The insufficient oxygen supply from arterial blood leads to tissue hypoxia. Hypoxia is a common feature of solid tumors and results from structural abnormalities of microvascular construction [1]. While normal end capillary oxygen pressure is approximately 5% (intermediate hypoxia), the oxygen pressure reduces to 1% or below (severe hypoxia) in solid tumors [2], [3]. Hypoxia induces genetic alterations, such as gene amplification, mutation, chromosomal rearrangement. Moreover, tumor hypoxia promotes malignant progression, including cell growth, invasion, angiogenesis, metastasis and resistance to chemotherapy and radiation therapy [4], [5], [6], [7].

Lysophosphatidic acid (LPA) is a simple phospholipid which is structured by a glycerol, a phosphate and a fatty acid [8], [9], [10]. LPA is endogenously produced from lysophosphatidylcholine (LPC) by a plasma enzyme, autotaxin (ATX) [11]. LPA binds to its specific G protein-coupled LPA receptors (LPA1 to LPA6) and exhibits a variety of cellular processes [8], [9], [10]. It is considered that LPA receptor-mediated signaling plays an important role in the pathogenesis of some human diseases, including cancer. Moreover, LPA receptors enhances or suppresses tumor progression, depending on the cancer cell type [12]. In recent studies, LPA receptor-mediated signaling contributes to the modulation of anticancer drug resistance in cancer cells. For instance, LPA2 elevates the cell survival of lung cancer cells treated with cisplatin (CDDP) [13]. Conversely, the cell survival to CDDP and dacarbazine is reduced through the activation of LPA5 in melanoma cells [14].

Pancreatic cancer is histologically characterized by remarkable desmoplastic tissue composed of several stromal cells as well as abundant extracellular matrix. Abnormal vascular structures lead to hypoxia and nutrient depletion within the tumor microenvironment of pancreatic cancer tissues [15], [16], [17]. Hypoxia promotes endothelial cell proliferation through the activation of multiple pro-angiogenic pathways [18]. In the present study, we investigated the roles of LPA receptor-mediated signaling in cellular functions modulated by endothelial (F2) cells in pancreatic cancer PANC-1 cells under hypoxic conditions.