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.