Platelets and Cancer

A special issue of Cancers (ISSN 2072-6694).

Deadline for manuscript submissions: closed (31 January 2020) | Viewed by 16730

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Guest Editor
Department of Neuroscience, Imaging and Clinical Sciences and Center for Advanced Studies and Technology (CAST), School of Medicine, “G. d’Annunzio” University, 66100 Chieti, Italy
Interests: platelets; colorectal cancer; metastasis; antiplatelet drugs; aspirin; P2Y12 antagonists; eicosanoids
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Department of Neuroscience, Imaging and Clinical Sciences, Laboratory of Systems Pharmacology and Translational Therapeutics, Center for Research on Aging and Translational Medicine (CeSI-MeT), 'G. D'Annunzio' University, Via dei Vestini, 31, 66100 Chieti, Italy
Interests: animal models of tumorigenesis and metastasis; intestinal inflammation; transgenic models in pharmacology

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Guest Editor
Department of Neuroscience, Imaging and Clinical Sciences, Laboratory of Systems Pharmacology and Translational Therapeutics, Center for Research on Aging and Translational Medicine (CeSI-MeT), 'G. D'Annunzio' University, Via dei Vestini, 31, 66100 Chieti, Italy
Interests: platelet-microparticles; liquid biopsy; tumor microenvironment; proteomics

Special Issue Information

Dear Colleagues,

Platelets, cytoplasmic fragments of megakaryocytes, are characterized by the absence of a nucleus and the presence of various granules (α-granules, dense granules, and lysosomes). These cell fragments are known for the role played in hemostasis and thrombosis. Platelet activation and aggregation, and the secretion of lipids, including thromboxane(TX)A2, and their granule content [rich in pro-aggregatory molecules like adenosine diphosphate (ADP)] are key events for clotting formation and stop bleeding. Moreover, to their central role in hemostasis and thrombosis platelets are implicated in: (i) inflammation; (ii) immune function; and (iii) pathogenic mechanisms, e.g., atherothrombosis, cancer and metastasis.

The role of platelets in cancer, particularly in tumor metastasis, was first suggested a long time ago, but convincing evidence was recently provided by the analyses of the vast amount of clinical information from placebo-controlled randomized clinical trials (RCTs) with aspirin for cardiovascular prevention.  The evidence was considered appropriate to recommend aspirin use for the primary prevention of cardiovascular disease and cancer by the U.S. Preventive Services Task Force.

The clinical data showing the efficacy of the antiplatelet agent aspirin as an anticancer agent, have catalyzed the work of researchers with different expertise who have uncovered the multifaceted roles played by platelets in tumor development and metastatic dissemination. Platelets act through the crosstalk with stromal cells and cancer cells mediated by the release of several soluble mediators and vesicles, including microparticles.

The biomedical research should exploit the new knowledge on the role of platelets in cancer and focus on the development of safer antiplatelet drugs that interfere with the molecular mechanisms involved in the crosstalk of platelets with the cells of the microenvironment and/or tumor cells. These new pharmacological agents may potentially stop cancer at the earliest stages of development, thus preventing tumor metastasis. Finally, the recent knowledge of the role of platelets in tumor immune escape opens the way to novel strategies to fight cancer based on the use of antiplatelet agents.

The evaluation of proteomics and transcriptomics signature of platelets and platelet-derived microparticles could represent a new strategy for the development of biomarkers for early cancer detection and/or therapeutic drug monitoring in cancer chemotherapy.

Due to the ability of platelets to interact with cancer cells and to deliver their cargo, platelets have been proposed as a “biomimetic drug delivery system” for anti-tumor drugs to prevent the occurrence of off-target adverse events associated with the use of traditional chemotherapy.

