Abstract
Sphingosine kinase (SphK)/sphingosine-1-phosphate (S1P)/S1P receptor (S1PR) signaling pathway has been implicated in a variety of pathological processes of ovarian cancer. However, the function of this axis in ovarian cancer angiogenesis remains incompletely defined. Here we provided the first evidence that SphK1/S1P/S1PR1/3 pathway played key roles in ovarian cancer angiogenesis. The expression level of SphK1, but not SphK2, was closely correlated with the microvascular density (MVD) of ovarian cancer tissue. In vitro, the angiogenic potential and angiogenic factor secretion of ovarian cancer cells could be attenuated by SphK1, but not SphK2, blockage and were restored by the addition of S1P. Moreover, in these cells, we found S1P stimulation induced the angiogenic factor secretion via S1PR1 and S1PR3, but not S1PR2. Furthermore, inhibition of S1PR1/3, but not S1PR2, attenuated the angiogenic potential and angiogenic factor secretion of the cells. in vivo, blockage of SphK or S1PR1/3 could attenuate ovarian cancer angiogenesis and inhibit angiogenic factor expression in mouse models. Collectively, the current study showed a novel role of SphK1/S1P/S1PR1/3 axis within the ovarian cancer, suggesting a new target to block ovarian cancer angiogenesis.
Highlights
Angiogenesis, the process through which new blood vessels sprout from pre-existing ones, is one of the hallmarks of cancer [1]
The angiogenic potential and angiogenic factor secretion of ovarian cancer cells could be attenuated by SphK1, but not SphK2, blockage and were restored by the addition of S1P
These findings suggested that SphK1 might be related to ovarian cancer angiogenesis
Summary
Angiogenesis, the process through which new blood vessels sprout from pre-existing ones, is one of the hallmarks of cancer [1]. Abundant evidence has indicated that ovarian cancer progression has close interactions with angiogenesis [2,3,4,5]. Angiogenesis is induced early and remained on during the multistage development of ovarian cancer, providing nutrients and oxygen for sustained neoplastic growth [2]. Ovarian cancer cells have been shown to be essential for regulating tumor-associated angiogenesis by secreting a series of proangiogenic growth factors into the tumor microenvironment [3]. Increased angiogenesis was associated with increased risk of disease progression in the patients with advanced-stage epithelial ovarian cancer (EOC) [4]. The current understanding of molecular mechanisms of ovarian cancer angiogenesis remains incomplete
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