PDAC patients and 3105 healthy people, and a Panx1 knockout tumor model and an adoptive platelet transfusion mouse model were established. We showed that the blood platelet counts were not significantly different between stage III/IV and stage I/II patients, while the number of the CD41+/CD62P+ platelets was significantly elevated in stage III/IV patients, indicating that CD41+/CD62P+ platelets are associated with a poor prognosis. Further analysis showed that a high level of CD41+/CD62P+ platelets was significantly correlated with microvascular invasion (P = 0.002), advanced 8th edition AJCC stage (P < 0.001), and a high CA19-9 level (P = 0.027) and independently predicted a poor prognosis for resectable I/II PDAC. Furthermore, we found significantly higher Panx1 expression in CD41+/CD62P+ platelets than in CD41+/CD62P- platelets in PDAC patients. Mechanistically, Panx1 was able to enhance IL-1β secretion in CD41+/CD62P+ platelets by phosphorylating p38 MAPK and consequently promoted the invasion and metastasis of PDAC cells. Finally, we synthesized a novel compound named PC63435 by the ligation of carbenoxolone (a Panx1 inhibitor) and PSGL-1 (a CD62P ligand). PC63435 specifically bound to CD41+/CD62P+ platelets, then blocked the Panx1/IL-1β pathway and reduced the proportion of CD41+/CD62P+ platelets, which suppressed PDAC tumor invasion and metastasis in vivo. These results demonstrated that the Panx1/IL-1β axis in CD41+/CD62P+ platelets enhanced PDAC cell malignancy and that this axis may be a promising target for PDAC therapy.
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Affiliation(s)
- Hao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, P. R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, PR China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, PR China
| | - Wang Jiang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, P. R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, PR China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, PR China
| | - Shi-Rong Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, P. R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, PR China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, PR China
| | - Peng-Cheng Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, P. R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, PR China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, PR China
| | - Tian-Jiao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, P. R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, PR China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, PR China
| | - Wei Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, P. R. China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China.,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, PR China.,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, PR China
| | - Hua-Xiang Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, P. R. China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China. .,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, PR China. .,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, PR China.
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, P. R. China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China. .,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, PR China. .,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, PR China.
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 20032, P. R. China. .,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, PR China. .,Shanghai Pancreatic Cancer Institute, Shanghai, 200032, PR China. .,Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, PR China. .,Department of Pancreatic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China.
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10
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Tissue factor-dependent coagulation activation in intracranial neoplasms: a comparative study. Blood Coagul Fibrinolysis 2022; 33:438-448. [PMID: 36165076 DOI: 10.1097/mbc.0000000000001164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The aim of the study was to investigate the concentration and activity of tissue factor (TF) and Tissue factor pathway inhibitor (TFPI) as well as the concentration of thrombin-antithrombin (TAT) complexes in patients with primary and metastatic intracranial neoplasms. The study included 69 patients with an average age of 62 years. Twenty-one patients were diagnosed with gliomas, 18 meningioma stage II (M) patients, and 30 metastatic brain tumour cases (Meta). The control group consisted of 30 individuals with a mean age of 57 years. In the plasma of all the participants and in tumour tissue-derived homogenate, the concentrations and activities of TF, TFPI, the concentration of TAT complexes and the concentration of total protein were measured. The results were converted per 1 mg of protein. The concentration of TF was over 80 times higher in the tumour tissue-derived homogenate in respect to patients' plasma levels. Plasma TF activity in intracranial cancer patients was almost six times higher compared with noncancer counterparts, while in the tumour tissue-derived homogenate it was more than 14 times higher than in the intracranial cancer patients' plasma, whereas the concentration of TFPI in the tumour tissue-derived homogenate was significantly lower than in the patients' plasma. However, a significantly higher TFPI activity in the tumour tissue derived than in the patients' plasma was reported. The high concentration and activity of TF, along with the coexisting low concentration and activity of TFPI in the plasma of intracranial tumour patients, is associated with a higher prothrombotic risk in these patients.
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11
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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: 28] [Impact Index Per Article: 9.3] [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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12
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Mamtimin M, Pinarci A, Han C, Braun A, Anders HJ, Gudermann T, Mammadova-Bach E. Extracellular DNA Traps: Origin, Function and Implications for Anti-Cancer Therapies. Front Oncol 2022; 12:869706. [PMID: 35574410 PMCID: PMC9092261 DOI: 10.3389/fonc.2022.869706] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 03/07/2022] [Indexed: 12/16/2022] Open
Abstract
Extracellular DNA may serve as marker in liquid biopsies to determine individual diagnosis and prognosis in cancer patients. Cell death or active release from various cell types, including immune cells can result in the release of DNA into the extracellular milieu. Neutrophils are important components of the innate immune system, controlling pathogens through phagocytosis and/or the release of neutrophil extracellular traps (NETs). NETs also promote tumor progression and metastasis, by modulating angiogenesis, anti-tumor immunity, blood clotting and inflammation and providing a supportive niche for metastasizing cancer cells. Besides neutrophils, other immune cells such as eosinophils, dendritic cells, monocytes/macrophages, mast cells, basophils and lymphocytes can also form extracellular traps (ETs) during cancer progression, indicating possible multiple origins of extracellular DNA in cancer. In this review, we summarize the pathomechanisms of ET formation generated by different cell types, and analyze these processes in the context of cancer. We also critically discuss potential ET-inhibiting agents, which may open new therapeutic strategies for cancer prevention and treatment.
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Affiliation(s)
- Medina Mamtimin
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany.,Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital, Munich, Germany
| | - Akif Pinarci
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany
| | - Chao Han
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany.,Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital, Munich, Germany
| | - Attila Braun
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany
| | - Hans-Joachim Anders
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany.,Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital, Munich, Germany
| | - Thomas Gudermann
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany.,German Center for Lung Research, Munich, Germany
| | - Elmina Mammadova-Bach
- Walther-Straub-Institute for Pharmacology and Toxicology, Ludwig-Maximilians-University, Munich, Germany.,Division of Nephrology, Department of Medicine IV, Ludwig-Maximilians-University Hospital, Munich, Germany
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13
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Alexander ET, Gilmour SK. Immunomodulatory role of thrombin in cancer progression. Mol Carcinog 2022; 61:527-536. [PMID: 35338515 DOI: 10.1002/mc.23398] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/24/2022] [Accepted: 01/26/2022] [Indexed: 11/06/2022]
Abstract
Coagulation proteases and the generation of thrombin are increased in tumors. In addition, chemotherapeutic agents commonly used to treat malignant cancers can exacerbate cancer-associated thromboses. Thrombin can modify tumor cell behavior directly through the activation of protease-activated receptors (PAR) or indirectly by generating fibrin matrices. In addition to its role in generating fibrin to promote hemostasis, thrombin acts directly on multiple effector cells of the immune system impacting both acute and chronic inflammatory processes. Thrombin-mediated release of interleukin-6, tumor necrosis factor-α, and monocyte chemoattractant protein-1 leads to the accumulation of multiple tumor-infiltrating immunosuppressive cell populations including myeloid derived suppresser cells, M2-like macrophages, and T regulatory cells. Ablation of PAR-1 from the tumor microenvironment, but not the tumor, has been shown to dramatically reduce tumor growth and metastasis in multiple tumor models. Thrombin-activated platelets release immunosuppressive cytokines including transforming growth factor-β that can inhibit natural killer cell activity, helping tumor cells to evade host immunosurveillance. Taken together, there is strong evidence that thrombin influences cancer progression via multiple mechanisms, including the tumor immune response, with thrombin emerging as a target for novel therapeutic strategies for cancer.
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Affiliation(s)
- Eric T Alexander
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
| | - Susan K Gilmour
- Lankenau Institute for Medical Research, Wynnewood, Pennsylvania, USA
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14
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Machine Learning analysis of high-grade serous ovarian cancer proteomic dataset reveals novel candidate biomarkers. Sci Rep 2022; 12:3041. [PMID: 35197484 PMCID: PMC8866540 DOI: 10.1038/s41598-022-06788-2] [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: 08/02/2021] [Accepted: 02/02/2022] [Indexed: 12/19/2022] Open
Abstract
Ovarian cancer is one of the most common gynecological malignancies, ranking third after cervical and uterine cancer. High-grade serous ovarian cancer (HGSOC) is one of the most aggressive subtype, and the late onset of its symptoms leads in most cases to an unfavourable prognosis. Current predictive algorithms used to estimate the risk of having Ovarian Cancer fail to provide sufficient sensitivity and specificity to be used widely in clinical practice. The use of additional biomarkers or parameters such as age or menopausal status to overcome these issues showed only weak improvements. It is necessary to identify novel molecular signatures and the development of new predictive algorithms able to support the diagnosis of HGSOC, and at the same time, deepen the understanding of this elusive disease, with the final goal of improving patient survival. Here, we apply a Machine Learning-based pipeline to an open-source HGSOC Proteomic dataset to develop a decision support system (DSS) that displayed high discerning ability on a dataset of HGSOC biopsies. The proposed DSS consists of a double-step feature selection and a decision tree, with the resulting output consisting of a combination of three highly discriminating proteins: TOP1, PDIA4, and OGN, that could be of interest for further clinical and experimental validation. Furthermore, we took advantage of the ranked list of proteins generated during the feature selection steps to perform a pathway analysis to provide a snapshot of the main deregulated pathways of HGSOC. The datasets used for this study are available in the Clinical Proteomic Tumor Analysis Consortium (CPTAC) data portal (https://cptac-data-portal.georgetown.edu/).