Prof. Dr. Paola Patrignani
Dr. Annalisa Bruno
Dr. Melania Dovizio
Guest Editors

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Published Papers (4 papers)

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Research

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18 pages, 1578 KiB  
Article
Personalized Indicator Thrombocytosis Shows Connection to Staging and Indicates Shorter Survival in Colorectal Cancer Patients with or without Type 2 Diabetes
by Zoltan Herold, Magdolna Herold, Julia Lohinszky, Magdolna Dank and Aniko Somogyi
Cancers 2020, 12(3), 556; https://doi.org/10.3390/cancers12030556 - 28 Feb 2020
Cited by 6 | Viewed by 2758
Abstract
Background: Pre- and postoperative thrombocytosis was reported to have significant effect on patient survival. However, the definition of thrombocytosis throughout the literature is not unified. Methods: A retrospective longitudinal observational study has been conducted with the inclusion of 150 colorectal cancer (CRC) patients [...] Read more.
Background: Pre- and postoperative thrombocytosis was reported to have significant effect on patient survival. However, the definition of thrombocytosis throughout the literature is not unified. Methods: A retrospective longitudinal observational study has been conducted with the inclusion of 150 colorectal cancer (CRC) patients and 100 control subjects. A new measure of platelet changes at an individual level, named personalized indicator thrombocytosis (PIT) was defined, including 4 anemia adjusted variants. Results: In concordance with the literature, PIT values of control subjects showed a slow decrease in platelet counts, while PIT values of CRC patients were significantly higher (p < 0.0001). More advanced staging (p < 0.0001) and both local (p ≤ 0.0094) and distant (p ≤ 0.0440) metastasis are associated with higher PIT values. Higher PIT values suggested shorter survival times (p < 0.0001). Compared to conventional, a PIT-based definition resulted in approximately 3-times more patients with thrombocytosis. 28% and 77% of the deceased patients had conventional- and PIT-based thrombocytosis, respectively. Conclusions: Compared to conventional thrombocytosis, as an individual metric, PIT values may indicate the condition of patients more precisely. Possible future applications of PIT may include its usage in therapy decision and early cancer detection; therefore, further investigations are recommended. Full article
(This article belongs to the Special Issue Platelets and Cancer)
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19 pages, 3901 KiB  
Article
Antiplatelet Drug Ticagrelor Enhances Chemotherapeutic Efficacy by Targeting the Novel P2Y12-AKT Pathway in Pancreatic Cancer Cells
by Omar Elaskalani, Alice Domenichini, Norbaini Binti Abdol Razak, Danielle E. Dye, Marco Falasca and Pat Metharom
Cancers 2020, 12(1), 250; https://doi.org/10.3390/cancers12010250 - 20 Jan 2020
Cited by 34 | Viewed by 6195
Abstract
Background: Extensive research has reported that extracellular ADP in the tumour microenvironment can stimulate platelets through interaction with the platelet receptor P2Y12. In turn, activated platelets release biological factors supporting cancer progression. Experimental data suggest that the tumour microenvironment components, of which platelets [...] Read more.
Background: Extensive research has reported that extracellular ADP in the tumour microenvironment can stimulate platelets through interaction with the platelet receptor P2Y12. In turn, activated platelets release biological factors supporting cancer progression. Experimental data suggest that the tumour microenvironment components, of which platelets are integral, can promote chemotherapy resistance in pancreatic ductal adenocarcinoma (PDAC). Thus, overcoming chemoresistance requires combining multiple inhibitors that simultaneously target intrinsic pathways in cancer cells and extrinsic factors related to the tumour microenvironment. We aimed to determine whether ticagrelor, an inhibitor of the ADP–P2Y12 axis and a well-known antiplatelet drug, could be a therapeutic option for PDAC. Methods: We investigated a functional P2Y12 receptor and its downstream signalling in a panel of PDAC cell lines and non-cancer pancreatic cells termed hTERT-HPNE. We tested the synergistic effect of ticagrelor, a P2Y12 inhibitor, in combination with chemotherapeutic drugs (gemcitabine, paclitaxel and cisplatin), in vitro and in vivo. Results: Knockdown studies revealed that P2Y12 contributed to epidermal growth factor receptor (EGFR) activation and the expression of SLUG and ZEB1, which are transcriptional factors implicated in metastasis and chemoresistance. Studies using genetic and pharmacological inhibitors showed that the P2Y12–EGFR crosstalk enhanced cancer cell proliferation. Inhibition of P2Y12 signalling significantly reduced EGF-dependent AKT activation and promoted the anticancer activity of anti-EGFR treatment. Importantly, ticagrelor significantly decreased the proliferative capacity of cancer but not normal pancreatic cells. In vitro, synergism was observed when ticagrelor was combined with several chemodrugs. In vivo, a combination of ticagrelor with gemcitabine significantly reduced tumour growth, whereas gemcitabine or ticagrelor alone had a minimal effect. Conclusions: These findings uncover a novel effect and mechanism of action of the antiplatelet drug ticagrelor in PDAC cells and suggest a multi-functional role for ADP-P2Y12 signalling in the tumour microenvironment. Full article
(This article belongs to the Special Issue Platelets and Cancer)
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Review

