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Tamoxifen Suppresses Platelet Activation-Supported Angiogenesis and Metastasis

2017; Lippincott Williams & Wilkins; Volume: 37; Issue: 4 Linguagem: Inglês

10.1161/atvbaha.117.309105

1524-4636

Pavel Davizon‐Castillo, Jorge Di Paola,

Angiogenesis and VEGF in Cancer

HomeArteriosclerosis, Thrombosis, and Vascular BiologyVol. 37, No. 4Tamoxifen Suppresses Platelet Activation-Supported Angiogenesis and Metastasis Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBTamoxifen Suppresses Platelet Activation-Supported Angiogenesis and Metastasis Pavel Davizon-Castillo and Jorge Di Paola Pavel Davizon-CastilloPavel Davizon-Castillo From the Department of Pediatrics, University of Colorado School of Medicine, Aurora; and Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora. and Jorge Di PaolaJorge Di Paola From the Department of Pediatrics, University of Colorado School of Medicine, Aurora; and Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora. Originally published1 Apr 2017https://doi.org/10.1161/ATVBAHA.117.309105Arteriosclerosis, Thrombosis, and Vascular Biology. 2017;37:611–612It has been known for decades that platelets are critical for providing adequate hemostasis. However, more recently, platelets have been implicated in other health- and disease-related processes, such as angiogenesis, wound healing, inflammation, tumor progression, and metastasis.1–4 Platelet interactions with tumor cells occur locally at the tissue level and also in the blood circulation. These interactions can lead to platelet activation, a process that results in the release of the contents of platelet granules to the tumor microenvironment. This platelet releasate includes large amounts of bioactive molecules which facilitate tumor growth, endothelial transmigration, and angiogenesis.5 In the bloodstream, platelets are also able to form aggregates with circulating tumor cells. As the platelets adhere to the circulating tumor cells' surfaces, this interaction can generate a shielding effect by facilitating immune evasion and preventing clearance of cancer cells. In addition, the interaction of platelets with circulating tumor cells can also promote epithelial to mesenchymal transition, a process that favors tumor growth and increases metastatic burden.1 Therefore, it has become evident that by several distinctive mechanisms, platelets promote tumor progression and metastasis.See accompanying article on page 664Tamoxifen is a chemotherapeutic agent that has been widely used over the past 40 years as endocrine therapy for estrogen-receptor positive (ER+) breast cancer. Tamoxifen is known to block estrogen receptors, therefore, disrupting important signaling pathways in tumor cells (process known as estrogen deprivation). In the current issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Johnson et al6 characterize an indirect platelet-mediated pathway by which Tamoxifen and its metabolite, 4-hydroxytamoxifen (4-OH), inhibit angiogenesis and metastasis (Figure). The investigators show that platelets from patients taking tamoxifen are less responsive to activation by the breast tumor cell line MCF-7. Moreover, the releasate from these platelets contain less vascular endothelial growth factor which, in vitro, results in decreased capillary tube formation, a surrogate marker of angiogenesis.Download figureDownload PowerPointFigure 1. A, Cancer cells can interact with platelets and trigger platelet activation. The platelet releasate contains high amounts of the proangiogenic molecule vascular endothelial growth factor (VEGF), promoting angiogenesis and metastasis. B, Tamoxifen and its metabolite 4-hydroxytamoxifen (4-OH) act directly on tumor cells and platelets. On platelets, Tamoxifen decreases the activation effect of cancer cells. The platelet releasate of these platelets contains lower amounts of the proangiogenic molecule VEGF and higher levels of the antiangiogenic molecule angiopoietin-1.The main conclusions of this study are supported by an extensive and convincing series of experiments that demonstrate the effect of Tamoxifen and its metabolite on platelet activation. The investigators show that platelets incubated with Tamoxifen or 4-OH exhibit decreased activation responses on stimulation with ADP or exposure to the cell line MCF-7. Interestingly, exposure to 4-OH also blocks the activation of platelets by the strong agonist thrombin-related activation peptide and the triple-negative tumor cell line MDA-MB-231. To confirm that this effect has functional consequences, the releasate of platelets exposed in vitro to Tamoxifen or 4-OH did not support the formation of capillary tubes when compared with controls. Furthermore, protein analysis by ELISA and membrane-based protein arrays of the releasates of platelets exposed to Tamoxifen or 4-OH show that the observed differences are associated with the release of significantly lower amounts of key proangiogenic molecules, such as vascular endothelial growth factor, and higher amounts of potent antiangiogenic mediators, such