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15
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Dotse E, Lim KH, Wang M, Wijanarko KJ, Chow KT. An Immunological Perspective of Circulating Tumor Cells as Diagnostic Biomarkers and Therapeutic Targets. Life (Basel) 2022; 12:323. [PMID: 35207611 PMCID: PMC8878951 DOI: 10.3390/life12020323] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 02/10/2022] [Accepted: 02/14/2022] [Indexed: 11/19/2022] Open
Abstract
Immune modulation is a hallmark of cancer. Cancer-immune interaction shapes the course of disease progression at every step of tumorigenesis, including metastasis, of which circulating tumor cells (CTCs) are regarded as an indicator. These CTCs are a heterogeneous population of tumor cells that have disseminated from the tumor into circulation. They have been increasingly studied in recent years due to their importance in diagnosis, prognosis, and monitoring of treatment response. Ample evidence demonstrates that CTCs interact with immune cells in circulation, where they must evade immune surveillance or modulate immune response. The interaction between CTCs and the immune system is emerging as a critical point by which CTCs facilitate metastatic progression. Understanding the complex crosstalk between the two may provide a basis for devising new diagnostic and treatment strategies. In this review, we will discuss the current understanding of CTCs and the complex immune-CTC interactions. We also present novel options in clinical interventions, targeting the immune-CTC interfaces, and provide some suggestions on future research directions.
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Affiliation(s)
- Eunice Dotse
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China; (E.D.); (K.H.L.); (M.W.)
| | - King H. Lim
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China; (E.D.); (K.H.L.); (M.W.)
| | - Meijun Wang
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China; (E.D.); (K.H.L.); (M.W.)
| | - Kevin Julio Wijanarko
- Department of Paediatrics, University of Melbourne, Parkville, VIC 3010, Australia;
- Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, Australia
| | - Kwan T. Chow
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong 999077, China; (E.D.); (K.H.L.); (M.W.)
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16
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Rovati G, Contursi A, Bruno A, Tacconelli S, Ballerini P, Patrignani P. Antiplatelet Agents Affecting GPCR Signaling Implicated in Tumor Metastasis. Cells 2022; 11:725. [PMID: 35203374 PMCID: PMC8870128 DOI: 10.3390/cells11040725] [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: 01/17/2022] [Revised: 02/10/2022] [Accepted: 02/16/2022] [Indexed: 11/16/2022] Open
Abstract
Metastasis requires that cancer cells survive in the circulation, colonize distant organs, and grow. Despite platelets being central contributors to hemostasis, leukocyte trafficking during inflammation, and vessel stability maintenance, there is significant evidence to support their essential role in supporting metastasis through different mechanisms. In addition to their direct interaction with cancer cells, thus forming heteroaggregates such as leukocytes, platelets release molecules that are necessary to promote a disseminating phenotype in cancer cells via the induction of an epithelial-mesenchymal-like transition. Therefore, agents that affect platelet activation can potentially restrain these prometastatic mechanisms. Although the primary adhesion of platelets to cancer cells is mainly independent of G protein-mediated signaling, soluble mediators released from platelets, such as ADP, thromboxane (TX) A2, and prostaglandin (PG) E2, act through G protein-coupled receptors (GPCRs) to cause the activation of more additional platelets and drive metastatic signaling pathways in cancer cells. In this review, we examine the contribution of the GPCRs of platelets and cancer cells in the development of cancer metastasis. Finally, the possible use of agents affecting GPCR signaling pathways as antimetastatic agents is discussed.
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Affiliation(s)
- Gianenrico Rovati
- Department of Pharmaceutical Sciences, University of Milan, 20122 Milan, Italy;
| | - Annalisa Contursi
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Annalisa Bruno
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Stefania Tacconelli
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Patrizia Ballerini
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Innovative Technologies in Medicine and Dentistry, “G. d’Annunzio” University, 66100 Chieti, Italy
| | - Paola Patrignani
- Laboratory of Systems Pharmacology and Translational Therapies, Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy; (A.C.); (A.B.); (S.T.); (P.B.)
- Department of Neuroscience, Imaging and Clinical Science, School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
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17
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Sugano H, Shirai Y, Sato S, Hamatani S, Hamura R, Taniai T, Horiuchi T, Gocho T, Eto K, Ikegami T. Thrombomodulin expression impacts the recurrence and long-term survival in pancreatic cancer. Ann Gastroenterol Surg 2021; 5:567-574. [PMID: 34337305 PMCID: PMC8316731 DOI: 10.1002/ags3.12447] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2020] [Revised: 01/17/2021] [Accepted: 01/29/2021] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Pancreatic cancer is one of the most aggressive digestive cancers. The tumor expression of thrombomodulin (TM) is correlated with favorable prognosis in several types of cancer. However, this correlation has not been confirmed in hepato-pancreato-biliary cancer. The aim of this study was to evaluate the prognostic value of TM expression in resected pancreatic ductal adenocarcinoma. METHODS The data of patients who underwent pancreatic resection for pancreatic invasive ductal adenocarcinoma were obtained from a prospectively maintained database. A total of 131 patients were included. Paraffin sections of tumor tissues were stained immunohistochemically using TM antibody. The patients were divided into two groups: the TM-positive or TM-negative group. RESULTS The specimens were TM-positive in 72 cases. TM expression was a significant factor of favorable prognosis in univariate analysis for disease-free (DFS) and overall survival (OS). The median OS in the TM-positive patients was 32.9 mo, which was better than the 20.0 mo in TM-negative patients (P =.006). TM positivity retained its significance on multivariate analysis for DFS (hazard ratio [HR] 0.651, 95% confidence interval [CI] 0.433-0.979, P =.039) and OS (HR 0.569, 95% CI 0.376-0.862, P =.008). CONCLUSIONS The tumor expression of TM is a favorable factor for OS in resected pancreatic invasive ductal adenocarcinoma.
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Affiliation(s)
- Hiroshi Sugano
- Department of SurgeryThe Jikei University School of MedicineTokyoJapan
- Division of Gene TherapyResearch Center for Medical ScienceThe Jikei University School of MedicineTokyoJapan
| | - Yoshihiro Shirai
- Department of SurgeryThe Jikei University School of MedicineTokyoJapan
- Division of Gene TherapyResearch Center for Medical ScienceThe Jikei University School of MedicineTokyoJapan
| | - Shun Sato
- Department of PathologyThe Jikei University School of MedicineTokyoJapan
| | - Shigeharu Hamatani
- Department of PathologyThe Jikei University School of MedicineTokyoJapan
| | - Ryoga Hamura
- Department of SurgeryThe Jikei University School of MedicineTokyoJapan
- Division of Gene TherapyResearch Center for Medical ScienceThe Jikei University School of MedicineTokyoJapan
| | - Tomohiko Taniai
- Department of SurgeryThe Jikei University School of MedicineTokyoJapan
- Division of Gene TherapyResearch Center for Medical ScienceThe Jikei University School of MedicineTokyoJapan
| | - Takashi Horiuchi
- Department of SurgeryThe Jikei University School of MedicineTokyoJapan
- Division of Gene TherapyResearch Center for Medical ScienceThe Jikei University School of MedicineTokyoJapan
| | - Takeshi Gocho
- Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Ken Eto
- Department of SurgeryThe Jikei University School of MedicineTokyoJapan
| | - Toru Ikegami
- Department of SurgeryThe Jikei University School of MedicineTokyoJapan
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18
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Lucotti S, Muschel RJ. Platelets and Metastasis: New Implications of an Old Interplay. Front Oncol 2020; 10:1350. [PMID: 33042789 PMCID: PMC7530207 DOI: 10.3389/fonc.2020.01350] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 06/26/2020] [Indexed: 12/17/2022] Open
Abstract
During the process of hematogenous metastasis, tumor cells interact with platelets and their precursors megakaryocytes, providing a selection driver for the metastatic phenotype. Cancer cells have evolved a plethora of mechanisms to engage platelet activation and aggregation. Platelet coating of tumor cells in the blood stream promotes the successful completion of multiple steps of the metastatic cascade. Along the same lines, clinical evidence suggests that anti-coagulant therapy might be associated with reduced risk of metastatic disease and better prognosis in cancer patients. Here, we review experimental and clinical literature concerning the contribution of platelets and megakaryocytes to cancer metastasis and provide insights into the clinical relevance of anti-coagulant therapy in cancer treatment.
