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expression was correlated to sunitinib resistance and poor prognosis of a large cohort of renal cell
[88]
carcinoma patients . An antibody directed against S1P (sphingomab/sonepcizumab) was proposed as a
[89]
new therapy for resistant renal cell carcinoma after encouraging results in mouse models . Finally, a phase
2 study of the effect of sonepcizumab in patients with advanced renal cell carcinoma who have previously
failed up to three therapies, including VEGF and/or mammalian target of rapamycin inhibitors, was
conducted. This study did not accomplish its primary endpoint (two-month progression-free survival of the
disease), but a median overall survival of 21.7 months was monitored. Moreover, treatment with
sonepcizumab was considered as safe .
[90]
Osteoblastic bone metastases are currently found in lung cancer patients and prostate cancer patients with
advanced disease. Osteoblasts actively synthetize bone in localized zones such as ribs, clavicles, or spinal
vertebrae. Newly synthetized bone is extremely fragile, generally provoking fractures and therefore intensive
pain. In the case of lung cancer, the five S1P receptors were expressed in several non-small and small lung
cancer-derived cell lines. Exogenous S1P had a pro-metastatic effect in these lung cancer cell models,
increasing cell migration and their chemotactic responsiveness to different growth factors, especially
HGF . SphK/S1P metabolic pathway has been extensively studied in the case of prostate cancer [92,93] .
[91]
Importantly, SphK1 activity and expression were increased in human prostate cancer resection specimens
[94]
and correlated with higher prostate specific antigen levels, higher tumor volumes, and disease relapse .
There is only one study reporting the implication of S1P metabolic pathway in prostate cancer-derived bone
metastasis. SphK1 activity was significantly increased in murine and human osteoblastic cell models.
Osteoblasts triggered proliferation of different prostate cancer cell lines through extracellular secretion of
S1P. In addition, osteoblast-derived S1P was able to induce chemo - or radioresistance of prostate cancer
cell models. Furthermore, blockade of SphK1 inhibited the proliferative effects of osteoblasts on prostate
cancer cells .
[95]

Finally, mixed bone metastases have zones of both active bone resorption and active bone formation. As
mentioned above, a small population of breast cancer patients can suffer from mixed bone metastasis, and
they can be found in, for example, colorectal cancer, which is the most common cause of death in these
patients. SphK/S1P signaling has been extensively described to have oncogenic roles in colorectal cancer or
colitis-associated colorectal cancer [96,97] . SphK1 activity was important for the promotion of metastasis in
[98]
colorectal cancer . SphK1 expression was indeed significantly increased in patients, and an elevated SphK1
was an independent predictor of distal metastasis . Other components of S1P signaling such as irreversibly
[99]
[100]
S1P-degrading enzyme, SPL and S1P transporter, and Spns2 or S1P receptors such as S1P 2 [102] or
[101]
S1P 4 [103] were recently implicated in different aspects of colorectal cancer or colitis-associated colorectal
cancer.
PROSTAGLANDINS/LEUKOTRIENES
Prostaglandins and leukotrienes belong to the super-family of eicosanoids. This family is composed of
bioactive lipids that all derive from arachidonic acid (AA). AA is released from cellular membranes
predominantly by cytosolic phospholipase A2α activity. Then, AA is processed by cyclooxygenases (COXs)
to form prostanoids, including prostaglandins (PGs), prostacyclin (PGI ), and thromboxane A2 (TXA2),
2
and by 5-lipoxygenase (5-LOX) to form leukotriene B (LTB ) and the cysteinyl leukotrienes (CysLTs):
4
4
LTC , LTD , and LTE [Figure 5].
4
4
4
Structure, synthesis, and receptors
Prostaglandins are generated by the action of prostaglandin G/H synthases, colloquially known as COXs,
bifunctional enzymes that contain both cyclooxygenase and peroxidase activity and exist as two distinct