Lysophosphatidic Acid Induction of Vascular Endothelial Growth Factor Expression in Human Ovarian Cancer Cells

Abstract

LPA stimulates ovarian tumor growth, at least in part, via induction of VEGF expression through transcriptional activation. However, this LPA response is not evident in normal ovarian surface epithelial cells. Our data suggest that Edg4, but not Edg2, plays a role in LPA stimulation of ovarian tumor growth.

Origin of carcinoma associated fibroblasts

“…[115][116][117][118] The fibroblast response is hardwired in the genome as part of the cancer's resemblance to a chronic wound, aiming at support of epithelial cell survival and expansion. [119][120][121][122][123][124][125][126][127][128] In addition to parsimony, this hypothesis offers clear predictions to scientifically test against corresponding null hypotheses; (1) That co-culture of cancer cells with normal fibroblasts will induce expression of CAF-specific genes in the fibroblasts, [63][64][65][66][67][68][69][70][71] [63][64][65][66][67][68][69][70][71] Many of the genes shown to be activated in these co-cultures are known markers of CAFs in vivo, such as MMP1, MMP3, collagens, TNC, etc. Evidence that this reciprocal interaction promotes cancer includes the anti-cancer effect of Imatinib, on carcinoma animal models.…”

Induction of protein growth factor systems in the ovaries of transgenic mice overexpressing human type 2 lysophosphatidic acid G protein-coupled receptor (LPA2)

“…Most ovarian cancers express elevated levels of vascular endothelial growth factor (VEGF) mRNA, and the plasma concentration of VEGF is increased in many ovarian cancer patients (Fujimoto et al, 1998;Hazelton et al, 1999;Zebrowski et al, 1999;Hu et al, 2001). As VEGF has essential roles in ovarian tumorigenesis, angiogenesis and vascular permeability, we evaluated the expression of VEGF-A and VEGF-B mRNAs in our human LPA 2 TG mice by Taqman real-time RT-PCR.…”

“…The stimulation by LPA of prostate and ovarian cancer cell proliferation is mediated both directly through a ras-ERK signaling pathway and by enhanced release of several endogenous protein growth factors (GFs), including IGF-II and vascular endothelial growth factor (VEGF) (Goetzl et al, 1999;Hu et al, 2001). Such endogenous GFs mediate up to 80% of the stimulation of cellular proliferation by LPA (Goetzl et al, 1999).…”

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

“…We and others have shown that LPA stimulates the migration and invasion of ovarian cancer cells (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). Although most, if not all, of these studies were conducted in established ovarian cancer cell lines, we have recently conducted LPA-and S1P-induced cell migration and invasion experiments in primary EOC and nonmalignant human ovarian surface epithelial cells (11,23).…”