Studies show that LPAR1 enhances metastasis and tumor motility [18]. Aberrant LPAR1 expressions were observed in many cancer cell lines and primary tumors, including ovarian cancer [24], breast cancer [25], liver cancer [26], gastric cancer [27], pancreatic cancer [28,29], lung cancer [30,31], glioblastoma (GBM) [32,33,34], and osteosarcoma [35]. Ovarian cancer is the most investigated cancer in studying the malignancy of LPA signaling. High LPAR1 expressions in ovarian serous cystadenocarcinoma correlate with high proliferation, invasion, migration, and poorer prognosis than those with low expressions [36]. LPAR1 also promotes the development of intratumoral heterogeneity by regulating PI3K/AKT signaling [36]. Retaining the stemness phenotype of ovarian cancer, an autocrine loop via the ATX-LPA-LPAR1-AKT1 signaling axis is critical [37]. In breast cancer, overexpression of LPAR1 in MCF-10A mammary epithelial cells causes cells to acquire an invasive phenotype [38], which correlates with the heparin-binding EGF-like growth factor [39] and mediate basal breast metastasis through LPAR1-PI3K-ZEB1-miR-21 pathways [25]. For hepatocellular carcinoma, LPA-LPAR1 enhances cancer invasion via inducing MMP-9 expression through coordinate activation of PI3K and p38 MAPK signaling cascade [26]. Similarly, increased cancer cell invasiveness mediated by LPAR1 was found in pancreatic cancer [28,29]. For lung A549 cancer cells, the LPAR1/Gi/MAP kinase/NF-κB pathway is involved in LPA-induced oncogenesis, and using the LPAR1/3 antagonist Ki16425 to block LPAR1-mediated signaling would significantly reduce tumor volume [31]. In GBM, LPAR1 expression is also significantly higher than other gliomas [32]. Of interest, the LPA pathway of microglia-and-GBM interaction is a target to improve survival because microglia-derived LPA and ATX upon hypoxia stress may promote GBM proliferation and migration [32]. A recent report indicates LPAR1/PKCα/progesterone receptor pathway is involved in GBM migration [40]. In prostate PC-3 cancer cells, hyperglycemia triggers enhanced vascular endothelial growth factor-C (VEGF-C) expression via the LPAR1/3-Akt-ROS-LEDGF signaling [40]. The LPA-mediated VEGF-C expression can be modified by calreticulin, a multifunctional chaperon protein. In addition, pharmacological LPAR1 receptor antagonism may significantly reduce tumoral lymphatic vessel density and nodal metastasis in tumor-bearing nude mice, suggesting the key role of LPAR1 in prostate cancer lymphatic metastasis [41].

