The role of sphingosine-1-phosphate in the tumor microenvironment and its clinical implications

Abstract

Elucidating the interaction between cancer and non-cancer cells, such as blood vessels, immune cells, and other stromal cells, in the tumor microenvironment is imperative in understanding the mechanisms underlying cancer progression and metastasis, which is expected to lead to the development of new therapeutics. Sphingosine-1-phosphate is a bioactive lipid mediator that promotes cell survival, proliferation, migration, angiogenesis/lymphangiogenesis, and immune responsiveness, which are all factors involved in cancer progression. Sphingosine-1-phosphate is generated inside cancer cells by sphingosine kinases and then exported into the tumor microenvironment. Although sphingosine-1-phosphate is anticipated to play an important role in the tumor microenvironment and cancer progression, determining sphingosine-1-phosphate levels in the tumor microenvironment has been difficult due to a lack of established methods. We have recently developed a method to measure sphingosine-1-phosphate levels in the interstitial fluid that bathes cancer cells in the tumor microenvironment, and reported that high levels of sphingosine-1-phosphate exist in the tumor interstitial fluid. Importantly, sphingosine-1-phosphate can be secreted from cancer cells and non-cancer components such as immune cells and vascular/lymphatic endothelial cells in the tumor microenvironment. Furthermore, sphingosine-1-phosphate affects both cancer and non-cancer cells in the tumor microenvironment promoting cancer progression. Here, we review the roles of sphingosine-1-phosphate in the interaction between cancer and non-cancer cells in tumor microenvironment, and discuss future possibilities for targeted therapies against sphingosine-1-phosphate signaling for cancer patients.

Targeting the S1P/S1PR1 axis mitigates cancer-induced bone pain and neuroinflammation

“…Altered spinal sphingolipid metabolism occurs in neuropathic rodents [26; 29; 47; 51; 57] and is implicated in neuronal cell death following both nerve injury [14] and ischemia-reperfusion injury [15]. Moreover, S1P levels in the tumor microenvironment are greatly increased by sphingolipid metabolism in tumor cells, erythrocytes and platelets that in turn promote tumor migration, proliferation and angiogenesis [44; 49]. It is important to note that while 66.1 cells implanted and sealed into the bone do not metastasize within the 14-day test period in the absence of fracture [32] and are not likely to contribute directly to increased S1P in the spinal cord, local increases in S1P in the tumor-bearing bone could sensitize peripheral afferents [11; 30; 46] and promote the development of CIBP and spinal S1P production by provoking adaptive glutamatergic and neuroinflammatory changes in the spinal cord [51].…”

Role of Mast Cells in Shaping the Tumor Microenvironment

“…b The protocol used by Huang to determine the tumor-released SCF as the main chemokine involved in MC recruitment main contributors to S1P production along with tumor cells. S1P promotes proliferation, migration, and survival of tumor cells [64]. In solid tumors such as thyroid tumors, histamine engagement of H1R and H2R results in tumor cell proliferation.…”

Clinical Impact of Sphingosine-1-Phosphate in Breast Cancer

“…S1P is generated inside the cells by two sphingosine kinases, SphK1 and SphK2. SphK1 is located in the cytosol close to the cell membrane where its substrate sphingosine resides [ 29 ], while SphK2 is localized in specific organelles, such as the nucleus and mitochondria [ 30 ] ( Figure 1() ). S1P produced inside cells by SphK1, but not SphK2, is secreted to the extracellular space by transporters and signals through its receptors on the outside of cells, a process referred to as “Inside-out” signaling [ 31 – 33 ].…”

“…S1P is now emerging as a key regulatory molecule in breast cancer through its ability to promote cell proliferation, migration, angiogenesis, and lymphangiogenesis ( Figure 1 ). Further, S1P secreted to the extracellular spaces, including the interstitial fluid and lymphatic fluid, has been suggested to be important for metastasis by stimulating S1P signaling [ 30 , 57 ]. In this section, we describe the roles of S1P in the TME and tumor progression ( Figure 2 ).…”