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Saier et al. J Cancer Metastasis Treat 2021;7:43 https://dx.doi.org/10.20517/2394-4722.2021.87 Page 15 of 24

reason, EP receptors antagonists are now considered more relevant with some under clinical
[133]
investigation [Figure 6].
Blockade of prostaglandin synthesis with aspirin, in combination with APT102, an ADPase, decreases breast
cancer and melanoma bone metastasis in mice [55,148] . B16 melanoma bone metastasis is also suppressed in
mPGES-1-deficient mice, suggesting that prostaglandins may drive tumor invasion and metastasis . Bone
[149]
seeking cells express COX-2 and produce PGE . TGF-β released from resorbed bone matrix enhances COX-
2
2 expression in cancer cells, leading to a vicious cycle between bone resorption and tumor growth . In
[150]
addition, PGE also indirectly contributes to bone resorption by stimulating the secretion of pro-osteoclastic
2
cytokines (IL-8 and IL-11) by cancer cells [151,152] . PGE /EP signaling upregulates matrix metallopeptidase
4
2
(MMP)-2, MMP-9, RANK-L, and Runt-related transcription factor 2 (RUNX2) and contributes to prostate
cancer cell proliferation and invasion via the cAMP-protein kinase A/phosphoinositide 3-kinase (PI3K)-Akt
signaling pathway . Overexpression of COX-2 in TM40D mouse breast cancer cells increased bone
[153]
[154]
metastasis by recruiting Treg cells through their EP and/or EP receptors , thus providing a favorable
4
2
metastatic environment against immune system surveillance. Nevertheless, in an immunocompromised
mouse model, the COX-2 inhibitor MF-tricyclic inhibited bone metastasis in mice inoculated with human
breast cancer cells, suggesting a direct antitumor action of COX-2 inhibitor and/or indirect action on bone
cells . Blockade of PGE -EP signaling in mice was shown to decrease bone metastasis, in part via the
[155]
4
2
abrogation of PGE -induced RANK-L expression in osteoblasts .
[156]
2
Leukotrienes
5-LOX is overexpressed in tissue samples of patients with bladder, breast, esophageal, kidney, oral,
pancreatic, and prostate cancer, as well as in established cancer cell lines [157-161] . 5-LOX expression is present
during the early neoplastic changes in cancers such as in pancreatic cancer, well before progression to
invasive disease , supporting the role of 5-LOX in early stages of carcinogenesis. Furthermore, 5-LOX
[158]
[158]
correlates with tumor stage and lymph node metastasis in colorectal adenocarcinomas . Leukotrienes may
modulate the initiation, progression, and metastasis of tumors through regulating the proliferation,
apoptosis, migration, and invasion of cancer cells. Addition of 5-LOX expression products to tumor cells led
[162]
to increased cell proliferation and activation of anti-apoptotic pathways . CYSLT receptor expression
1
negatively correlates with survival of patients with prostate, breast, and colon cancers and metastatic uveal
melanoma . Conversely, low expression of CYSLT is associated with poor prognosis in colon cancer. In
[105]
2
this context, CYSLT signaling leads to terminal differentiation of colon carcinoma cells and growth
2
inhibition . LTC4S overexpression is found in patients with chronic myeloid leukemia, and high LTC4S
[163]
levels are correlated with tumor aggressiveness in prostate cancer [164,165] . Activation of LTD /CYSLT
4
1
signaling has been shown to promote cell proliferation and survival through multiple parallel pathways,
including GSK3β/β-catenin, PKC/Raf/ERK1, and ERK2 signaling [166,167] . LTD increases cancer cell survival
4
[168]
by upregulating COX-2 expression and PGE production , indicating a crosstalk between CysLTs and the
2
prostaglandins pathways. LTD /CYSLT promotes migration and invasion in colon cancer cells by
4
1
regulating MMP-9 expression , whereas CysLT signaling reduces cancer cell migration , suggesting
[169]
[163]
2
opposing roles of these receptors in cancer cell motility. LTB levels are increased in human colon and
4
prostate cancers . Inhibition of LTB synthesis reduced colon cancer cell growth in patient-derived
[163]
4
xenograft mouse model and inhibited the burden of esophageal adenocarcinoma in a rat model [170,171] .
Although in vivo LTB may have both direct and indirect pro-tumor action, in vitro LTB /BLT signaling
1
4
4
directly stimulates colon cancer cell growth and survival through MAPK/ERK- and PI3K-Akt-dependent
pathways [172,173] . LTB , by acting on BLT , increases mesenchymal markers and promotes epithelial-to-
2
4
mesenchymal transition in several human cancer cell lines [174,175] . BLT appears to also affect cancer
1
progression through immune modulation. Notably, PD-1 blockade fails to reduce melanoma growth in