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Affiliation(s)
- Serena Lucotti
- Children's Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children's Health, Meyer Cancer Center, Weill Cornell Medicine, New York, NY, United States
| | - Ruth J Muschel
- Cancer Research UK and MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom
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19
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Castle J, Blower E, Bundred NJ, Harvey JR, Thachil J, Marshall A, Cox K, Cicconi S, Holcombe C, Palmieri C, Kirwan CC. Rivaroxaban compared to no treatment in ER-negative stage I-III early breast cancer patients (the TIP Trial): study protocol for a phase II preoperative window-of-opportunity study design randomised controlled trial. Trials 2020; 21:749. [PMID: 32854772 PMCID: PMC7534806 DOI: 10.1186/s13063-020-04675-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Accepted: 08/12/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Breast cancer patients are at a four-fold increased risk of developing a venous thromboembolism (VTE), a major cause of death in this group. Conversely, coagulation factors promote tumour growth and metastasis. This has been evidenced in preclinical models, with an inhibitory effect of anticoagulants on cancer growth through proliferative, angiogenic, apoptotic, cancer stem cell and metastatic processes. The extrinsic clotting pathway is also more upregulated in patients in the relatively poorer prognosis oestrogen receptor (ER)-negative breast cancer subgroup, with increased tumour stromal expression of the coagulation factors Tissue Factor and thrombin. Rivaroxaban (Xarelto®, Bayer AG, Leverkusen, Germany) is a direct oral anticoagulant (DOAC). It is a Factor Xa inhibitor that is routinely prescribed for the prevention of stroke in non-valvular atrial fibrillation and for both VTE prophylaxis and treatment. This trial will assess the anti-proliferative and other anti-cancer progression mechanisms of Rivaroxaban in ER-negative early breast cancer patients. METHODS This UK-based preoperative window-of-opportunity phase II randomised control trial will randomise 88 treatment-naïve early breast cancer patients to receive 20 mg OD Rivaroxaban treatment for 11 to 17 days or no treatment. Treatment will be stopped 24 h (range 18-36 h) prior to surgery or repeat core biopsy. All patients will be followed up for 2 weeks following surgery or repeat core biopsy. The primary endpoint is change in tumour Ki67. Secondary outcome measures include tumour markers of apoptosis and angiogenesis, extrinsic clotting pathway activation and systemic markers of metastasis, tumour load and coagulation. DISCUSSION Laboratory evidence supports an anti-cancer role for anticoagulants; however, this has failed to translate into survival benefit when trialled in patients with metastatic disease or poor prognosis cancers, such as lung cancer. Subgroup analysis supported a potential survival benefit in better prognosis advanced disease patients. This is the first study to investigate the anti-cancer effects of anticoagulants in early breast cancer. TRIAL REGISTRATION UK National Research Ethics Service (NRES) approval 15/NW/0406, MHRA Clinical Trials Authorisation 48380/0003/001-0001. The sponsor is Manchester University NHS Foundation Trust, and the trial is co-ordinated by Cancer Research UK Liverpool Cancer Trials Unit (LCTU). EudraCT 2014-004909-33 , registered 27 July 2015. ISRCTN14785273 .
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Affiliation(s)
- John Castle
- Manchester Cancer Research Centre, The University of Manchester, Wilmslow Road, Manchester, M20 4GJ UK
| | - Emma Blower
- Manchester Cancer Research Centre, The University of Manchester, Wilmslow Road, Manchester, M20 4GJ UK
| | - Nigel J. Bundred
- Manchester Cancer Research Centre, The University of Manchester, Wilmslow Road, Manchester, M20 4GJ UK
- The Nightingale Centre, Wythenshawe Hospital, Manchester, M23 9LT UK
| | - James R. Harvey
- The Nightingale Centre, Wythenshawe Hospital, Manchester, M23 9LT UK
| | - Jecko Thachil
- Department of Haematology, Manchester Royal Infirmary, Manchester, M13 9WL UK
| | - Andrea Marshall
- Warwick Clinical Trials Unit, University of Warwick, Coventry, CV4 7AL UK
| | - Karina Cox
- Department of Breast Surgery, Maidstone Hospital, Maidstone, ME16 9QQ UK
| | - Silvia Cicconi
- Cancer Research UK Liverpool Cancer Trials Unit, Liverpool, L69 3GL UK
| | - Chris Holcombe
- Breast Unit, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, L3 9TA UK
| | - Carlos Palmieri
- Department of Molecular and Clinical Cancer Medicine, Liverpool, L69 3GA UK
| | - Cliona C. Kirwan
- Manchester Cancer Research Centre, The University of Manchester, Wilmslow Road, Manchester, M20 4GJ UK
- The Nightingale Centre, Wythenshawe Hospital, Manchester, M23 9LT UK
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20
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Anticoagulants and cancer mortality in the Finnish randomized study of screening for prostate cancer. Cancer Causes Control 2019; 30:877-888. [PMID: 31209595 DOI: 10.1007/s10552-019-01195-x] [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: 12/11/2018] [Accepted: 06/12/2019] [Indexed: 12/21/2022]
Abstract
PURPOSE Anticoagulants may reduce mortality of cancer patients, though the evidence remains controversial. We studied the association between different anticoagulants and cancer death. METHODS All anticoagulant use during 1995-2015 was analyzed among 75,336 men in the Finnish Randomized Study of Screening for Prostate Cancer. Men with prevalent cancer were excluded. Multivariable Cox regression was performed to compare risk of death from any cancer and disease-specific death from 9 specific cancer types between (1) anticoagulant users overall and (2) warfarin users compared to anticoagulant non-users and (3) warfarin or (4) low-molecular-weight heparins (LMWH) compared to users of other anticoagulants. Medication use was analyzed as time-dependent variable to minimize immortal time bias. 1-, 2- and 3-year lag-time analyses were performed. RESULTS During a median follow-up of 17.2 years, a total of 27,233 men died of whom 8033 with cancer as the primary cause of death. In total, 32,628 men (43%) used anticoagulants. Any anticoagulant use was associated with an increased risk of cancer death (HR = 2.50, 95% CI 2.37-2.64) compared to non-users. Risk was similar independent of the amount, duration, or intensity of use. The risk increase was observed both among warfarin and LMWH users, although not as strong in warfarin users. Additionally, cancer-specific risks of death were similar to overall cancer mortality in all anticoagulant categories. CONCLUSION Our study does not support reduced cancer mortality among anticoagulant users. Future studies on drug use and cancer mortality should be adjusted for anticoagulants as they are associated with significantly higher risk of cancer death.
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21
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Rachidi S, Kaur M, Lautenschlaeger T, Li Z. Platelet count correlates with stage and predicts survival in melanoma. Platelets 2019; 30:1042-1046. [DOI: 10.1080/09537104.2019.1572879] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Saleh Rachidi
- Resident Physician, Department of Dermatology, Johns Hopkins University, Baltimore, MD, USA
| | - Maneet Kaur
- PhD student in Biostatistics and Epidemiology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA
| | | | - Zihai Li
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
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22
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Rachidi S, Li H, Wallace K, Li Z, Balch C, Lautenschlaeger T. Preoperative platelet counts and postoperative outcomes in cancer surgery: a multicenter, retrospective cohort study. Platelets 2019; 31:79-87. [PMID: 30744463 DOI: 10.1080/09537104.2019.1573977] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Revised: 01/15/2019] [Accepted: 01/22/2019] [Indexed: 02/07/2023]
Abstract
Platelets play roles in malignancy, wound healing, and immunity. Nevertheless, their significance in postoperative outcomes is not established. This is a retrospective cohort study of 100,795 patients undergoing cancer surgery in 2010 and 2014 in >500 hospitals. Patients were stratified into five groups based on preoperative platelet counts. Multivariable logistic regression was used to determine the risk of 30-day mortality, morbidities, readmission, and prolonged hospitalization using the mid-normal group as a reference. We adjusted for demographic variables, comorbidities, and operation complexity. In the 2014 cohort, multivariable analysis showed that mortality was higher in patients with thrombocytopenia (OR 1.49, 95% CI [1.23-1.81]), high-normal platelets (OR 1.29, [1.06-1.55]), and thrombocytosis (OR 1.78, [1.45-2.19]). Composite postoperative morbidity followed a similar trend with thrombocytopenia (OR 1.34, [1.25-1.43]), high-normal counts (OR 1.41, [1.33-1.49]), and thrombocytosis (OR 2.20, [2.05-2.36]). Concordantly, the risks of prolonged hospitalization and 30-day readmission followed the same pattern. These results were validated in a large colon cancer cohort from the 2010 database. In conclusion, platelet count is a prognostic indicator in cancer surgeries. This could be related to the role of platelets in wound healing and immunity on one hand, and propagating malignancy on the other.
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Affiliation(s)
- Saleh Rachidi
- Department of Dermatology, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Hong Li
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Kristin Wallace
- Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC, USA
| | - Zihai Li
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA
| | - Charles Balch
- Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Tim Lautenschlaeger
- Department of Radiation Oncology, Indiana University Health, Indianapolis, IN, USA
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23
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Thrombin Generation and Cancer: Contributors and Consequences. Cancers (Basel) 2019; 11:cancers11010100. [PMID: 30654498 PMCID: PMC6356447 DOI: 10.3390/cancers11010100] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2018] [Revised: 01/04/2019] [Accepted: 01/08/2019] [Indexed: 12/19/2022] Open
Abstract
The high occurrence of cancer-associated thrombosis is associated with elevated thrombin generation. Tumour cells increase the potential for thrombin generation both directly, through the expression and release of procoagulant factors, and indirectly, through signals that activate other cell types (including platelets, leukocytes and erythrocytes). Furthermore, cancer treatments can worsen these effects. Coagulation factors, including tissue factor, and inhibitors of coagulation are altered and extracellular vesicles (EVs), which can promote and support thrombin generation, are released by tumour and other cells. Some phosphatidylserine-expressing platelet subsets and platelet-derived EVs provide the surface required for the assembly of coagulation factors essential for thrombin generation in vivo. This review will explore the causes of increased thrombin production in cancer, and the availability and utility of tests and biomarkers. Increased thrombin production not only increases blood coagulation, but also promotes tumour growth and metastasis and as a consequence, thrombin and its contributors present opportunities for treatment of cancer-associated thrombosis and cancer itself.
