Ovarian cancer-derived lysophosphatidic acid stimulates secretion of VEGF and stromal cell-derived factor-1α from human mesenchymal stem cells

Abstract

Lysophosphatidic acid (LPA) stimulates growth and invasion of ovarian cancer cells and tumor angiogenesis. Cancer-derived LPA induces differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) to α-smooth muscle actin (α-SMA)-positive cancer-associated fibroblasts. Presently, we explored whether cancer-derived LPA regulates secretion of pro-angiogenic factors from hASCs. Conditioned medium (CM) from the OVCAR-3 and SKOV3 ovarian cancer cell lines stimulated secretion angiogenic factors such as stromal-derived factor-1α (SDF-1α) and VEGF from hASCs. Pretreatment with the LPA receptor inhibitor Ki16425 or short hairpin RNA lentiviral silencing of the LPA1 receptor abrogated the cancer CM-stimulated expression of α-SMA, SDF-1, and VEGF from hASCs. LPA induced expression of myocardin and myocardin-related transcription factor-A, transcription factors involved in smooth muscle differentiation, in hASCs. siRNA-mediated depletion of endogenous myocardin and MRTF-A abrogated the expression of α-SMA, but not SDF-1 and VEGF. LPA activated RhoA in hASCs and pretreatment with the Rho kinase inhibitor Y27632 completely abrogated the LPA-induced expression of α-SMA, SDF-1, and VEGF in hASCs. Moreover, LPA-induced α-SMA expression was abrogated by treatment with the ERK inhibitor U0126 or the phosphoinositide-3-kinase inhibitor LY294002, but not the PLC inhibitor U73122. LPA-induced VEGF secretion was inhibited by LY294002, whereas LPA-induced SDF-1 secretion was markedly attenuated by U0126, U73122, and LY294002. These results suggest that cancer-secreted LPA induces differentiation of hASCs to cancer-associated fibroblasts through multiple signaling pathways involving Rho kinase, ERK, PLC, and phosphoinositide-3-kinase.

TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms

“…4E). LPA has been reported to induce expression of total MKL1 in hASCs (Jeon et al, 2010;Jeon et al, 2008a), but in our experiments using 5 mM LPA we neither observed an upregulation of total MKL1 transcript levels compared to control cells, nor of one of the MKL1 isoforms alone (Fig. 4F).…”

“…In contrast to bone marrow, adipose tissue constitutes an easily accessible source for large numbers of patient-derived MSCs, which have an enormous potential for future applications in tissue regeneration (Zuk, 2010). Importantly, hASCs have been shown to differentiate into myofibroblasts and CAFs under the influence of tumor-secreted factors, such as TGF-b, and to promote the in vitro invasiveness of breast cancer cells (Jeon et al, 2010;Jotzu et al, 2011;Kakudo et al, 2012). We found that MKL1_S, but not MKL1_L, was strongly upregulated in primary hASCs within 24 h of TGF-b-induced myofibroblast differentiation.…”

Autotaxin – A Target for the Treatment of Drug-Resistant Ovarian Cancer?

“…Finally, iPLA2, one of the enzymes involved in the synthesis of LPA, can promote cell cycle progression in the absence of exogenous growth factors (Song et al 2007). LPA induces the production of the major angiogenic factor VEGF by ovarian cancer cells (Hu et al 2001) and mesenchymal stem cells (Jeon et al 2010). LPA also increases VEGF receptor expression on endothelial cells.…”

“…The effect of LPA is apparently amplified by VEGF-induced expression of autotaxin by ovarian cancer cells (Ptaszynska et al 2008) and endothelial cells (Ptaszynska et al 2010) thereby potentiating LPA production. LPA also promotes the expression of other pro-angiogenic factors including IL-8 by tumor cells and SDF-1 by mesenchymal stem cells (Jeon et al 2010). These observations suggest a key role for autotaxin and LPA in ovarian cancer driven angiogenesis and have led to the suggestion that autotaxin may also be a therapeutic target for inhibiting angiogenesis (Ptaszynska et al 2010).…”

CARMA3: A novel scaffold protein in regulation of NF-κB activation and diseases

“…In addition, LPA stimulates secretion of VEGF [71] and promotes ovarian cancer angiogenesis, migration, and invasion [72] . Furthermore, LPA enhances secretion of IL-6, a pleiotropic cytokine that is involved in ovarian carcinogenesis via the Gi/PI3K/AKT/NF-κB pathway [64] .…”