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  • 1
    In: Blood Advances, American Society of Hematology, Vol. 3, No. 2 ( 2019-01-22), p. 198-211
    Abstract: It is now recognized that compounds released from tumor cells can activate platelets, causing the release of platelet-derived factors into the tumor microenvironment. Several of these factors have been shown to directly promote neovascularization and metastasis, yet how the feedback between platelet releasate and the tumor cell affects metastatic phenotype remains largely unstudied. Here, we identify that breast tumor cells secrete high levels of interleukin 8 (IL-8, CXCL8) in response to platelet releasate, which promotes their invasive capacity. Furthermore, we found that platelets activate the Akt pathway in breast tumor cells, and inhibition of this pathway eliminated IL-8 production. We therefore hypothesized inhibiting platelets with aspirin could reverse the prometastatic effects of platelets on tumor cell signaling. Platelets treated with aspirin did not activate the Akt pathway, resulting in reduced IL-8 secretion and impaired tumor cell invasion. Of note, patients with breast cancer receiving aspirin had lower circulating IL-8, and their platelets did not increase tumor cell invasion compared with patients not receiving aspirin. Our data suggest platelets support breast tumor metastasis by inducing tumor cells to secrete IL-8. Our data further support that aspirin acts as an anticancer agent by disrupting the communication between platelets and breast tumor cells.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 2876449-3
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  • 2
    In: Blood Advances, American Society of Hematology, Vol. 6, No. 20 ( 2022-10-25), p. 5668-5675
    Abstract: Programmed death ligand 1 (PD-L1) is an immune checkpoint protein that suppresses cytotoxic T lymphocytes and is often overexpressed in cancers. Due to favorable clinical trial results, immune checkpoint inhibition (ICI) is part of Food and Drug Administration approved immuno-oncology therapies; however, not all patients benefit from ICI therapy. High blood platelet-to-lymphocyte ratio has been associated with failure of ICI treatment, but whether platelets have a role in hindering ICI response is unclear. Here, we report that coculturing platelets with cancer cell lines increased protein and gene expression of tumor cell PD-L1, which was reduced by antiplatelet agents, such as aspirin and ticagrelor. Platelet cytokine arrays revealed that the well-established cytokines, including interferon-γ, were not the main regulators of platelet-mediated PD-L1 upregulation. Instead, the high molecular weight epidermal growth factor (EGF) is abundant in platelets, which caused an upregulation of tumor cell PD-L1. Both an EGF-neutralizing antibody and cetuximab (EGF receptor [EGFR] monoclonal antibody) inhibited platelet-induced increases in tumor cell PD-L1, suggesting that platelets induce tumor cell PD-L1 in an EGFR-dependent manner. Our data reveal a novel mechanism for platelets in tumor immune escape and warrant further investigation to determine if targeting platelets improves ICI therapeutic responses.