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24
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Li Z, Riesenberg B, Metelli A, Li A, Wu BX. The Role of Platelets in Tumor Growth, Metastasis, and Immune Evasion. Platelets 2019. [DOI: 10.1016/b978-0-12-813456-6.00030-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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25
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Qi Y, Chen W, Liang X, Xu K, Gu X, Wu F, Fan X, Ren S, Liu J, Zhang J, Li R, Liu J, Liang X. Novel antibodies against GPIbα inhibit pulmonary metastasis by affecting vWF-GPIbα interaction. J Hematol Oncol 2018; 11:117. [PMID: 30223883 PMCID: PMC6142402 DOI: 10.1186/s13045-018-0659-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2018] [Accepted: 08/31/2018] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Platelet glycoprotein Ibα (GPIbα) extracellular domain, which is part of the receptor complex GPIb-IX-V, plays an important role in tumor metastasis. However, the mechanism through which GPIbα participates in the metastatic process remains unclear. In addition, potential bleeding complication remains an obstacle for the clinical use of anti-platelet agents in cancer therapy. METHODS We established a series of screening models and obtained rat anti-mouse GPIbα monoclonal antibodies (mAb) 1D12 and 2B4 that demonstrated potential value in suppressing cancer metastasis. To validate our findings, we further obtained mouse anti-human GPIbα monoclonal antibody YQ3 through the same approach. RESULTS 1D12 and 2B4 affected the von Willebrand factor (vWF)-GPIbα interaction via binding to GPIbα aa 41-50 and aa 277-290 respectively, which markedly inhibited the interaction among platelets, tumor cells, and endothelial cells in vitro, and reduced the mean number of surface nodules in the experimental and spontaneous metastasis models in vivo. As expected, YQ3 inhibited lung cancer adhesion and demonstrated similar value in metastasis. More importantly, for all three mAbs in our study, none of their Fabs induced thrombocytopenia. CONCLUSION Our results therefore supported the hypothesis that GPIbα contributes to tumor metastasis and suggested potential value of using anti-GPIbα mAb to suppress cancer metastasis.
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Affiliation(s)
- Yingxue Qi
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Rd, Shanghai, 200237, People's Republic of China
| | - Wenchun Chen
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Xinyu Liang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Rd, Shanghai, 200237, People's Republic of China
| | - Ke Xu
- Central laboratory, General Surgery, Putuo Hospital, and Interventional Cancer Institute of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, 164 Lanxi Rd, Shanghai, 200062, People's Republic of China.
| | - Xiangyu Gu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Rd, Shanghai, 200237, People's Republic of China
| | - Fengying Wu
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Xuemei Fan
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Shengxiang Ren
- Department of Medical Oncology, Shanghai Pulmonary Hospital, Thoracic Cancer Institute, Tongji University School of Medicine, Shanghai, People's Republic of China
| | - Junling Liu
- Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, People's Republic of China
| | - Jun Zhang
- Division of Hematology, Oncology and Blood & Marrow Transplantation, Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa Carver College of Medicine, Iowa City, IA, 52242, USA
| | - Renhao Li
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA
| | - Jianwen Liu
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Rd, Shanghai, 200237, People's Republic of China.
| | - Xin Liang
- State Key Laboratory of Bioreactor Engineering & Shanghai Key Laboratory of New Drug Design, School of Pharmacy, East China University of Science and Technology, 130 Meilong Rd, Shanghai, 200237, People's Republic of China.
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26
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Cho A, McKelvey KJ, Lee A, Hudson AL. The intertwined fates of inflammation and coagulation in glioma. Mamm Genome 2018; 29:806-816. [PMID: 30062485 DOI: 10.1007/s00335-018-9761-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 07/17/2018] [Indexed: 12/17/2022]
Abstract
Inflammation and coagulation are two intertwined pathways with evolutionary ties being traced back to the hemocyte, a single cell type in invertebrates that has functions in both the inflammatory and coagulation pathways. These systems have functioned together throughout evolution to provide a solid defence against infection, damaged cells and irritants. While these systems work in harmony the majority of the time, they can also become dysregulated or corrupted by tumours, enhancing tumour proliferation, invasion, dissemination and survival. This review aims to give a brief overview of how these systems work in harmony and how dysregulation of these systems aids in the development and progression of cancer, using glioma as an example.
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Affiliation(s)
- Angela Cho
- The Brain Cancer Group, Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, St Leonards, NSW, 2065, Australia.,Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia.,Sydney Medical School Northern, University of Sydney, Camperdown, NSW, 2065, Australia
| | - Kelly J McKelvey
- The Brain Cancer Group, Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, St Leonards, NSW, 2065, Australia.,Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia.,Sydney Medical School Northern, University of Sydney, Camperdown, NSW, 2065, Australia
| | - Adrian Lee
- The Brain Cancer Group, Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, St Leonards, NSW, 2065, Australia.,Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia.,Sydney Medical School Northern, University of Sydney, Camperdown, NSW, 2065, Australia
| | - Amanda L Hudson
- The Brain Cancer Group, Bill Walsh Translational Cancer Research Laboratory, Kolling Institute, St Leonards, NSW, 2065, Australia. .,Northern Sydney Local Health District, St Leonards, NSW, 2065, Australia. .,Sydney Medical School Northern, University of Sydney, Camperdown, NSW, 2065, Australia.
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27
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Postdiagnosis aspirin use and overall survival in patients with melanoma. J Am Acad Dermatol 2018; 78:949-956.e1. [DOI: 10.1016/j.jaad.2017.12.076] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 12/18/2017] [Accepted: 12/25/2017] [Indexed: 02/08/2023]
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28
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Gresele P, Momi S, Malvestiti M, Sebastiano M. Platelet-targeted pharmacologic treatments as anti-cancer therapy. Cancer Metastasis Rev 2018; 36:331-355. [PMID: 28707198 DOI: 10.1007/s10555-017-9679-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Platelets act as multifunctional cells participating in immune response, inflammation, allergy, tissue regeneration, and lymphoangiogenesis. Among the best-established aspects of a role of platelets in non-hemostatic or thrombotic disorders, there is their participation in cancer invasion and metastasis. The interaction of many different cancer cells with platelets leads to platelet activation, and on the other hand platelet activation is strongly instrumental to the pro-carcinogenic and pro-metastatic activities of platelets. It is thus obvious that over the last years a lot of interest has focused on the possible chemopreventive effect of platelet-targeted pharmacologic treatments. This article gives an overview of the platelet-targeted pharmacologic approaches that have been attempted in the prevention of cancer development, progression, and metastasis, including the application of anti-platelet drugs currently used for cardiovascular disease and of new and novel pharmacologic strategies. Despite the fact that very promising results have been obtained with some of these approaches in pre-clinical models, with the exclusion of aspirin, clinical evidence of a beneficial effect of anti-platelet agents in cancer is however still largely missing. Future studies with platelet-targeted drugs in cancer must carefully deal with design issues, and in particular with the careful selection of patients, and/or explore novel platelet targets in order to provide a solution to the critical issue of the risk/benefit profile of long-term anti-platelet therapy in the prevention of cancer progression and dissemination.
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Affiliation(s)
- P Gresele
- Section of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Via Enrico dal Pozzo, 06126, Perugia, Italy.
| | - S Momi
- Section of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Via Enrico dal Pozzo, 06126, Perugia, Italy
| | - M Malvestiti
- Section of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Via Enrico dal Pozzo, 06126, Perugia, Italy
| | - M Sebastiano
- Section of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Via Enrico dal Pozzo, 06126, Perugia, Italy
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29
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Wojtukiewicz MZ, Hempel D, Sierko E, Tucker SC, Honn KV. Antiplatelet agents for cancer treatment: a real perspective or just an echo from the past? Cancer Metastasis Rev 2018; 36:305-329. [PMID: 28752248 PMCID: PMC5557869 DOI: 10.1007/s10555-017-9683-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The association between coagulation and cancer development has been observed for centuries. However, the connection between inflammation and malignancy is also well-recognized. The plethora of evidence indicates that among multiple hemostasis components, platelets play major roles in cancer progression by providing surface and granular contents for several interactions as well as behaving like immune cells. Therefore, the anticancer potential of anti-platelet therapy has been intensively investigated for many years. Anti-platelet agents may prevent cancer, decrease tumor growth, and metastatic potential, as well as improve survival of cancer patients. On the other hand, there are suggestions that antiplatelet treatment may promote solid tumor development in a phenomenon described as "cancers follow bleeding." The controversies around antiplatelet agents justify insight into the subject to establish what, if any, role platelet-directed therapy has in the continuum of anticancer management.
