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

Abstract

We have already established human xenographic models for the effect of lysophosphatidic acid (LPA) on tumor metastasis in vivo. The purpose of this work is to establish a preclinical LPA effect model in immunocompetent mice. We first characterized the mouse epithelial ovarian cancer (EOC) cell line ID8 for its responsiveness to LPA in cell proliferation, migration, and invasion and compared these properties with those of human EOC. The signaling pathways related to cell migration were further investigated using pharmacologic and genetic approaches. The effects of LPA on the tumorigenesis of ID8 cells and mouse survival were then examined using two different mouse models (i.p. and orthotopic injections). LPA stimulated cell proliferation, migration, and invasion of mouse EOC ID8 cells in a manner closely resembling its activity in human EOC cells. The signaling pathways involved in LPAinduced cell migration in ID8 cells were also similar to those identified in human EOC cells. We have identified cyclooxygenase-1 and 15-lipoxygenase as two new signaling molecules involved in LPA-induced cell migration in both human and mouse EOC cells. In addition, LPA enhanced the tumorigenesis/metastasis of ID8 cell in vivo as assessed by increased tumor size, early onset of ascites formation, and reduced animal survival. We have established the first LPA-EOC preclinical model in immunocompetent mice. Because ID8 cells respond to LPA similar to human EOC cells, this model is very valuable in developing and testing therapeutic reagents targeting LPA in

Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer

“…LPA, a proinflammatory lysophospholipid, is implicated in the etiology of a number of human cancers, including ovarian cancer (14). LPA has been reported to enhance tumor growth of ID8 cells and ascites formation in female C57BL/6 mice (20). We demonstrated that apoA-I and apoA-I mimetic peptides bind LPA, but the apoA-I mimetic peptides bind LPA with an affinity that is six orders of magnitude greater than apoA-I.…”

“…LPA has been identified as an important mediator of tumor development, progression, and metastases in humans (18,19). Li et al recently demonstrated that LPA stimulates cell migration, invasion, and colony formation, as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice (20). We have previously demonstrated that apoA-I and apoA-I mimetic peptides bind lipids with high affinity, and apoA-I mimetic peptides are several to four to six orders of magnitude better than apoA-I in binding oxidized lipids (26).We first examined whether apoA-I and L-4F can bind LPA using surface plasmon resonance, as described previously (26).…”

“…Several reports identified altered fatty acid composition of lysophosphatidyl choline and elevated LPA levels in the ascites and malignant effusions of ovarian cancer patients (18,19). LPA induces migration and invasion in both mouse and human epithelial ovarian cancer cells (20). Recent studies demonstrate that the mouse epithelial cancer cell line named ID8 is an ideal model system to test the effects of LPA and therapeutic agents of ovarian cancer in immunocompetent mouse models (21,22).…”

GPCRs and cancer

“…Closely resembling the LPAeffects in human ovarian cancer cells, LPA induced metastasis of epithelial ovarian cancer in immuno-competent mice [23] .…”

Apolipoprotein A-I: A Molecule of Diverse Function

“…Pro-inflammatory and pro-angiogenic lysophospholipids such as lysophosphatidic acid (LPA) have been repeatedly shown to be associated with tumor progression and poor prognosis, and are normally cleared from the serum by apo A-I, which is downregulated in ovarian, gastric and pancreatic cancer patients. Both apo A-I as well as apo A-I mimetic peptides have the ability to bind pro-inflammatory phospholipids like LPA [41], but the apo A-I mimetic peptides bind LPA with a greater affinity than apo A-I, causing their removal from serum and lowering their serum levels. Thus apo A-I controls the rate of cell proliferation in a tumor and the tumor growth [42].…”