A lipid mediated paracrine signaling network stimulates tumor associated macrophage development in cancer and metastasis

Abstract

Abstract Tumor microenvironment consist of dynamic interactions between tumor cells and the surrounding non-transformed cells. Inflammatory cells constitute a major population of the non-transformed cells. Tumor associated macrophages (TAMs), the predominant population of inflammatory cells have major roles in cancer progression and metastasis but the exact stimulus and triggers for the tumor cells-macrophage interaction remains unclear. Autotaxin or lysophospholipaseD (LysoPLD) catalyses the synthesis of lyophosphatidic acid - the smallest phospholipid from lysophosphatidylcholine by its enzymatic action. Autotaxin is implicated in breast cancer, ovarian cancer and many other cancers. Lysophosphatidic acid (LPA) is involved in numerous biological processes encompassing cell growth, cell proliferation, cell migration, cancer and metastasis. LPA effects are mediated on different cell types via its cognate G-protein coupled receptors (GPCRs) or non-receptor pathways. Our recent study has shown that LPA converts monocytes into macrophages both in mice and humans and has an important role to play with immune cells. Here, we show that cancer cells in tumor growth are associated with tumor associated macrophages via a signature paracrine link. Our studies identify previously unknown signaling link between tumor cells and macrophages. Furthermore, we identify that suppression of this paracrine network can suppress tumor growth. This study suggests that inhibition of this paracrine network may act as a new therapeutic approach to control cancer and metastasis