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Affiliation(s)
- Marek Z Wojtukiewicz
- Department of Oncology, Medical University of Bialystok, 12 Ogrodowa St., 15-025, Bialystok, Poland.
| | - Dominika Hempel
- Department of Radiotherapy, Comprehensive Cancer Center in Bialystok, Bialystok, Poland
| | - Ewa Sierko
- Department of Clinical Oncology, Comprehensive Cancer Center in Bialystok, Bialystok, Poland
| | - Stephanie C Tucker
- Department of Pathology-School of Medicine, Bioactive Lipids Research Program, Detroit, MI, 48202, USA
| | - Kenneth V Honn
- Department of Pathology-School of Medicine, Bioactive Lipids Research Program, Detroit, MI, 48202, USA.,Departments of Chemistry, Wayne State University, Detroit, MI, 48202, USA.,Department of Oncology, Karmanos Cancer Institute, Detroit, MI, 48202, USA
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30
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Roselli M, Mineo T, Martini F, Mariotti S, Ambrogi V, Spila A, D'Alessandro R, Basili S, Guadagni F, Ferroni P. Soluble Selectin Levels in Patients with Lung Cancer. Int J Biol Markers 2018. [DOI: 10.1177/172460080201700107] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Increased expression of selectins has been found on endothelial cells of venules and capillaries in the tumor stroma of non-small cell lung cancer, suggesting their functional role in the process of chemotaxis for tumor cells. The present study was aimed at analyzing the role of both soluble (s)P-selectin and sE-selectin levels in association with clinico-pathological variables in 116 patients with lung cancer, 38 patients with benign diseases and 59 healthy donors. The results obtained showed that sP-selectin and sE-selectin levels were higher in patients with lung cancer compared to normal donors (p<0.02 and p<0.005, respectively). No differences were observed among patients with various benign diseases for both selectins. Increased levels of sP-selectin and sE-selectin were significantly associated with squamous lung cancer at late stages (p<0.05), but not adenocarcinoma. Both sP- and sE-selectin were independently related to the stage of squamous lung cancer by stepwise regression analysis (p<0.02 and p<0.03, respectively), while only sE-selectin was independently related to the presence of distant metastasis in the same histotype (p<0.02). These results suggest that measurement of plasma soluble selectins might represent a useful laboratory parameter in the management of patients with squamous lung cancer.
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Affiliation(s)
- M. Roselli
- Clinical Oncology Section, Department of Surgery, Tor Vergata University, Rome
| | - T.C. Mineo
- Thoracic Surgery, Tor Vergata University, Rome
| | - F. Martini
- Department of Experimental Medicine and Pathology, La Sapienza University, Rome
| | - S. Mariotti
- Clinical Oncology Section, Department of Surgery, Tor Vergata University, Rome
| | - V. Ambrogi
- Thoracic Surgery, Tor Vergata University, Rome
| | - A. Spila
- Laboratory of Clinical Pathology, Regina Elena Cancer Institute, Rome
| | - R. D'Alessandro
- Laboratory of Clinical Pathology, Regina Elena Cancer Institute, Rome
| | - S. Basili
- Department of Medical Therapy, La Sapienza University, Rome - Italy
| | - F. Guadagni
- Laboratory of Clinical Pathology, Regina Elena Cancer Institute, Rome
| | - P. Ferroni
- Department of Experimental Medicine and Pathology, La Sapienza University, Rome
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31
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Chemotherapy-induced metastasis: mechanisms and translational opportunities. Clin Exp Metastasis 2018; 35:269-284. [PMID: 29307118 DOI: 10.1007/s10585-017-9870-x] [Citation(s) in RCA: 112] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2017] [Accepted: 12/20/2017] [Indexed: 12/13/2022]
Abstract
Tumors often overcome the cytotoxic effects of chemotherapy through either acquired or environment-mediated drug resistance. In addition, signals from the microenvironment obfuscate the beneficial effects of chemotherapy and may facilitate progression and metastatic dissemination. Seminal mediators in chemotherapy-induced metastasis appear to be a wide range of hematopoietic, mesenchymal and immune progenitor cells, originating from the bone marrow. The actual purpose of these cells is to orchestrate the repair response to the cytotoxic damage of chemotherapy. However, these repair responses are exploited by tumor cells at every step of the metastatic cascade, ranging from tumor cell invasion, intravasation and hematogenous dissemination to extravasation and effective colonization at the metastatic site. A better understanding of the mechanistic underpinnings of chemotherapy-induced metastasis will allow us to better predict which patients are more likely to exhibit pro-metastatic responses to chemotherapy and will help develop new therapeutic strategies to neutralize chemotherapy-driven prometastatic changes.
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32
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Škovierová H, Okajčeková T, Strnádel J, Vidomanová E, Halašová E. Molecular regulation of epithelial-to-mesenchymal transition in tumorigenesis (Review). Int J Mol Med 2017; 41:1187-1200. [PMID: 29286071 PMCID: PMC5819928 DOI: 10.3892/ijmm.2017.3320] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2017] [Accepted: 11/23/2017] [Indexed: 12/13/2022] Open
Abstract
Numerous studies over the past two decades have focused on the epithelial-to-mesenchymal transition (EMT) and its role in the development of metastasis. Certain studies highlighted the importance of EMT in the dissemination of tumor cells and metastasis of epithelium-derived carcinomas. Tumor metastasis is a multistep process during which tumor cells change their morphology, and start to migrate and invade distant sites. The present review discusses the current understanding of the molecular mechanisms contributing to EMT in embryogenesis, fibrosis and tumorigenesis. Additionally, the signaling pathways that initiate EMT through transcriptional factors responsible for the activation and suppression of various genes associated with cancer cell migration were investigated. Furthermore, the important role of the epigenetic modifications that regulate EMT and the reverse process, mesenchymal-to-epithelial transition (MET) are discussed. MicroRNAs are key regulators of various intracellular processes and current knowledge of EMT has significantly improved due to microRNA characterization. Their effect on signaling pathways and the ensuing events that occur during EMT at the molecular level is becoming increasingly recognized. The current review also highlights the role of circulating tumor cells (CTCs) and CTC clusters, and their ability to form metastases. In addition, the biological properties of different types of circulating cells based on their tumor-forming potential are compared.
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Affiliation(s)
- Henrieta Škovierová
- Biomedical Center Martin, Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 03601, Slovakia
| | - Terézia Okajčeková
- Biomedical Center Martin, Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 03601, Slovakia
| | - Ján Strnádel
- Biomedical Center Martin, Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 03601, Slovakia
| | - Eva Vidomanová
- Biomedical Center Martin, Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 03601, Slovakia
| | - Erika Halašová
- Biomedical Center Martin, Department of Molecular Medicine, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Martin 03601, Slovakia
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33
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Seizer P, May AE. Platelets and matrix metalloproteinases. Thromb Haemost 2017; 110:903-9. [DOI: 10.1160/th13-02-0113] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2013] [Accepted: 06/18/2013] [Indexed: 11/05/2022]
Abstract
SummaryMatrix metalloproteinases (MMPs) and their inhibitors essentially contribute to a variety of pathophysiologies by modulating cell migration, tissue degradation and inflammation. Platelet-associated MMP activity appears to play a major role in these processes. First, platelets can concentrate leukocyte-derived MMP activity to sites of vascular injury by leukocyte recruitment. Second, platelets stimulate MMP production in e.g. leukocytes, endothelial cells, or tumour cells by direct receptor interaction or/and by paracrine pathways. Third, platelets synthesise and secrete a variety of MMPs including MMP-1, MMP-2, MMP-3, and MMP-14 (MT1-MMP), and potentially MMP-9 as well as the tissue inhibitors of metalloproteinase (TIMPs). This review focuses on platelet-derived and platelet-induced MMPs and their inhibitors.
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34
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Lux J, Vezeridis AM, Hoyt K, Adams SR, Armstrong AM, Sirsi SR, Mattrey RF. Thrombin-Activatable Microbubbles as Potential Ultrasound Contrast Agents for the Detection of Acute Thrombosis. ACS APPLIED MATERIALS & INTERFACES 2017; 9:37587-37596. [PMID: 28994575 PMCID: PMC5691601 DOI: 10.1021/acsami.7b10592] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/23/2023]
Abstract
Acute deep vein thrombosis (DVT) is the formation of a blood clot in the deep veins of the body that can lead to fatal pulmonary embolism. Acute DVT is difficult to distinguish from chronic DVT by ultrasound (US), the imaging modality of choice, and is therefore treated aggressively with anticoagulants, which can lead to internal bleeding. Here we demonstrate that conjugating perfluorobutane-filled (PFB-filled) microbubbles (MBs) with thrombin-sensitive activatable cell-penetrating peptides (ACPPs) could lead to the development of contrast agents that detect acute thrombosis with US imaging. Successful conjugation of ACPP to PFB-filled MBs was confirmed by fluorescence microscopy and flow cytometry. Fluorescein-labeled ACPP was used to evaluate the efficiency of thrombin-triggered cleavage by measuring the mean fluorescence intensity of ACPP-labeled MBs (ACPP-MBs) before and after incubation at 37 °C with thrombin. Lastly, control MBs and ACPP-MBs were infused through a tube containing a clot, and US contrast enhancement was measured with or without the presence of a thrombin inhibitor after washing the clot with saline. With thrombin activity, 91.7 ± 14.2% of the signal was retained after ACPP-MB infusion and washing, whereas only 16.7 ± 4% of the signal was retained when infusing ACPP-MBs in the presence of hirudin, a potent thrombin inhibitor.