as angiopoietin-1. Finally, in vitro invasion assays demonstrated that cancer cells exposed to the releasate of platelets treated with Tamoxifen or 4-OH had decreased migration, indicating that these cancer cells have less metastatic potential.Although this work is of clear significance and paves the road for further investigations, there are still many unanswered questions. The specific mechanism(s) by which Tamoxifen and 4-OH modulate platelet activity is not completely understood. Although platelets have estrogen receptors, it has previously been shown that inhibition of those receptors does not abrogate platelet responses to Tamoxifen. The mechanism of action of Tamoxifen or 4-OH could alternatively be explained by an effect on thrombopoiesis, perhaps facilitating selective packaging of platelet α-granules with antiangiogenic content generating platelet populations with less proangiogenic/metastatic potential.Interestingly, by modulating platelet activation, Tamoxifen could potentially also contribute to decreasing the incidence of cancer-associated thrombosis in patients with breast cancer.Johnson et al6 findings should, however, offer a cautionary note to scientists using genetic animal models that rely on the administration of Tamoxifen to express or silence genes in models of metastasis or thrombosis and hemostasis given the proposed effect of Tamoxifen on platelet function, angiogenesis, and metastasis.In summary, Johnson et al6 have characterized a platelet-mediated pathway by which Tamoxifen and its metabolite 4-OH indirectly restrain angiogenesis and metastasis. Although these compounds directly affect breast cancer cells by causing estrogen deprivation, platelets exposed to Tamoxifen can potentially limit tumor progression in situ (providing less proangiogenic signals) and hinder the metastatic burden of circulating tumor cells.DisclosuresNone.FootnotesCorrespondence to Jorge Di Paola, MD, University of Colorado Denver, School of Medicine, Mail Stop 8302, Bldg RC1N, 12800 E 19th Ave, Room P18-4100, Aurora, Colorado 80045. E-mail [email protected]References1. Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis.Cancer Cell. 2011; 20:576–590. doi: 10.1016/j.ccr.2011.09.009.CrossrefMedlineGoogle Scholar2. Janowska-Wieczorek A, Wysoczynski M, Kijowski J, Marquez-Curtis L, Machalinski B, Ratajczak J, Ratajczak MZ. Microvesicles derived from activated platelets induce metastasis and angiogenesis in lung cancer.Int J Cancer. 2005; 113:752–760. doi: 10.1002/ijc.20657.CrossrefMedlineGoogle Scholar3. Peterson JE, Zurakowski D, Italiano JE, Michel LV, Connors S, Oenick M, D'Amato RJ, Klement GL, Folkman J. VEGF, PF4 and PDGF are elevated in platelets of colorectal cancer patients.Angiogenesis. 2012; 15:265–273. doi: 10.1007/s10456-012-9259-z.CrossrefMedlineGoogle Scholar4. Palumbo JS, Talmage KE, Massari JV, La Jeunesse CM, Flick MJ, Kombrinck KW, Jirousková M, Degen JL. Platelets and fibrin(ogen) increase metastatic potential by impeding natural killer cell-mediated elimination of tumor cells.Blood. 2005; 105:178–185. doi: 10.1182/blood-2004-06-2272.CrossrefMedlineGoogle Scholar5. Labelle M, Begum S, Hynes RO. Platelets guide the formation of early metastatic niches.Proc Natl Acad Sci USA. 2014; 111:E3053–E3061.CrossrefMedlineGoogle Scholar6. Johnson KE, Forward JA, Tippy MD, Ceglowski JR, El-Husayni S, Kulenthirarajan R, Machlus KR, Mayer EL, Italiano JE, Battinelli EM. Tamoxifen directly inhibits platelet angiogenic potential and platelet-mediated metastasis.Arterioscler Thromb Vasc Biol. 2017; 37:664–674. doi: 10.1161/ATVBAHA.116.308791.LinkGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Hassan A, Wober J, Vollmer G, Abadi A and Ahmed N (2022) Flexible Etherified and Esterified Triphenylethylene Derivatives and Their Evaluation on ER‐positive and Triple‐Negative Breast Cancer Cell Lines, ChemMedChem, 10.1002/cmdc.202100720, 17:7, Online publication date: 5-Apr-2022. Ahmed N, Samec M, Liskova A, Kubatka P and Saso L (2021) Tamoxifen and oxidative stress: an overlooked connection, Discover Oncology, 10.1007/s12672-021-00411-y, 12:1, Online publication date: 1-Dec-2021. Plazak M, Hankinson S, Sorensen E, Reed B, Ravichandran B and Ton V (2020) Novel Use of Tamoxifen to Reduce Recurrent Gastrointestinal Bleeding in Patients with Left Ventricular Assist Devices, Journal of Cardiovascular Translational Research, 10.1007/s12265-020-10084-7, 14:3, (484-491), Online publication date: 1-Jun-2021. Silva A, Haupenthal F, Morais A, Ascenço A, Sebastião A, Cavalcanti M and Freitas R (2018) Relationship between Tamoxifen and the Absorption of Subfascial Autologous Fat Grafts, Plastic and Reconstructive Surgery, 10.1097/PRS.0000000000004415, 141:6, (1408-1415), Online publication date: 1-Jun-2018. April 2017Vol 37, Issue 4 Advertisement Article InformationMetrics © 2017 American Heart Association, Inc.https://doi.org/10.1161/ATVBAHA.117.309105PMID: 28330945 Originally publishedApril 1, 2017 KeywordsEditorialstamoxifenplatelet activationimmune evasionangiopoietin-1inflammationPDF download Advertisement