Several anti platelet therapies have been evaluated in the

Several anti-platelet therapies have been evaluated in the context of bone metastasis. In vitro, a dual anti-platelet treatment using the soluble ADPase APT102 and an inhibitor of TxA2 synthesis (Aspirin) markedly affected tumor cell-induced platelet aggregation without altering tumor cell viability. While in vivo, ATP102 and Aspirin treatment did not affect primary tumor growth, the combined treatment significantly attenuated the melanoma and breast cancer bone autotaxin inhibitor formation in mice [16].
Megakaryocytes and bone mass acquisition Mature Megakaryocytes (MKs) are located in the bone marrow in vascular sinusoid areas where they undergo changes leading to the production of platelets [17]. Knockout mice for the transcription factors Nf-E2 and GATA-1 have marked and mild thrombocytopenia, respectively, which in both cases are associated with an increase in MK number revealing that Nf-E2 and GATA-1 are required for MK terminal differentiation and platelet production [18]. Intriguingly, both Nf-E2-/-and GATA-1-/-mice exhibit high bone mass phenotypes increased [Bone Mineral Density (BMD), Bone Volume over Tissue Volume ratio (BV/TV), trabecular and cortical thicknesses]. MKs produce a large variety of factors, among them are bone regulators such as [Bone Morphogenetic Protein-2,-4,-6 (BMP-2,-4,-6) and TGFβ] [19], which may account for MK-stimulating bone formation. On the other hand, osteoblasts secrete multiple cytokines that control hematopoiesis [Leukemia Inhibitor Factor (LIF), Stem Cell Factor (SCF) and IL6] including MK proliferation and differentiation [20]. Consequently, MK and osteoblasts could stimulate each other, establishing a “win-win” situation at localised bone sites. Osteoblast proliferation is enhanced by MKs via a process regulated in part by integrin signaling (α3β1, α5β1, αIIbβ3) controlling subcellular localization of the tyrosine kinase Pyk2 in osteoblasts [21]. MKs also produce the physiological osteoclast inhibitor Osteoprotegerin (OPG) that could explain the inhibitory effect of MK conditioned media on osteoclastogenesis However, conditioned media collected from MKs derived from OPG-/-mice also provides inhibition, thus minimizing the contribution of OPG in the endogenous anti-osteoclastic activity of MKs but confirming the secretion of unidentified osteoclast inhibitors by MKs [22].
Megakaryocytes and bone metastasis Thrombopoietin (TPO) is a master regulator of Megakaryocytopoiesis and platelet production [17]. Transgenic mice overexpressing TPO exhibit an increase in MK number in the bone marrow and develop a high bone mass phenotype [23]. TPO inhibits osteoclast differentiation and their resorption activity in vitro. Thus, in vivo TPO might inhibit osteoclast function both directly and indirectly through increased production of MK-derived osteoclast inhibitors for inducing osteoclerosis [24]. The increased expansion of MKs in BALB/c nude mice in response to a 5-day TPO administration prior to the intracardiac injection of PC3 prostate cancer cells remarkably decreases the extent of skeletal lesions and tumor burden [25]. This unexpected result may be because TPO primarily increases the production of platelets by MKs and thrombocytosis create a more favorable metastatic environment for PC3 cells in the circulation. The platelet-production-independent function of MKs might predominate in this phenomenon. Mouse primary MKs inhibit proliferation of prostate carcinoma cell lines (PC3, C4-2b, VCaP) in in vitro co-culture systems. Intercellular contacts between MKs and PC3 cells lead to downregulation of cyclinD1 in cancer cells and upregulation of pro-apoptotic factors (such as ASC and DAPK1), favoring apoptosis and inhibition of skeletal tumor growth. Therefore, the anti-tumor effect of MKs in synergy with their anti-osteoclastic action is likely the reason for inhibition of PC3 cell bone metastasis development. Nonetheless, such an anti-metastatic activity of MKs has not been reported in other types of organs and tissues. In contrast to their action on prostate cancer cell lines, MKs stimulate the proliferation of osteosarcoma cells [25]. Further experimental work is required to determine whether the anti-bone metastasis activity of MKs could be generalized to other types of solid tumors.