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Affiliation(s)
- Jacques Lux
- Department of Radiology, Translational Research in Ultrasound Theranostics (TRUST) Program, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8514, United States
| | - Alexander M. Vezeridis
- Department of Radiology, University of California, San Diego, La Jolla, California 92093, United States
| | - Kenneth Hoyt
- Department of Radiology, Translational Research in Ultrasound Theranostics (TRUST) Program, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8514, United States
- Department of Bioengineering, University of Texas at Dallas, Richardson, Texas 75080, United States
| | - Stephen R. Adams
- Department of Pharmacology, University of California, San Diego, La Jolla, California 92093, United States
| | - Amanda M. Armstrong
- Department of Radiology, Translational Research in Ultrasound Theranostics (TRUST) Program, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8514, United States
| | - Shashank R. Sirsi
- Department of Radiology, Translational Research in Ultrasound Theranostics (TRUST) Program, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8514, United States
- Department of Bioengineering, University of Texas at Dallas, Richardson, Texas 75080, United States
| | - Robert F. Mattrey
- Department of Radiology, Translational Research in Ultrasound Theranostics (TRUST) Program, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-8514, United States
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35
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Contursi A, Sacco A, Grande R, Dovizio M, Patrignani P. Platelets as crucial partners for tumor metastasis: from mechanistic aspects to pharmacological targeting. Cell Mol Life Sci 2017; 74:3491-3507. [PMID: 28488110 PMCID: PMC11107532 DOI: 10.1007/s00018-017-2536-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2016] [Revised: 05/02/2017] [Accepted: 05/03/2017] [Indexed: 02/08/2023]
Abstract
Platelets are anucleated cells that circulate in the blood as sentinels of tissue integrity. In fact, they are rich in a plethora of proteins and other factors stored in different granules which they selectively release upon stimulation. Moreover, platelets synthesize a vast number of lipids and release various types of vesicles, including exosomes which are rich in genetic material. Platelets possess a central function to interact with other cell types, including inflammatory cells and cancer cells. Recent findings have enlightened the capacity of platelets to induce changes in the phenotype of cancer cells which acquire invasiveness thus enhancing their metastatic potential. Thus, it has been hypothesized that targeting the platelet may represent a novel strategy to prevent the development and progression of cancer. This is supported by the efficacy of the antiplatelet agent low-dose aspirin. Studies are ongoing to verify whether other antiplatelet agents share the anticancer effectiveness of aspirin.
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Affiliation(s)
- Annalisa Contursi
- Section of Cardiovascular and Pharmacological Sciences, Department of Neuroscience, Imaging and Clinical Science, and CeSI-MeT (Centro Scienze dell' Invecchiamento e Medicina Traslazionale), "G. d'Annunzio" University, Via dei Vestini 31, 66100, Chieti, Italy
| | - Angela Sacco
- Section of Cardiovascular and Pharmacological Sciences, Department of Neuroscience, Imaging and Clinical Science, and CeSI-MeT (Centro Scienze dell' Invecchiamento e Medicina Traslazionale), "G. d'Annunzio" University, Via dei Vestini 31, 66100, Chieti, Italy
| | - Rosalia Grande
- Section of Cardiovascular and Pharmacological Sciences, Department of Neuroscience, Imaging and Clinical Science, and CeSI-MeT (Centro Scienze dell' Invecchiamento e Medicina Traslazionale), "G. d'Annunzio" University, Via dei Vestini 31, 66100, Chieti, Italy
| | - Melania Dovizio
- Section of Cardiovascular and Pharmacological Sciences, Department of Neuroscience, Imaging and Clinical Science, and CeSI-MeT (Centro Scienze dell' Invecchiamento e Medicina Traslazionale), "G. d'Annunzio" University, Via dei Vestini 31, 66100, Chieti, Italy
| | - Paola Patrignani
- Section of Cardiovascular and Pharmacological Sciences, Department of Neuroscience, Imaging and Clinical Science, and CeSI-MeT (Centro Scienze dell' Invecchiamento e Medicina Traslazionale), "G. d'Annunzio" University, Via dei Vestini 31, 66100, Chieti, Italy.
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36
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Platelet Integrins in Tumor Metastasis: Do They Represent a Therapeutic Target? Cancers (Basel) 2017; 9:cancers9100133. [PMID: 28956830 PMCID: PMC5664072 DOI: 10.3390/cancers9100133] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Revised: 09/22/2017] [Accepted: 09/25/2017] [Indexed: 12/14/2022] Open
Abstract
Platelets are small anucleated cell fragments that ensure the arrest of bleeding after a vessel wall injury. They are also involved in non-hemostatic function such as development, immunity, inflammation, and in the hematogeneous phase of metastasis. While the role of platelets in tumor metastasis has been recognized for 60 years, the molecular mechanism underlying this process remains largely unclear. Platelets physically and functionally interact with various tumor cells through surface receptors including integrins. Platelets express five integrins at their surface, namely α2β1, α5β1, α6β1, αvβ3, and αIIbβ3, which bind preferentially to collagen, fibronectin, laminin, vitronectin, and fibrinogen, respectively. The main role of platelet integrins is to ensure platelet adhesion and aggregation at sites of vascular injury. Two of these, α6β1 and αIIbβ3, were proposed to participate in platelet–tumor cell interaction and in tumor metastasis. It has also been reported that pharmacological agents targeting both integrins efficiently reduce experimental metastasis, suggesting that platelet integrins may represent new anti-metastatic targets. This review focuses on the role of platelet integrins in tumor metastasis and discusses whether these receptors may represent new potential targets for novel anti-metastatic approaches.
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37
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Hasin T, Iakobishvili Z, Weisz G. Associated Risk of Malignancy in Patients with Cardiovascular Disease: Evidence and Possible Mechanism. Am J Med 2017; 130:780-785. [PMID: 28344133 DOI: 10.1016/j.amjmed.2017.02.024] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2017] [Revised: 02/10/2017] [Accepted: 02/13/2017] [Indexed: 12/31/2022]
Abstract
Cardiovascular disease and malignancy are leading causes of morbidity and mortality. Increased risk of malignancy was identified in patients with cardiovascular disease, including patients with heart failure, heart failure after myocardial infarction, patients undergoing cardiac intervention, and patients after a thrombotic event. Common risk factors and biological pathways can explain this association and are explored in this review. Further research is needed to establish the causes of malignancy in this population and direct possible intervention.
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Affiliation(s)
- Tal Hasin
- Department of Cardiology, Shaare Zedek Medical Center, Jerusalem, Israel.
| | - Zaza Iakobishvili
- Department of Cardiology, Rabin Medical Center, Petach Tiqwa, Israel
| | - Giora Weisz
- Department of Cardiology, Shaare Zedek Medical Center, Jerusalem, Israel
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38
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Goyama S, Shrestha M, Schibler J, Rosenfeldt L, Miller W, O’Brien E, Mizukawa B, Kitamura T, Palumbo JS, Mulloy JC. Protease-activated receptor-1 inhibits proliferation but enhances leukemia stem cell activity in acute myeloid leukemia. Oncogene 2017; 36:2589-2598. [PMID: 27819671 PMCID: PMC5418093 DOI: 10.1038/onc.2016.416] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2016] [Revised: 09/04/2016] [Accepted: 09/30/2016] [Indexed: 01/27/2023]
Abstract
Eradication of leukemia stem cells (LSCs) is the ultimate goal of treating acute myeloid leukemia (AML). We recently showed that the combined loss of Runx1/Cbfb inhibited the development of MLL-AF9-induced AML. However, c-Kit+/Gr-1- cells remained viable in Runx1/Cbfb-deleted cells, indicating that suppressing RUNX activity may not eradicate the most immature LSCs. In this study, we found upregulation of several hemostasis-related genes, including the thrombin-activatable receptor PAR-1 (protease-activated receptor-1), in Runx1/Cbfb-deleted MLL-AF9 cells. Similar to the effect of Runx1/Cbfb deletion, PAR-1 overexpression induced CDKN1A/p21 expression and attenuated proliferation in MLL-AF9 cells. To our surprise, PAR-1 deficiency also prevented leukemia development induced by a small number of MLL-AF9 leukemia stem cells (LSCs) in vivo. PAR-1 deficiency also reduced leukemogenicity of AML1-ETO-induced leukemia. Re-expression of PAR-1 in PAR-1-deficient cells combined with a limiting-dilution transplantation assay demonstrated the cell-dose-dependent role of PAR-1 in MLL-AF9 leukemia: PAR-1 inhibited rapid leukemic proliferation when there were a large number of LSCs, while a small number of LSCs required PAR-1 for their efficient growth. Mechanistically, PAR-1 increased the adherence properties of MLL-AF9 cells and promoted their engraftment to bone marrow. Taken together, these data revealed a multifaceted role for PAR-1 in leukemogenesis, and highlight this receptor as a potential target to eradicate primitive LSCs in AML.
