ArticleBlood advances2019
Hepatic thrombopoietin gene silencing reduces platelet count and breast cancer progression in transgenic MMTV-PyMT mice.
Article in Blood advances, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 55 citations in OpenAlex.
- Glycoprotein Ibα-Dependent Platelet Activation is Essential for Tumor Cell-Platelet Interaction and Experimental Metastasis.MedComm · 2025Article
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- Elucidating the Role of THPO and Related Molecular Markers in Lymph Node Metastasis and Prognosis of Gastric Cancer: Insights From TCGA Data Analysis.Genetics research · 2025Article
- Article
- Preoperative thromboelastography parameters in predicting the tumour stage of oral squamous cell carcinoma.BMC cancer · 2024Article
- Platelet Contributions to the (Pre)metastatic Tumor Microenvironment.Seminars in thrombosis and hemostasis · 2024Review
- The prospects of microphysiological systems in modeling platelet pathophysiology in cancer.Platelets · 2023Review
- Breast metastatic tumors in lung can be substituted by lung-derived malignant cells transformed by alternative splicing H19 lncRNA.Breast cancer research : BCR · 2023Article
- Platelets and (Lymph)angiogenesis.Cold Spring Harbor perspectives in medicine · 2023Review
- Scoping Review on Platelets and Tumor Angiogenesis: Do We Need More Evidence or Better Analysis?International journal of molecular sciences · 2022Article
- Pro-inflammatory megakaryocyte gene expression in murine models of breast cancer.Science advances · 2022Article
- Incidence and Risk Factors for Venous Thromboembolism in Female Patients Undergoing Breast Surgery.Cancers · 2022Article
- Platelet Count and Survival after Cancer.Cancers · 2022Article
- Aspirin and antiplatelet treatments in cancer.Blood · 2021Article
- Lessons to learn from tumor-educated platelets.Blood · 2021Review
- Bone marrow niches in the regulation of bone metastasis.British journal of cancer · 2021Review
- Exosomal HMGB1 Promoted Cancer Malignancy.Cancers · 2021Article
- The Thrombopoietin Receptor, MPL, Is a Therapeutic Target of Opportunity in the MPN.Frontiers in oncology · 2021Review
- Endogenous thrombopoietin promotes non-small-cell lung carcinoma cell proliferation and migration by regulating EGFR signalling.Journal of cellular and molecular medicine · 2020Article
- Thrombopoietin is required for full phenotype expression in a JAK2V617F transgenic mouse model of polycythemia vera.PloS one · 2020Article
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Authors and funding
13 authors at 2 institutions in 2 countries.
Funding
Abstract
In humans, platelet count within the normal range is required for physiological hemostasis, but, adversely, platelets also support pathological thrombosis. Moreover, by releasing growth factors, they may enhance neoplastic proliferation. We hypothesize that platelet count correlates with platelet-dependent pathologies, even within the range of hemostatic competence. Because platelet production is promoted by thrombopoietin signaling through the myeloproliferative leukemia virus oncogene (cMPL), a receptor expressed on megakaryocytes, we evaluated the feasibility of selective targeting of hepatic thrombopoietin production to test this hypothesis. We synthesized murine- and primate-specific antisense oligonucleotides (THPO-ASO) that silence hepatic thrombopoietin gene (THPO) expression without blocking extrahepatic THPO. Repeated doses of THPO-ASO were administered to mice and a baboon, causing a sustained 50% decline in plasma thrombopoietin levels and platelet count within 4 weeks in both species. To investigate whether reducing platelet count within the translationally relevant hemostatic range could alter a neoplastic process, we administered THPO-ASO to 6-week-old transgenic MMTV-PyMT mice that develop early ductal atypia that progresses into cMPL-negative fatal metastatic breast cancer within 2 to 3 months. THPO-ASO treatment increased the average time to euthanasia (primary humane endpoint) at 2 cm3 combined palpable tumor volume. Our results show that THPO-ASO reduced blood platelet count, plasma platelet factor 4, vascular endothelial growth factor, thrombopoietin levels, bone marrow megakaryocyte density, tumor growth rate, proliferation index, vascularization, platelet and macrophage content, and pulmonary metastases vs untreated controls. These findings confirm that sustained and moderate pharmacological platelet count reduction is feasible with THPO-ASO administration and can delay progression of certain platelet-dependent pathological processes within a safe hemostatic platelet count range.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.