br Role of LPA in tumor angiogenesis

Role of LPA in tumor angiogenesis and skeletal metastasis The angiogenesis switch is essential for tumor expansion and escape of tumor Vicriviroc maleate from the primary site and forming distant metastases. Evidence for the role of LPA2 and LPA3 in the mobility of endothelial cells and the formation of neo-vessels have been demonstrated [30]. VEGF is one of the most important angiogenic factor produced by cancer cells [31]. LPA stimulates VEGF production by ovarian cancer cells via LPA2 and LPA3 activations [24], [32]. Based on quantitative PCR analyses, correlation of expression between VEGF, LPA2 and LPA3 was confirmed on a clinical level on human ovarian biopsies [33]. Renal carcinomas are among the most vascularized tumors. Ki16425 treatment dampened renal cell carcinoma (RCC) tumorigenesis in vivo and decreased the number of CD34 positive vessels in tumor xenografts suggesting that LPA1–3 signaling controls RCC angiogenesis [34]. LPA1 and LPA2 are also associated with the production of pro-angiogenic factors in colon cancer cells [15]. However, such findings might not be extended to all types of cancers as highlighted by breast cancer cells that are known to express high amounts of VEGF [35], we found that LPA was not able to further increase the secretion of VEGF from a series of breast cancer cell lines [36]. This observation might explain why Debio0719, which is the R-racemic and active form of Ki16425 [23], while inhibiting breast cancer metastasis to the lungs and bone has no effect on breast cancer cell proliferation and angiogenesis in vivo, and as a consequence does not alter the growth of breast primary tumors [23]. Bone is a frequent metastatic site for breast cancers. We showed that LPA and ATX are not involved in the bone tropism of breast cancer cells but we demonstrated that increased LPA production in the bone environment, at least as a consequence of ATX expression by tumor cells, increased the extent of osteolytic lesions by acting directly on tumor cell proliferation and on bone cell differentiation and indirectly on bone resorption [37], [38]. Compiling recent works indicates that LPA exhibits pleiotropic activity in the context of bone metastasis [39].
Role of LPA in the resistance to anti-cancer therapies Cancer cells frequently develop strategies to escape or resist drug treatments. Such drug resistance mechanisms involve decrease in molecule absorption, increase drug efflux, activation of detoxification systems and resistance to apoptosis [40]. LPA might also favor the establishment of cancer drug resistance through potential involvement of different receptors. Ovarian cancer cells expressing high levels of LPA1 are more resistant to cisplatin-induced apoptosis than cells with low levels of this receptor [6]. Recently, Fukui and colleagues showed that exogenous expression of LPA3 in hepatocarcinoma and breast cancer cells favor cell survival under cisplatin and doxorubicine treatments [41]. The authors further showed that resistance to these drugs was associated with the activation of Mdr1a and Mdr1b genes controling the expression of the ABC transporter [41]. Blocking LPA1 and LPA3 in vivo using Ki16425 also prevent and delay the resistance of renal carcinoma cells to the tyrosine kinase inhibitor sunitinib [34]. Altogether these data suggest a prevalent role individually or in combination of LPA1 and LPA3 in multi-drug resistance mechanisms. Recent works showed that a specific agonist of LPA2 is able to reduce the mortality of γ-irradiated mice [42]. This radiomitigative effect involved the decrease of caspase activation, DNA fragmentation, PARP-1 cleavage, inhibition of Bax, translocation and cytochrome c release, and activation of ERK1/2, and Akt [42]. These data indicate that LPA2 has a pro-survival activity in cells submitted to γ-irradiation. Conversely, it can be hypothesized that blocking LPA2 might be a useful strategy for sensitizing cancer cells to radiotherapies, although this assumption requires further investigation.