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Affiliation(s)
- S Goyama
- Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center and the University of Cincinnati College of Medicine,
Cincinnati, OH, USA
- Division of Cellular Therapy, The Institute of Medical Science, The
University of Tokyo, Tokyo, Japan
| | - M Shrestha
- Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center and the University of Cincinnati College of Medicine,
Cincinnati, OH, USA
| | - J Schibler
- Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center and the University of Cincinnati College of Medicine,
Cincinnati, OH, USA
| | - L Rosenfeldt
- Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center and the University of Cincinnati College of Medicine,
Cincinnati, OH, USA
| | - W Miller
- Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center and the University of Cincinnati College of Medicine,
Cincinnati, OH, USA
| | - E O’Brien
- Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center and the University of Cincinnati College of Medicine,
Cincinnati, OH, USA
| | - B Mizukawa
- Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center and the University of Cincinnati College of Medicine,
Cincinnati, OH, USA
| | - T Kitamura
- Division of Cellular Therapy, The Institute of Medical Science, The
University of Tokyo, Tokyo, Japan
| | - JS Palumbo
- Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center and the University of Cincinnati College of Medicine,
Cincinnati, OH, USA
| | - JC Mulloy
- Cancer and Blood Diseases Institute, Cincinnati Children’s
Hospital Medical Center and the University of Cincinnati College of Medicine,
Cincinnati, OH, USA
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39
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Liu Y, Zhao Y, Wang Y, Zhu P, Wei Z, Wang S, Tao L, Liu Z, Wu H, Sheng X, Lu Y. Suppressive role of diallyl trisulfide in the activated platelet-mediated hematogenous metastasis of MDA-MB-231 human breast cancer cells. Int J Mol Med 2017; 39:1516-1524. [DOI: 10.3892/ijmm.2017.2953] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 02/16/2017] [Indexed: 11/05/2022] Open
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40
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Ebrahimi S, Rahmani F, Behnam-Rassouli R, Hoseinkhani F, Parizadeh MR, Keramati MR, Khazaie M, Avan A, Hassanian SM. Proinflammatory signaling functions of thrombin in cancer. J Cell Physiol 2017; 232:2323-2329. [PMID: 28004386 DOI: 10.1002/jcp.25753] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Accepted: 12/20/2016] [Indexed: 12/19/2022]
Abstract
Thrombin-induced activation of protease-activated receptors (PARs) represents a link between inflammation and cancer. Proinflammatory signaling functions of thrombin are associated with several inflammatory diseases including neurodegenerative, cardiovascular, and of special interest in this review cancer. Thrombin-induced inflammatory responses up-regulates expression of cytokines, adhesion molecules, angiogenic factors, and matrix-degrading proteases that facilitate tumor cells proliferation, angiogenesis, invasion, and metastasis. This review summarizes the current knowledge about the mechanisms of thrombin-mediated proinflammatory responses in cancer pathology for a better understanding and hence a better management of this disease.
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Affiliation(s)
- Safieh Ebrahimi
- Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Farzad Rahmani
- Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Fatemeh Hoseinkhani
- Department of Medical Biochemistry, School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Parizadeh
- Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Keramati
- Cancer Molecular Pathology Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Khazaie
- Department of Medical Physiology, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Molecular Medicine Group, Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Department of Medical Biochemistry, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Metabolic Syndrome Research Center, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Microanatomy Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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41
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Wojtukiewicz MZ, Hempel D, Sierko E, Tucker SC, Honn KV. Thrombin-unique coagulation system protein with multifaceted impacts on cancer and metastasis. Cancer Metastasis Rev 2017; 35:213-33. [PMID: 27189210 DOI: 10.1007/s10555-016-9626-0] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The association between blood coagulation and cancer development is well recognized. Thrombin, the pleiotropic enzyme best known for its contribution to fibrin formation and platelet aggregation during vascular hemostasis, may also trigger cellular events through protease-activated receptors, PAR-1 and PAR-4, leading to cancer progression. Our pioneering findings provided evidence that thrombin contributes to cancer metastasis by increasing adhesive potential of malignant cells. However, there is evidence that thrombin regulates every step of cancer dissemination: (1) cancer cell invasion, detachment from primary tumor, migration; (2) entering the blood vessel; (3) surviving in vasculature; (4) extravasation; (5) implantation in host organs. Recent studies have provided new molecular data about thrombin generation in cancer patients and the mechanisms by which thrombin contributes to transendothelial migration, platelet/tumor cell interactions, angiogenesis, and other processes. Though a great deal is known regarding the role of thrombin in cancer dissemination, there are new data for multiple thrombin-mediated events that justify devoting focus to this topic with a comprehensive approach.
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Affiliation(s)
- Marek Z Wojtukiewicz
- Department of Oncology, Medical University of Bialystok, 12 Ogrodowa St., 15-025, Bialystok, Poland. .,Department of Clinical Oncology, Comprehensive Cancer Center in Bialystok, Bialystok, Poland.
| | - Dominika Hempel
- Department of Oncology, Medical University of Bialystok, 12 Ogrodowa St., 15-025, Bialystok, Poland.,Department of Radiotherapy, Comprehensive Cancer Center in Bialystok, Bialystok, Poland
| | - Ewa Sierko
- Department of Oncology, Medical University of Bialystok, 12 Ogrodowa St., 15-025, Bialystok, Poland.,Department of Radiotherapy, Comprehensive Cancer Center in Bialystok, Bialystok, Poland
| | - Stephanie C Tucker
- Bioactive Lipids Research Program, Department of Pathology-School of Medicine, Wayne State University, Detroit, MI, USA
| | - Kenneth V Honn
- Bioactive Lipids Research Program, Department of Pathology-School of Medicine, Wayne State University, Detroit, MI, USA.,Department of Chemistry, Wayne State University, Detroit, MI, USA.,Department of Oncology, Karmanos Cancer Institute, Detroit, MI, USA
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42
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Dasgupta A, Lim AR, Ghajar CM. Circulating and disseminated tumor cells: harbingers or initiators of metastasis? Mol Oncol 2017; 11:40-61. [PMID: 28085223 PMCID: PMC5423226 DOI: 10.1002/1878-0261.12022] [Citation(s) in RCA: 157] [Impact Index Per Article: 19.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 11/02/2016] [Accepted: 11/04/2016] [Indexed: 12/12/2022] Open
Abstract
Tumor cells leave the primary tumor and enter the circulation. Once there, they are called circulating tumor cells (CTCs). A fraction of CTCs are capable of entering distant sites and persisting as disseminated tumor cells (DTCs). An even smaller fraction of DTCs are capable of progressing toward metastases. It is known that the DTC microenvironment plays an important role in sustaining their survival, regulating their growth, and conferring resistance to therapy. But we still have much to learn about the nature of these rare cell populations to predict which will progress and what exactly should cause concern for future relapse. Although recent technological advances in our ability to detect and molecularly and functionally characterize CTCs and DTCs promise to unravel this ambiguity, the timing of dissemination and the precise source of CTCs and DTCs profiled will impact the conclusions that can be made from these endeavors. In this review, we discuss the biology of CTCs and DTCs; the technologies to detect, isolate, and profile these cells; and the exceptions we must apply to our understanding of what role these cells play in the metastatic process. We conclude that a greater effort to understand the unique biology of these cells in context will positively impact our ability to use these cells to predict outcome, monitor treatment efficacy, and reveal therapeutically relevant targets to deplete these populations and ultimately prevent metastasis.
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Affiliation(s)
- Arko Dasgupta
- Public Health Sciences Division/Translational Research Program and Human Biology DivisionFred Hutchinson Cancer Research CenterSeattleWAUSA
| | - Andrea R. Lim
- Public Health Sciences Division/Translational Research Program and Human Biology DivisionFred Hutchinson Cancer Research CenterSeattleWAUSA
- Program in Molecular and Cellular BiologyUniversity of WashingtonSeattleWAUSA
| | - Cyrus M. Ghajar
- Public Health Sciences Division/Translational Research Program and Human Biology DivisionFred Hutchinson Cancer Research CenterSeattleWAUSA
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Abstract
Although many studies have demonstrated that components of the hemostatic system may be involved in signaling leading to cancer progression, the potential mechanisms by which they contribute to cancer dissemination are not yet precisely understood. Among known coagulant factors, tissue factor (TF) and thrombin play a pivotal role in cancer invasion. They may be generated in the tumor microenvironment independently of blood coagulation and can induce cell signaling through activation of protease-activated receptors (PARs). PARs are transmembrane G-protein-coupled receptors (GPCRs) that are activated by a unique proteolytic mechanism. They play important roles in vascular physiology, neural tube closure, hemostasis, and inflammation. All of these agents (TF, thrombin, PARs—mainly PAR-1 and PAR-2) are thought to promote cancer invasion and metastasis at least in part by facilitating tumor cell migration, angiogenesis, and interactions with host vascular cells, including platelets, fibroblasts, and endothelial cells lining blood vessels. Here, we discuss the role of PARs and their activators in cancer progression, focusing on TF- and thrombin-mediated actions. Therapeutic options tailored specifically to inhibit PAR-induced signaling in cancer patients are presented as well.
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44
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Warren KM, Islam MM, LeDuc PR, Steward R. 2D and 3D Mechanobiology in Human and Nonhuman Systems. ACS APPLIED MATERIALS & INTERFACES 2016; 8:21869-21882. [PMID: 27214883 DOI: 10.1021/acsami.5b12064] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/05/2023]
Abstract
Mechanobiology involves the investigation of mechanical forces and their effect on the development, physiology, and pathology of biological systems. The human body has garnered much attention from many groups in the field, as mechanical forces have been shown to influence almost all aspects of human life ranging from breathing to cancer metastasis. Beyond being influential in human systems, mechanical forces have also been shown to impact nonhuman systems such as algae and zebrafish. Studies of nonhuman and human systems at the cellular level have primarily been done in two-dimensional (2D) environments, but most of these systems reside in three-dimensional (3D) environments. Furthermore, outcomes obtained from 3D studies are often quite different than those from 2D studies. We present here an overview of a select group of human and nonhuman systems in 2D and 3D environments. We also highlight mechanobiological approaches and their respective implications for human and nonhuman physiology.