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19 pages, 295 KiB  
Review
Antiplatelet Agents for Cancer Prevention: Current Evidences and Continuing Controversies
by Corinne Frere, Manon Lejeune, Pierre Kubicek, Dorothée Faille, Zora Marjanovic and the Groupe Francophone Thrombose et Cancer
Cancers 2019, 11(11), 1639; https://doi.org/10.3390/cancers11111639 - 24 Oct 2019
Cited by 9 | Viewed by 3091
Abstract
Over the past two decades, aspirin has emerged as a promising chemoprotective agent to prevent colorectal cancer (CRC). In 2016, the mounting evidence supporting its chemoprotective effect, from both basic science and clinical research, led the US Preventive Services Task Force to recommend [...] Read more.
Over the past two decades, aspirin has emerged as a promising chemoprotective agent to prevent colorectal cancer (CRC). In 2016, the mounting evidence supporting its chemoprotective effect, from both basic science and clinical research, led the US Preventive Services Task Force to recommend regular use of low-dose aspirin in some subgroups of patients for whom the benefits are deemed to outweigh the risks. In contrast, data on the chemoprotective effect of aspirin against other cancers are less clear and remain controversial. Most data come from secondary analyses of cardiovascular prevention trials, with only a limited number reporting cancer outcomes as a prespecified endpoint, and overall unclear findings. Moreover, the potential chemoprotective effect of aspirin against other cancers has been recently questioned with the publication of 3 long-awaited trials of aspirin in the primary prevention of cardiovascular diseases reporting no benefit of aspirin on overall cancer incidence and cancer-related mortality. Data on the chemoprotective effects of other antiplatelet agents remain scarce and inconclusive, and further research to examine their benefit are warranted. In this narrative review, we summarize current clinical evidence and continuing controversies on the potential chemoprotective properties of antiplatelet agents against cancer. Full article
(This article belongs to the Special Issue Platelets and Cancer)
22 pages, 1942 KiB  
Review
Platelets and Hepatocellular Cancer: Bridging the Bench to the Clinics
by Quirino Lai, Alessandro Vitale, Tommaso M. Manzia, Francesco G. Foschi, Giovanni B. Levi Sandri, Martina Gambato, Fabio Melandro, Francesco P. Russo, Luca Miele, Luca Viganò, Patrizia Burra, Edoardo G. Giannini and on behalf of the Associazione Italiana per lo Studio del Fegato (AISF) HCC Special Interest Group
Cancers 2019, 11(10), 1568; https://doi.org/10.3390/cancers11101568 - 15 Oct 2019
Cited by 34 | Viewed by 3885
Abstract
Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules [...] Read more.
Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells’ extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet–tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC. Full article
(This article belongs to the Special Issue Platelets and Cancer)
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