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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 5 of 24

(RANK-L)-induced osteoclastogenesis. Both genetic ablation and pharmacological inhibition of LPA
1
remarkably alter mineral matrix resorption of mature osteoclasts and prevent ovariectomy-induced bone
loss [16,26] . These results demonstrate that, under pathophysiological context, the production of LPA in bone
might profoundly affect osteoclast function. Mice with global deletion of Lpar1 revealed remarkable
resistance to bone destruction in an arthritis model induced by type II collagen injection , confirming the
[27]
LPA-dependence of osteoclast function here under an inflammation context. This study showed decreased
infiltration of macrophages and differentiation into Th17, but not Th1 or Th2, which were also suppressed
under pharmacological inhibition of LPA . Thus, in the context of bone metastasis, in addition to its action
1
on osteoclasts by stimulating osteolysis, LPA could also promote the recruitment of immune cells that may
contribute to the progression of metastases. Furthermore, we recently showed that mature osteoclasts
produce functionally active ATX, thereby highlighting these cells as an additional source of LPA in bone .
[28]
Intriguingly, although osteoclast-derived ATX was revealed to be dispensable for bone development as well
as in the classical pathological model of bone loss induced by ovariectomy, we found that autocrine activity
of ATX on osteoclasts is required for systemic bone loss and bone erosion induced by inflammation, as
observed in tumor necrosis factor (TNF)-transgenic(tg) mice, or after mouse treatment with LPS as well as
in the arthritic mouse model using K/BxN-serum transfer . In the context of bone metastasis, treatment
[28]
with BMP22 of mice harboring pre-established bone metastases from the ATX-null MDA-BO2 breast
cancer cells significantly reduced the progression of osteolytic lesions . This clearly demonstrates that non-
[29]
tumoral ATX controls osteoclastic bone resorption. It is of course possible that ATX produced by different
types of cells from the bone environment could act in a paracrine manner on osteoclasts; however, as we
found under inflammatory conditions, osteoclast-derived ATX might act in an autocrine manner to
stimulate malignant osteolysis. However, this assertion requires further investigation.

Role of LPA in cancer and bone metastasis
Autotaxin’s name was originally attributed due to its action on melanoma cells as a new autocrine factor
stimulating tumor cell invasion . The ATX/LPA axis was later recognized as a major regulator of
[30]
tumorigenesis through its action on cancer cell proliferation and survival, as well as through the promotion
of angiogenesis and the control of the metastatic cascade by stimulating cell migration and invasion [31,32] .
Increased LPA levels are found in different types of cancers [33-35] . Endogenous expression of ATX in 4T1
mouse carcinoma cells as well as high ATX expression in human MDA-BO2-ATX transfected breast cancer
cells provide a higher propensity to these cells of generating bone metastases . The main reason is likely to
[26]
reside in the fact that these cells express high levels of LPA receptor, resulting in high sensitivity to LPA
1
stimulation. By activating LPA , LPA promotes cell motility and proliferation, but the prominent action of
1
LPA/LPA signaling in the context of bone metastasis might be linked to the increase in the secretion of
1
growth factors such as vascular endothelial growth factor (VEGF) [36,37] and cytokines [such as interleukin
(IL)-6, IL-8, granulocyte-macrophage colony-stimulating factor, and monocyte chemoattractant protein 1]
that are known to affect bone remodeling. Osteomimetism was shown to characterize breast cancer bone-
seeking cells . Gene signature of LPA signaling was not associated with osteomimetism. However, cancer
[38]
cells and bone cells (osteoblasts and osteocytes) share the characteristics that, by activating LPA receptor,
1
LPA also stimulates the secretion of IL-6 and IL-8 [chemokine (C-X-C motif) ligand 15 protein in
mouse] [39,40] . Overexpression of LPA in MDA-BO2/LPA transfected cells dramatically increases the extent
1
1
of osteolytic lesion areas, whereas pharmacological inhibition of this receptor using Ki16425 and Debio
0719, two LPA antagonists, reduced cytokine production and the progression of osteolytic bone
1/3
metastasis. Intriguingly, endogenous expression of ATX was revealed to be dispensable for cancer cells to
metastasize to bone, as shown by the above-mentioned MDA-BO2 cells that do not express ATX but which
are a sub-clone of MDA-MB-231 cells isolated in vivo for their exclusive bone tropism .
[41]