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Affiliation(s)
- Kristin M Warren
- Departments of Mechanical Engineering, Biomedical Engineering, Computational Biology, and Biological Sciences, Carnegie Mellon University , Pittsburgh, Pennsylvania 15213, United States
| | - Md Mydul Islam
- Department of Mechanical and Aerospace Engineering and Burnett School of Biomedical Sciences, University of Central Florida , Orlando, Florida 32827, United States
| | - Philip R LeDuc
- Departments of Mechanical Engineering, Biomedical Engineering, Computational Biology, and Biological Sciences, Carnegie Mellon University , Pittsburgh, Pennsylvania 15213, United States
| | - Robert Steward
- Department of Mechanical and Aerospace Engineering and Burnett School of Biomedical Sciences, University of Central Florida , Orlando, Florida 32827, United States
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45
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Role of platelets in cancer and cancer-associated thrombosis: Experimental and clinical evidences. Thromb Res 2016; 139:65-76. [PMID: 26916298 DOI: 10.1016/j.thromres.2016.01.006] [Citation(s) in RCA: 149] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 01/01/2016] [Accepted: 01/05/2016] [Indexed: 12/15/2022]
Abstract
The primary hemostatic function of platelets has been recognized for more than a century, but increasing experimental and clinical evidences suggest that platelets are also important mediators of cancer. Cancer indeed influences platelet physiology, and activated platelets participate in each step of cancer development by promoting tumor growth, angiogenesis, metastasis, and cancer-associated thrombosis. Based on both the results of numerous experimental models addressing the involvement of platelets in cancer progression and the results of epidemiologic studies on the use of anti-platelet drugs to prevent cancer, platelets have been proposed as a potential target to reduce the short-term risk of cancer, cancer dissemination and cancer mortality. However, the cancer-associated thrombosis and the risk of bleeding due to anti-platelet drugs are not enough evaluated in experimental models. Therefore, the interesting contribution of platelets to cancer and cancer-associated thrombosis requires the standardization of preclinical and clinical models.
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46
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Lou XL, Sun J, Gong SQ, Yu XF, Gong R, Deng H. Interaction between circulating cancer cells and platelets: clinical implication. Chin J Cancer Res 2015; 27:450-60. [PMID: 26543331 DOI: 10.3978/j.issn.1000-9604.2015.04.10] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Metastasis is the main cause of cancer-associated mortality. During this complicated process, some cancer cells, also called circulating tumor cells (CTCs), detach from primary sites, enter bloodstream and extravasate at metastatic site. Thrombocytosis is frequently observed in patients with metastatic cancers suggesting the important role of platelets in metastasis. Therefore this review focuses on how platelets facilitate the generation of CTCs, protect them from various host attacks, such as immune assaults, apoptosis and shear stress, and regulate CTCs intravasation/extravasation. Platelet-derived cytokines and receptors are involved in this cascade. Identification the mechanisms underlie platelet-CTCs interactions could lead to the development of new platelet-targeted therapeutic strategy to reduce metastasis.
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Affiliation(s)
- Xiao-Liang Lou
- 1 Molecular Medicine and Genetics Center, 2 Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang 330000, China ; 3 Renmin Institute of Forensic Medicine, Nanchang 330000, China
| | - Jian Sun
- 1 Molecular Medicine and Genetics Center, 2 Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang 330000, China ; 3 Renmin Institute of Forensic Medicine, Nanchang 330000, China
| | - Shu-Qi Gong
- 1 Molecular Medicine and Genetics Center, 2 Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang 330000, China ; 3 Renmin Institute of Forensic Medicine, Nanchang 330000, China
| | - Xue-Feng Yu
- 1 Molecular Medicine and Genetics Center, 2 Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang 330000, China ; 3 Renmin Institute of Forensic Medicine, Nanchang 330000, China
| | - Rui Gong
- 1 Molecular Medicine and Genetics Center, 2 Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang 330000, China ; 3 Renmin Institute of Forensic Medicine, Nanchang 330000, China
| | - Huan Deng
- 1 Molecular Medicine and Genetics Center, 2 Department of Pathology, The Fourth Affiliated Hospital of Nanchang University, Nanchang 330000, China ; 3 Renmin Institute of Forensic Medicine, Nanchang 330000, China
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47
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Liu P, Wang Y, Tong L, Xu Y, Zhang W, Guo Z, Ni H. Elevated preoperative plasma D-dimer level is a useful predictor of chemoresistance and poor disease outcome for serous ovarian cancer patients. Cancer Chemother Pharmacol 2015; 76:1163-71. [DOI: 10.1007/s00280-015-2900-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2015] [Accepted: 10/27/2015] [Indexed: 12/21/2022]
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48
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Qian W, Tao L, Wang Y, Zhang F, Li M, Huang S, Wang A, Chen W, Yue Z, Chen L, Liu Y, Huang C, Zhang L, Li Y, Lu Y. Downregulation of Integrins in Cancer Cells and Anti-Platelet Properties Are Involved in Holothurian Glycosaminoglycan-Mediated Disruption of the Interaction of Cancer Cells and Platelets in Hematogenous Metastasis. J Vasc Res 2015; 52:197-209. [PMID: 26488158 DOI: 10.1159/000439220] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 07/30/2015] [Indexed: 11/19/2022] Open
Abstract
Activated platelets have been recognized as an accessory character in the cascade of tumor hematogenous metastasis, and intervention of tumor cell attachment to the activated platelets or microemboli formation might be a leading strategy to prevent tumor cells surviving in the blood vessels and sequential metastasis. Recently, we have demonstrated that holothurian glycosaminoglycan (hGAG), a sulfated polysaccharide with potent anticoagulant activity extracted from the sea cucumber Holothuria leucospilota Brandt, was highly efficacious against tumor metastasis. In this study, we identified the potential effects of hGAG on the disruption of interactions of cancer cells and platelets and the underlying mechanisms, which were supported by the following evidence: hGAG (1) inhibited thrombin-induced platelet activation and aggregation, (2) reduced adhesion between platelet and breast cancer cells, and abrogated platelets/cancer cells adhering to fibrinogen, (3) attenuated platelet-cancer cell complex formation (the number and size of aggregates) and (4) suppressed both mRNA and protein levels of β1 and β3 integrins, matrix metalloproteinase (MMP)-2 and MMP-9, while increasing the expression of the MMP inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1 in MDA-MB-231 cells. These results suggested that both the antiplatelet properties and mitigation of the levels of cellular adhesion molecules contributed to the anticancer effects of hGAG, and might thus be exploited for clinical adjuvant therapy to attenuate tumor hematogenous metastasis.
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Affiliation(s)
- Wenhui Qian
- Department of Pharmaceutics, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
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Spek CA, Versteeg HH, Borensztajn KS. Anticoagulant therapy of cancer patients: Will patient selection increase overall survival? Thromb Haemost 2015; 114:530-6. [PMID: 25994568 DOI: 10.1160/th15-02-0124] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2015] [Accepted: 03/11/2015] [Indexed: 12/20/2022]
Abstract
Already since the early 1800s, it has been recognised that malignancies may provoke thromboembolic complications, and indeed cancer patients are at increased risk of developing venous thrombosis. Interestingly, case control studies of deep-vein thrombosis suggested that low-molecular-weight heparin (LMWH) improved survival of cancer patients. This led to the hypothesis that cancer cells might 'take advantage' of a hypercoagulable state to more efficiently metastasise. Initial randomised placebo control trials showed that LMWH improve overall survival of cancer patients, especially in those patients with a relatively good prognosis. The failure of recent phase III trials, however, tempers enthusiasm for anticoagulant treatment in cancer patients despite an overwhelming body of literature showing beneficial effects of anticoagulants in preclinical models. Instead of discarding LMWH as potential (co)treatment modality in cancer patients, these disappointing recent trials should guide future preclinical research on anticoagulants in cancer biology. Most and for all, the underlying mechanisms by which coagulation drives tumour progression need to be elucidated. This could ultimately allow selection of cancer patients most likely to benefit from anticoagulant treatment and/or from targeted therapy downstream of coagulation factor signalling.
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Affiliation(s)
- C Arnold Spek
- C. Arnold Spek, H2-157, Academic Medical Center, Meibergdreef 9, 1105AZ, Amsterdam, The Netherlands, Tel.: +31 20 5668750, E-mail:
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50
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Wang J, Xiao J, Wen D, Wu X, Mao Z, Zhang J, Ma D. Endothelial cell-anchored tissue factor pathway inhibitor regulates tumor metastasis to the lung in mice. Mol Carcinog 2015; 55:882-96. [DOI: 10.1002/mc.22329] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2014] [Revised: 02/27/2015] [Accepted: 03/26/2015] [Indexed: 11/10/2022]
Affiliation(s)
- Jiping Wang
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology; Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University; Shanghai China
| | - Jiajun Xiao
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology; Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University; Shanghai China
| | - Danping Wen
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology; Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University; Shanghai China
| | - Xie Wu
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology; Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University; Shanghai China
| | - Zuohua Mao
- Department of Parasitology and Microbiology; Shanghai Medical College, Fudan University; Shanghai China
| | - Jin Zhang
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology; Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University; Shanghai China
| | - Duan Ma
- Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology; Institute of Biomedical Sciences, School of Basic Medical Sciences, Collaborative Innovation Center of Genetics and Development, Fudan University; Shanghai China
- Children's Hospital; Fudan University; Shanghai China
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