Abstract
A high incidence of hemangiosarcoma (HSA) was observed in mice treated for 2 years with siponimod, a sphingosine-1-phosphate receptor 1 (S1P1) functional antagonist, while no such tumors were observed in rats under the same treatment conditions. In 3-month rat (90 mg/kg/day) and 9-month mouse (25 and 75 mg/kg/day) in vivo mechanistic studies, vascular endothelial cell (VEC) activation was observed in both species, but VEC proliferation and persistent increases in circulating placental growth factor 2 (PLGF2) were only seen in the mouse. In mice, these effects were sustained over the 9-month study duration, while in rats increased mitotic gene expression was present at day 3 only and PLGF2 was induced only during the first week of treatment. In the mouse, the persistent VEC activation, mitosis induction, and PLGF2 stimulation likely led to sustained neo-angiogenesis which over life-long treatment may result in HSA formation. In rats, despite sustained VEC activation, the transient mitotic and PLGF2 stimuli did not result in the formation of HSA. In vitro, the mouse and rat primary endothelial cell cultures mirrored their respective in vivo findings for cell proliferation and PLGF2 release. Human VECs, like rat cells, were unresponsive to siponimod treatment with no proliferative response and no release of PLGF2 at all tested concentrations. Hence, it is suggested that the human cells also reproduce a lack of in vivo response to siponimod. In conclusion, the molecular mechanisms leading to siponimod-induced HSA in mice are considered species specific and likely irrelevant to humans.
Highlights
Hemangiosarcoma (HSA) is a malignant tumor arising from anarchical proliferation of vascular endothelial cells (Carmeliet 2005) and may arise from transformation of tissue-resident endothelial cell populations, from circulating progenitors, adult stem cells recruited from bone marrow, or possibly from extramedullary sites of hematopoiesis such as the liver and spleen (Cohen et al 2009)
Hemangiosarcoma (HSA) is a malignant tumor arising from the transformation and proliferation of vascular endothelial cells and is a rare tumor in humans with less than 0.001% affected
Mouse vascular endothelial cells show a high background rate of proliferation and are responsive to pro-angiogenic signals compared to rat and human (Duddy et al 1999), which is likely related to the high spontaneous rate of HSA in mice (Cohen et al 2009; Ohnishi et al 2007)
Summary
Hemangiosarcoma (HSA) is a malignant tumor arising from anarchical proliferation of vascular endothelial cells (Carmeliet 2005) and may arise from transformation of tissue-resident endothelial cell populations, from circulating progenitors, adult stem cells recruited from bone marrow, or possibly from extramedullary sites of hematopoiesis such as the liver and spleen (Cohen et al 2009). In CD1 mice, the spontaneous incidence of HSA is reported to be about 3.1% on average, observed mainly in liver, spleen,. Sphingosine-1-phosphate (S1P) is a biologically active sphingolipid, interacting with five S1P receptors with various tissue expressions and involved in a number of pathways during embryological development as well as in adult biology (Blaho and Hla 2014; Rosen et al 2013). Modulation of S1P receptors results in inhibition of the egress of lymphocytes from lymph nodes and Peyer’s patches, and thereby reduces the recirculation of lymphocytes to blood and tissues including the CNS (Blaho and Hla 2014; Fyrst and Saba 2010)
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