LPAR2 activation has been shown to associate with cell survival because of its anti-apoptosis function. For ovarian cancer, tumors with overexpression of LPAR2 were associated with poorer survivals compared with controls [42]. Furthermore, LPAR2 signaling promotes invasion and metastasis through the production of VEGF [43], EGFR [44], interleukin-8 [45], and urokinase plasminogen activation [46], implying the multiple hyper-vascularization processes. LPAR2-Gi-Src-EGFR-ERK signaling cascade may mediate cell movement and LPA-stimulated COX-2 expression [47]. Together with LPAR1, LPAR2 regulates phosphorylation of ezrin/radixin/moesin (ERM) proteins, known as membrane-cytoskeleton linkers, and leads to promotion of ovarian OVCAR-3 cancer cell migration through cytoskeletal reorganization and formation of membrane protrusions [48]. The metastatic activity of gastric SGC-7901 cells was enhanced as well through LPA-LPAR2-Notch pathway activation [27]. LPAR2 is the major LPAR in colon cancer, and most of the cellular signals by LPAR2 were primarily mediated through interaction with scaffold proteins Na⁺/H⁺ exchanger regulatory factor 2 (NHERF2) [49]. In another two reports, LPA-LPAR2 may facilitate colon cancer proliferation via transcription factor Kruppel-like factor 5 (KLF5) and hypoxia-inducible factor 1α (HIF-1α) activations. The LPAR2 associated HIF-1α expression also promoted breast cancer proliferation/migration and conferred poor prognosis in the Chinese population [50]. Regarding the link between chronic inflammation and cancer, Lin et al. found genetic LPAR2 depletion may attenuate colon cancer development in a colitis mice model triggered by azoxymethane and dextran sulfate sodium [51]. Noteworthy, LPAR2 activation may exert anti-migration effects by blocking EGF-induced migration and invasion of pancreatic Panc-1 cancer cells through the G_12/13/Rho signaling pathway [52]. G_i2 protein is also involved in enhanced ovarian cancer invasion and migration via the HIF1α-LPA-LPAR2 axis [24]. The distinct structure of LPAR2 from other LPARs is its carboxyl-terminal tail contains a zinc finger-binding motif to interact with TRIP6 and pro-apoptotic Siva-1. TRIP6 has a PSD95/Dlg/ZO-1 (PDZ)-binding motif to interact with scaffold proteins, particularly NHERF2 [53]. Siva-1 is an early response gene activated by DNA damage that promotes apoptosis through binding up the antiapoptotic Bxl-XL protein. Moreover, Siva-1 acts with p53 and the ubiquitin ligase Mdm2 in the nucleus complexes, and the polyubiquitinated complex would be degraded once the LPA-LPAR2 axis is activated. The functional significance of the LPAR2-activated assembly leads to up-regulation of ERK1/2, PI3K-Akt, and NFκB prosurvival pathways and the subsequent inhibition of apoptosis [54]. LPAR2 can protect cancer cells against apoptotic stress after irradiation and chemotherapy by augmenting DNA damage repair response and inhibiting the mitochondrial apoptosis cascade [55].

LPAR3 is the predominant receptor subtype in colon, liver, and lung cancers. LPAR3-expressing cells significantly promote motility and invasiveness through Ras-, Rac-, Rho-, and PI3K-signaling pathways [20]. In hepatocellular carcinoma, Zuckerman et al. reported distinct LPAR3 expressions within the tumor and normal tissues, and LPAR3 may enhance liver cancer migration via the LPAR3-Gi-ERK/MAPK pathway [56]. Okabe et al. found LPAR3 contributes to hepatocellular carcinoma proliferation and invasion via the β-catenin pathway in rat hepatic RH7777 cancer cells. They also demonstrated that tumor cells with high LPAR3 expression were resistant to cisplatin and doxorubicin through multidrug-resistance-related up-regulation of genes [20]. In melanoma, LPAR3 is essential to promote viability and proliferation, and the Src homology 3 domain is required for LPAR3 to mediate viability in melanoma SK-MEL-2 cells [57,58]. In ovarian cancer, LPAR3 promotes cell expansion and invasion in SKOV-3 cells, and tumors with overexpression of LPAR3 were associated with poor survival [42]. Besides G_q and G_i proteins, LPAR3 can also activate G_12/13, increase dephosphorylation and nuclear translocation of YAP, and induce migration of ovarian cancer cells [59]. In addition, the LPA/LPAR3 signaling may initiate mutation-independent epithelial-to-mesenchymal transition (EMT) through β1-integrin-dependent activation of Wnt/β-catenin signaling [60]. Pharmacological suppression of LPAR3 would suppress motility and invasion in various cancers, including hamster pancreatic cancer cells [61], human triple-negative breast cancers [62], fibrosarcoma HT1080 cells, and osteosarcoma HOS cells [63]. Direct targeting of LPAR3 by miR-15b has been shown to repress cell proliferation and drive the senescence and apoptosis of ovarian cancer cells through the PI3K/Akt pathway [64], suggesting the potential mRNA treatment against LPAR3.

