The type 1 lysophosphatidic acid receptor is a target for therapy in bone metastases

Abstract

Platelet-derived lysophosphatidic acid (LPA) supports the progression of breast and ovarian cancer metastasis to bone. The mechanisms through which LPA promotes bone metastasis formation are, however, unknown. Here we report that silencing of the type 1 LPA receptor (LPA 1) in cancer cells blocks the production of tumor-derived cytokines that are potent activators of osteoclastmediated bone destruction and significantly reduces the progression of osteolytic bone metastases. Moreover, functional blockade of LPA action on its cognate receptor LPA 1 using a pharmacological antagonist mimics the effects of silencing LPA 1 in tumor cells in vitro and substantially reduces bone metastasis progression in animals. Overall, these results suggest that inhibition of plateletderived LPA action on LPA 1 expressed by tumor cells may be a promising therapeutic target for patients with bone metastases.breast cancer ͉ platelet ͉ treatment B one is a frequent metastatic site for many cancers (1). Bone metastasis formation is associated with a high morbidity rate because of intractable bone pain, pathological fractures, hypercalcemia, and nerve compression (1). Bone-residing metastatic cells are not directly able to destroy bone. Instead, they secrete paracrine factors [IL-6, IL-8, and parathyroid hormone-related peptide (PTHrP)] that stimulate osteoblast-mediated bone resorption, leading to osteolysis (1). In this respect, bisphosphonates (as inhibitors of osteoclast activity) are the standard of care in the treatment of patients with bone metastases. Unfortunately, these treatments are only palliative and do not provide a life-prolonging benefit to metastatic patients (2), indicating that more efficacious therapies are required.We have recently demonstrated that the naturally occurring bioactive lipid, lysophosphatidic acid (LPA), produced by activated blood platelets (3), is coopted by breast and ovarian cancer cells as a tumor mitogen and an inducer of tumor-derived cytokine (IL-6 and IL-8) that, altogether, promote the progression of bone metastases (4). Endogenous receptors through which LPA promotes breast cancer progression and bone metastasis are, however, unknown. LPA binds to three GTPbinding protein-coupled receptors, LPA 1 (5), LPA 2 (6), and LPA 3 (7), that mediate the growth factor-like activity of LPA in a large variety of cell types in culture, including cancer cells (8). Interestingly, mRNA levels for LPA receptors are up-regulated in various cancers (9-11). Yet, the clinical significance of such observations remains to be determined. Using both genetic and pharmacological approaches in vitro and in vivo, we demonstrate here that inhibition of LPA action on its receptor LPA 1 is a promising therapeutic target in cancer, especially for metastasis to bone.

Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice

“…Most of the studies on the mechanisms of LPA in ovarian cancer have been conducted in vitro. Only recently, animal studies showing a role for LPA and/or its receptors in the development of cancers in vivo have been published (5)(6)(7)(8)(9). We have recently provided the first direct evidence that LPA stimulates tumor metastasis in vivo, which is inhibited by LY294002, a phosphatidylinositol 3-kinase inhibitor, and by 17-dimethylaminoethylamino-17-demethoxygeldanamycin, an inhibitor of the heat shock protein 90, which stabilizes hypoxia-inducible factor-1α (10,11).…”

GPCRs and cancer

“…Aberrant expressions and mutations of LPA receptors have been found in several types of tumors, suggesting their involvement in the growth advantage of cancer cells [3,14,15] . For instance, LPA1 was inversely correlated in breast cancer tissues with the Nm23 metastases regulator [16] and contributed to bone metastasis in breast cancer xenografts [17] . Furthermore, LPA induced migration in breast cancer cells by activating LPA1, which promoted the phosphorylation of nonmuscle myosin II (NM II) light chain through the activation of ROCK and RhoA activity [18] .…”

Lysophosphatidic acid impairs glucose homeostasis and inhibits insulin secretion in high-fat diet obese mice

“…The available pharmacological tools targeting ATX/LPA signalling are still scarce [7][8][9]. Ki16425 [10] is a mixed LPA receptor antagonist that exhibits close and preferential affinity for the LPA1R and LPA3R subtypes (250 and 360 nmol/l, respectively) [8,10] and its in vivo antagonist efficiency has been documented [11][12][13].…”