    Type of Medium: Online Resource
    ISSN: 2473-9529 , 2473-9537
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2022
    detail.hit.zdb_id: 2876449-3
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  • 3
    Online Resource
    Online Resource
    American Society of Hematology ; 2021
    In:  Blood Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1006-1006
    In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1006-1006
    Abstract: Introduction: Programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) are important immune checkpoint proteins in cancer immunotherapy and targeted therapies against PD-L1 have significantly prolonged many patients' lives. Recently, high baseline platelet to lymphocyte ratio was reported to be associated with decreased patient response rate to immune checkpoint inhibition (ICI) therapies, including anti-PD-L1 therapy, suggesting the potential role of platelets in tumor immunity. Platelets express PD-L1 on their surface, and platelets binding to PD-L1 negative tumor cells can "decorate" tumor cells with PD-L1 and protect against T cell-mediated cytotoxicity. However, whether platelet can affect PD-L1 expression on tumor cells is still unknown. Methods: In this study, we designed platelet-tumor cell co-culture systems to investigate whether direct or indirect exposure to platelets affects tumor cell PD-L1 surface expression. Considering platelets can be artificially activated by commonly used cell culture medium, the co-culture was performed in platelet resuspension buffer (HEPES, NaCl, KCl, MgCl2, NaHCO3, Glucose, pH7.4) supplied with fetal bovine serum and L-glutamine. After 24 hours of co-culture, platelets were washed out and fresh culturing medium was added to tumor cells and cultured for another 24 hours. At the end of the experiments, tumor cells were harvested and the PD-L1 expression analyzed by flow cytometry and RT-qPCR. Results and discussion: Here we report that direct co-culture of platelets with either breast cancer cell line MDA-MB-468 or lung cancer cell line A549 increased tumor cell PD-L1 surface expression by up-regulating PD-L1 transcription. This platelet-induced tumor cell PD-L1 up-regulation can be partly reduced by pre-treating platelets with antiplatelet agents such as aspirin and ticagrelor, suggesting platelet activation contributes to platelet induced tumor cell PD-L1 up-regulation. The up-regulation of tumor cell PD-L1 by platelets was not due to abundant platelet cytokines such as C-C Motif Chemokine Ligand 5 (CCL5) and C-X-C motif chemokine 5 (CXCL5). However, both an epidermal growth factor (EGF) neutralizing antibody and cetuximab (EGFR neutralizing monoclonal antibody) decreased the platelet-induced increase in tumor cell PD-L1, suggesting that platelets initiate tumor cell PD-L1 transcription through the EGF signaling pathway. Our data indicate a novel function of platelets in tumor immunity and warrant further investigation to determine if targeting platelets offers a novel adjuvant approach to improve ICI therapy. Disclosures Italiano: Sierra Oncology: Consultancy; PlateletBio: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Carrick Therapeutics: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 4
    Online Resource
    Online Resource
    American Society of Hematology ; 2019
    In:  Blood Vol. 134, No. Supplement_1 ( 2019-11-13), p. 12-12
    In: Blood, American Society of Hematology, Vol. 134, No. Supplement_1 ( 2019-11-13), p. 12-12
    Abstract: The first association between platelets and cancer dates back to the 19th century, where unexpected blood clots were perceived as a potential forewarning of occult malignancy. More recently, platelets have been shown to promote the progression of solid tumors through diverse mechanisms, including stimulation of angiogenesis, protection from immune surveillance, and facilitating cancer cell intravasation and arrest in the microvasculature. While several have studied the interplay between platelets and cancer, how cancer affects megakaryocytes (MKs) remains uncharted. The number of platelets and their content is predominantly determined by MKs, which are responsible for platelet production and protein packaging. Despite this, very little is known about how the bone marrow environment regulates platelet production by MKs, or how such processes are altered in disease states. We hypothesize that in cancer, tumor-derived factors reprogram MKs to upregulate pro-metastatic and pro-neovascularization proteins for delivery to subsequent platelets, ultimately producing platelets with a more "pro-malignant" phenotype. We first interrogated this question by exposing fetal liver-derived murine MKs (FLMKs) to the releasate of a triple-negative human breast cancer line (MDA-MB-231) for 24 hours. MKs were then lysed and processed for liquid chromatography-mass spectrometry (LC-MS) and bulk proteomic analysis. Several pro-metastatic proteins were upregulated in these MKs, most notably metalloproteinases (MMP2, MMP3), which play important roles in cell invasion and are secreted by platelet alpha granules. We further interrogated MMP expression by exposing MKs expanded from human placental cord-derived hematopoetic stem cells to MDA-MB-231 releasate, followed by specific probing for MMP and tissue inhibitor of metalloproteinase (TIMP) expression. Our findings show marked increases in MMP1 (3-fold), MMP2 (3.75-fold), MMP3 (3-fold), MMP9 (two-fold), MMP13 (2.2-fold) and TIMP1 (7.8-fold) compared to MKs exposed to control media. These initial experiments demonstrate that factors secreted by tumor cells can alter levels of cancer-promoting proteins in MKs. Whether such changes arise from direct endocytosis, or through altered protein synthesis by the MK remains an important question. Our next aim was to assess if cancer affects MK protein content in vivo. To test this hypothesis, we isolated bone marrow-derived MKs from mice bearing mammary tumors following orthotopic injection of the triple-negative murine breast cancer cell line, Met-1. MKs were sorted from other bone marrow cells based on size (10-50 µm) and integrin ⍺IIbβ3 (glycoprotein IIb/IIIa, CD41/61) surface expression. Samples were then subject to LC-MS and bulk proteomic analysis. Blinded hierarchal clustering clearly segregated samples of tumor-bearing and non-tumor-bearing mice, with statistically significant differences observed for 182/1046 identified proteins. Ingenuity Pathway Analysis releveled that 41 of these significant proteins whose expression was increased are directly associated with cancer, most notably S100A8, Cathepsin G and Lipocalin-2. These data highlight clear alterations of MK protein expression in cancer. Subsequent experiments will assess if these factors are also increased in the platelet progeny and can be released following tumor-mediated platelet activation to augment disease progression. Finally, we wanted to determine what tumor-derived factors are responsible for altered MK protein expression in breast cancer. We found that plasma levels of several proinflammatory cytokines were increased in our tumor-bearing model, including G-CSF (14-fold) and IL-6 (1.6-fold), which have previously been reported to increase myeloid expansion and thrombopoietin production, respectively. Further studies will be taken to determine if these and/or other factors can alter MK protein content in isolation and if changes in the MK can be reversed through inhibition of these cytokines. In summary, our findings demonstrate that soluble factors released from a primary tumor are able to modulate the bone marrow niche and reprogram MKs, resulting in the increased expression of several proteins known to promote cancer. Future work will explore if agents that affect platelet production and/or function can reverse the MK reprogramming in cancer. Disclosures Italiano: Ionis Research Funding: Research Funding; Platelet Biogenesis: Employment, Equity Ownership.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
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    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2019
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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  • 5
    Online Resource
    Online Resource
    Cold Spring Harbor Laboratory ; 2023
    In:  Cold Spring Harbor Perspectives in Medicine Vol. 13, No. 1 ( 2023-01), p. a041174-
    In: Cold Spring Harbor Perspectives in Medicine, Cold Spring Harbor Laboratory, Vol. 13, No. 1 ( 2023-01), p. a041174-
    Type of Medium: Online Resource
    ISSN: 2157-1422
    Language: English
    Publisher: Cold Spring Harbor Laboratory
    Publication Date: 2023
    detail.hit.zdb_id: 2628603-8
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  • 6
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-11-12)
    Abstract: Citalopram, a selective serotonin reuptake inhibitor (SSRI), inhibits platelet function in vitro . We have previously shown that this action is independent of citalopram’s ability to block serotonin uptake by the serotonin transporter and must therefore be mediated via distinct pharmacological mechanisms. We now report evidence for two novel and putative mechanisms of citalopram-induced platelet inhibition. Firstly, in platelets, citalopram blocked U46619-induced Rap1 activation and subsequent platelet aggregation, but failed to inhibit U46619-induced increases in cytosolic Ca 2+ . Similarly, in neutrophils, citalopram inhibited Rap1 activation and downstream functions but failed to block PAF-induced Ca 2+ mobilisation. In a cell-free system, citalopram also reduced CalDAG-GEFI-mediated nucleotide exchange on Rap1B. Secondly, the binding of anti-GPVI antibodies to resting platelets was inhibited by citalopram. Furthermore, citalopram-induced inhibition of GPVI-mediated platelet aggregation was instantaneous, reversible and displayed competitive characteristics, suggesting that these effects were not caused by a reduction in GPVI surface expression, but by simple competitive binding. In conclusion, we propose two novel, putative and distinct inhibitory mechanisms of action for citalopram: (1) inhibition of CalDAG-GEFI/Rap1 signalling, and (2) competitive antagonism of GPVI in platelets. These findings may aid in the development of novel inhibitors of CalDAG-GEFI/Rap1-dependent nucleotide exchange and novel GPVI antagonists.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2615211-3
