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Page 6 of 24 Saier et al. J Cancer Metastasis Treat 2021;7:43 https://dx.doi.org/10.20517/2394-4722.2021.87

High ATX expression in primary tumors is frequently associated with a poor prognosis in cancer
patients [42-44] . Intriguingly, the expression of ATX directly by tumor cells is often low, as found in most breast
[45]
cancer cell lines. It has been well established by Brindley et al. that tumor microenvironment is a major
[45]
source of ATX . We showed that challenging mature osteoclasts with inflammatory molecules such as
TNF and LPS upregulates the secretion of ATX through a NF-κB pathway . In addition, inflammatory
[28]
cytokines and chemokines released by breast and thyroid cancer cells have been shown to induce the
expression of ATX in tumor-associated fibroblasts and adipocytes . Furthermore, during our study on the
[46]
role of non-tumoral ATX in the formation of bone metastases, we found that blood platelets uptake
circulating ATX that is naturally present in the bloodstream and store ATX in their granular compartments,
which is eventually released under tumor cell-induced platelet aggregation . Non-tumoral ATX released by
[29]
platelets is functionally active as it catalyzes the production of LPA, which ultimately acts on cancer cells to
promote survival, invasion, and bone metastasis [19,29] . Overall, ATX present in the tumor environment
appears as a major promoter of tumor growth and metastasis. Therefore, a new paradigm is emerging at the
level of bone metastasis where multiple vicious cycles establish and interconnect together. The first well-
known vicious cycle was characterized in 1997 by T Guise, establishing the cross talk between tumor growth
and bone resorption [Figure 2]. We showed that the production and activity of LPA following tumor cell-
[47]
induced platelet aggregation constitute a second vicious cycle between tumor cells and blood platelets taking
place at the bone metastasis site . Non-tumoral ATX released by activated platelets is likely to contribute to
[19]
this bone resorption-independent vicious cycle. Furthermore, by acting on fibroblasts, adipocytes, and,
potentially, osteoclasts, tumor cell-derived inflammatory cytokines might contribute to an additional vicious
cycle through the secretion of ATX.

Role of LPA in bone pain
Bone pain is the most common complication of bone metastases for cancer patients . LPA is well known
[48]
[31]
to promote neuropathic pain , but pain occurring in the context of bone metastasis depends on different
mechanisms; as shown primarily by Yoneda et al. , the release of protons from vacuolar resorption pits
[49]
during osteoclastic resorption create acidic microenvironments that stimulate sensory nociceptive neurons
that innervate bone. This is likely to explain why anti-resorptive agents, such as bisphosphonates and
denosumab, efficiently reduce bone pain in bone metastasis patients . Although LPA might indirectly
[3]
promote metastasis-induced bone pain through the stimulation of osteoclast activity, it might also have a
direct action. Using an osteosarcoma-induced bone pain model in rat, Zhao et al. showed that, two weeks
[50]
after cancer cell implantation in vivo, sural C-fibers become more sensitive to LPA stimulation, an effect
that was blocked after treatment with VPC32183, an antagonist of LPA receptor. The analysis of dorsal root
1
ganglion neurons showed increased LPA receptor expression two weeks after cancer cell injection into the
1
rat tibia . In this context, bone pain was regulated by LPA through LPA signaling in dorsal root ganglion
[51]
1
neurons, potentiating potential vanilloid 1 (TRPV1) receptors via protein kinase Cε pathway. In addition, in
this rat model, mechanical allodynia and thermal hyperalgesia were alleviated under treatment with
[51]
VPC32183 . Furthermore, using paw withdrawal threshold and flinching behavior assays, Wu et al.
[52]
demonstrated that Rho/ROCK signaling mediates P2X -induced bone cancer pain downstream of LPA
1
3
activation. Collectively, these results strongly suggest that LPA might play an important role in pain
associated with bone metastasis. However, which LPA receptor is involved is not well understood. Although
LPA is likely to mediate LPA-induced bone cancer pain, the analysis of conditional knock-out of Lpar1 in
1
dorsal root ganglion neurons and its impact on pain in bone metastasis has not been investigated yet.
SPHINGOSINE 1-PHOSPHATE
Structure, synthesis, and receptors
Sphingolipids are another class of phospholipids that are a part of cell membrane. They comprise a polar
head and two non-polar tail domains. Sphingosine, a long chain amino-alcohol, is an integral component of