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      Lessons to learn from tumor-educated platelets

      review-article
      1 , 2 , 1 , 2 ,
      Blood
      American Society of Hematology

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          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.

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          Most cited references86

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          Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing

          Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.).
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            The lung is a site of platelet biogenesis and a reservoir for hematopoietic progenitors

            Platelets are critical for hemostasis, thrombosis, and inflammatory responses 1,2 , yet the events leading to mature platelet production remain incompletely understood 3 . The bone marrow (BM) is proposed to be a major site of platelet production although indirect evidence points towards a potential pulmonary contribution to platelet biogenesis 4-7 . By directly imaging the lung microcirculation in mice 8 , we discovered that a large number of megakaryocytes (MKs) circulate through the lungs where they dynamically release platelets. MKs releasing platelets in the lung are of extrapulmonary origin, such as the BM, where we observed large MKs migrating out of the BM space. The lung contribution to platelet biogenesis is substantial with approximately 50% of total platelet production or 10 million platelets per hour. Furthermore, we identified populations of mature and immature MKs along with hematopoietic progenitors that reside in the extravascular spaces of the lung. Under conditions of thrombocytopenia and relative stem cell deficiency in the BM 9 , these progenitors can migrate out of the lung, repopulate the BM, completely reconstitute blood platelet counts, and contribute to multiple hematopoietic lineages. These results position the lung as a primary site of terminal platelet production and an organ with considerable hematopoietic potential.
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              Tumour-educated macrophages promote tumour progression and metastasis.

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                Author and article information

                Journal
                Blood
                Blood
                bloodjournal
                blood
                Blood
                Blood
                American Society of Hematology (Washington, DC )
                0006-4971
                1528-0020
                10 June 2021
                03 May 2021
                10 June 2021
                : 137
                : 23
                : 3174-3180
                Affiliations
                [1 ]Hematology Division, Brigham and Women’s Hospital, Boston, MA; and
                [2 ]Department of Medicine, Harvard Medical School, Harvard University, Boston, MA
                Author information
                https://orcid.org/0000-0002-1100-8409
                https://orcid.org/0000-0003-1916-047X
                Article
                2021/BLD2019003976C
                10.1182/blood.2019003976
                8351883
                33940594
                0b4dc880-3322-4141-a0d7-5af97b1580ca
                © 2021 by The American Society of Hematology

                This article is made available via the PMC Open Access Subset for unrestricted reuse and analyses in any form or by any means with acknowledgment of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

                History
                : 02 June 2020
                : 30 November 2020
                Page count
                Pages: 7
                Categories
                Review Article
                Platelets and Thrombopoiesis
                Thrombosis and Hemostasis
                Review Series
                Platelets and Cancer

                Hematology
                Hematology

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