In contrast to LPAR1–3, LPAR4 and LPAR5 negatively affected cancer cell proliferation and motility [65]. LPAR4 attenuates tumor motility and colony formation in colon cancer cell lines. Knockdown of LPAR4 in the long-term 5FU treated DLD1 cells increased cell motility [66,67]. Similarly, LPAR4 depletion increases tumor motility in pancreatic cancer cells [65] and increases tumor proliferation in head and neck carcinoma [68]. Another recent study by Eino et al. found that LPAR4 is critical for developing a fine capillary network in brain tumors [69]. LPAR4 promotes endothelial cell-cell adhesion and VCAM-1 expression via RhoA/ROCK signaling, enhancing anti-PD1 therapy efficacy and lymphocyte infiltration [69]. However, a contradictory pro-tumorigenesis was found in fibrosarcoma. In HT1080 cells, LPAR4 promotes cell invasion and invadopodium formation via cAMP/EPAC/Rac1 signaling [70]. Of interest, LPAR4/6 is necessary for embryogenic angiogenesis to activate YAP and transcriptional coactivator TAZ via the G₁₂/G₁₃ signaling pathway [71]. In the malignancies, YAP promotes cancer proliferation and migration in bladder cancers through YAP-Mask2 [72] and lung cancers through LKB1-YAP-human telomerase RAN (hTERC), respectively [73]. These suggested the involvement of LPAR4 in YAP-mediated cancer progression.

LPAR5 was considered a negative regulator in cancer cell motility and survival [69]. The inhibitory effect of LPAR5 on cell motility has been shown in pancreatic cancer [69] and sarcoma [74]. Nevertheless, contradictory effects of LPAR5 were found in different cancers. Okabe et al. reported upregulation of the LPAR5 gene with aberrant unmethylated status enhanced cell proliferation and motility in rat liver-derived hepatoma RH7777 and lung-derived adenocarcinoma RLCNR cells [75]. Blocking LPAR5 in thyroid cancer with a selective LPA5 antagonist TCLPA5 attenuated cancer proliferation and migration via PI3K/Akt signaling in vivo and in vitro [76]. Moreover, depletion of LPAR5 in murine B16-F10 melanoma resulted in fewer lung metastasis [77]. Interestingly, LPAR5 appears to mediate chemorepulsion in response to LPA. The underlying mechanism was proposed to be mediated via a non-canonical elevation of cAMP along with reduced PIP3 signaling in melanoma B16 cells [78]. LPAR5 expression is markedly increased in long-term cisplatin-treated melanoma cells [8]. Therefore, LPAR5 knockdown significantly conferred chemo-resistance and enhanced cancer cell survival [8]. In addition to the cancer cell growth and metastasis, LPAR5 was shown to suppress the function of CD8-positive cytotoxic T cells by inhibiting intracellular Ca²⁺ mobilization and ERK activation, suggesting LPAR5 might act as a mediator of immune suppression [79].

Reports regarding LPAR6 in cancer are relatively limited compared with other LPARs [2]. Several articles investigated the role of LPAR6 in liver, pancreatic, and colon cancers. LPAR6 expression in hepatocellular carcinoma correlated with poorer survival [80] and increased microvascular invasion [81]. Moreover, LPAR6 promotes hepatocellular carcinoma proliferation via the NCOA3-LPAR6-HGF signaling cascade, and the tumor-suppressive effect by depletion of LPAR6 is similar to that of anti-HGF treatment [82]. In pancreatic cancer, LPAR6 knockdown also inhibited cancer invasion and colony formation [67]. However, LPAR6 can, by contrast, be a negative regulator in different cancers. LPAR6 knockdown caused larger colonies [83] and enhanced motility in colon DLD1 and HCT116 cancer cells [67]. The role of LPAR6 in various cancer types should be further characterized in the future.

In conclusion, it deserves our attention that multiple therapeutic agents undergo clinical trials or preclinical evaluation for various diseases via inhibition of LPA signaling. Their safety is generally acceptable, and the LPAR antagonists are potentially effective and novel for improving pain and current cancer therapies. In general, being inflammatory mediators, LPA signaling inhibitors could be potential therapeutic modalities for chemoprevention, enhancing the efficacy of chemotherapy and radiotherapy and improving prognosis.