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  • 7
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-02-22)
    Abstract: Citalopram prevents serotonin (5-HT) uptake into platelets by blocking the serotonin reuptake transporter (SERT). Although some clinical data suggest that selective serotonin reuptake inhibitors (SSRIs) may affect haemostasis and thrombosis, these poorly-characterised effects are not well understood mechanistically and useful in vitro data is limited. We sought to determine whether the inhibitory effects of citalopram on platelets are mediated via its pharmacological inhibition of 5-HT transport. We quantified the inhibitory potency of ( RS )-, ( R )- and ( S )-citalopram on platelet function. If SERT blockade is the primary mechanism for citalopram-mediated platelet inhibition, these potencies should show quantitative congruence with inhibition of 5-HT uptake. Our data show that citalopram inhibits platelet aggregation, adhesion and thromboxane production with no difference in potency between ( R )- and ( S )-isomers. By contrast, citalopram had a eudysmic ratio of approximately 17 ( S   〉   R ) for SERT blockade. Furthermore, nanomolar concentrations of citalopram inhibited 5-HT uptake into platelets but had no effect on other platelet functions, which were inhibited by micromolar concentrations. Our data indicate that citalopram-induced inhibition of platelets in vitro is not mediated by blockade of 5-HT transport. This raises a new question for future investigation: by what mechanism(s) does citalopram inhibit platelets?
    Type of Medium: Online Resource
    ISSN: 2045-2322
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2018
    detail.hit.zdb_id: 2615211-3
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  • 8
    Online Resource
    Online Resource
    Ovid Technologies (Wolters Kluwer Health) ; 2018
    In:  Current Opinion in Hematology Vol. 25, No. 5 ( 2018-09), p. 410-415
    In: Current Opinion in Hematology, Ovid Technologies (Wolters Kluwer Health), Vol. 25, No. 5 ( 2018-09), p. 410-415
    Type of Medium: Online Resource
    ISSN: 1065-6251
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2018
    detail.hit.zdb_id: 2026995-X
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  • 9
    In: Science Advances, American Association for the Advancement of Science (AAAS), Vol. 8, No. 41 ( 2022-10-14)
    Abstract: Breast cancer creates pro-inflammatory megakaryocytes, producing “super-charged” platelets that exacerbate tumor cell metastasis.
    Type of Medium: Online Resource
    ISSN: 2375-2548
    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2022
    detail.hit.zdb_id: 2810933-8
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  • 10
    Online Resource
    Online Resource
    American Society of Hematology ; 2021
    In:  Blood Vol. 137, No. 23 ( 2021-06-10), p. 3174-3180
    In: Blood, American Society of Hematology, Vol. 137, No. 23 ( 2021-06-10), p. 3174-3180
    Abstract: Platelets have long been known to play important roles beyond hemostasis and thrombosis. Now recognized as a bona fide mediator of malignant disease, platelets influence various aspects of cancer progression, most notably tumor cell metastasis. Interestingly, platelets isolated from cancer patients often display distinct RNA and protein profiles, with no clear alterations in hemostatic activity. This phenotypically distinct population, termed tumor-educated platelets, now receive significant attention for their potential use as a readily available liquid biopsy for early cancer detection. Although the mechanisms underpinning platelet education are still being defined, direct uptake and storage of tumor-derived factors, signal-dependent changes in platelet RNA processing, and differential platelet production by tumor-educated megakaryocytes are the most prominent scenarios. This article aims to cover the various modalities of platelet education by tumors, in addition to assessing their diagnostic potential.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2021
    detail.hit.zdb_id: 1468538-3
    detail.hit.zdb_id: 80069-7
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