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  • br Outstanding questions br Conflict


    Outstanding questions
    Conflict of interest
    Acknowledgments This work was supported by the Dutch Cancer SocietyUL2015-7599 KWF (EZ).
    Platelets and cancer metastasis Blood platelets play a primary role in wound healing and hemostasis. Since the first observation made (on himself) by the surgeon A. Trousseau in the late 1800s, thrombosis is now accepted to be associated with poor cancer outcomes. Aspirin prevents distant metastasis of adenocarcinomas that accounts for the early reduction in cancer deaths in trials of daily aspirin versus control [1]. Clear demonstration of platelets controlling metastasis emerged in the mid-1900s through platelet depletion experiments that remarkably inhibited the incidence of lung metastases in mice [2]. Therefore, platelets are now considered as preeminent factors of cancer metastasis. Metastatic tumor cells induce platelet aggregation and embolus formation. In turn, platelets release a plethora of factors that contribute to circulating tumor cell (CTC) survival in a stressed condition generated in the bloodstream. Shear stress and Natural Killer cytotoxic cells are the main threats to CTCs inside the blood vessels [3]. At later steps of the metastatic cascade, interaction of CTCs with platelets favors extravasation and seeding of CTCs to distant organs. Platelets and endothelial cells express several types of selectins that support transient CTC adhesion to the vessel wall [4]. Plasma fibrinogen and its platelet-specific receptor, αIIbβ3 integrin, also contribute to platelet-CTCs emboli [5]. Both members of the β3 integrin family, platelet αIIbβ3 and tumor αVβ3, are involved in CTC adhesion and invasion under flow conditions [6]. In addition to contribute to multiple steps of the metastatic cascade, platelets are also important modulators of inflammation and angiogenesis. These aspects of platelet functions are outside the scope of the present review but have been very well described in recent publications [7,8].
    Platelets and bone remodeling Clinical studies focused on the role of plasma rich platelets (PRP) demonstrated the involvement of thrombocytes in bone remodeling under acute and physiologic conditions [9]. Platelet cotransporter localize around the sites of fractures or micro-fractures, wherein they release intragranular growth factors such as Platelet-Derived Growth Factor (PDGF), Vascular Endothelial Growth Factor (VEGF), Insuline-Like Growth Factor 1 (IGF-1) or Transforming Growth Factor 2 (TGFβ), all known to recruit osteogenic cells [10]. Thromboxane A2 (TxA2) and Prostaglandins were also identified as bone remodeling modulators [9]. The role of platelets in osteoclastogenesis and bone resorption remains controversial. Several studies showed that activated platelets and PRP can enhance osteoclastogenesis via a RANKL-dependent mechanism [11], whereas others showed inhibitory effects [12]. Such discrepancies might derive from complex experimental settings using functional platelets in vitro.
    Platelets and bone metastasis It is now well established that platelets are essential for cancer metastatic dissemination and progression to the bone, as revealed by the seminal work using β3-deficient mice that exhibited a 95% decrease in skeletal tumor burden after intracardiac inoculation of B16 melanoma cells [13]. The use of osteoclast defective src-/-mice and specific platelet aggregation inhibitors could discriminate between the roles of β3 integrins of osteoclasts and of platelets. Integrin αIIbβ3 controls both platelet aggregation and CTC homing to the bone microenvironment, whereas osteoclast integrin αVβ3 drives bone osteolysis [13]. Our group extended the role of platelet αIIbβ3 integrin, not only to the onset of skeletal metastasis but also to the progression of bone metastasis, by treating metastasis harboring mice with integrilin, a pharmacological αIIbβ3 antagonist [14]. This study also revealed the role of platelet-derived lysophosphatidic acid (LPA) as an enhancer of bone metastasis in metastatic breast cancer models. LPA is a bioactive lipid that exhibits growth factor-like activities by promoting proliferation, survival migration and the secretion of pro-osteoclastic cytokines [Interleukin 6 (IL-6) and 8, (IL-8), monocyte chimoattractant protein 1 (MCP-1), chemokine (C-X-C motif) ligand 1 (Groα)] [14]. LPA is the final product of the lysophospholipase D activity of autotaxin (ATX) that controls the physiological levels of LPA in blood. We recently demonstrated that nontumoral circulating ATX can be stored in α-granules of resting platelets and released upon breast cancer cell stimulation contributing to metastasis formation [15].