Coming of Age for Autotaxin and Lysophosphatidate Signaling: Clinical Applications for Preventing, Detecting and Targeting Tumor-Promoting Inflammation

Abstract

A quarter-century after the discovery of autotaxin in cell culture, the autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of the literature on this axis has been published during the last five years. In cancer biology, LPA signaling is increasingly being recognized as a central mediator of the progression of chronic inflammation in the establishment of a tumor microenvironment which promotes cancer growth, immune evasion, metastasis, and treatment resistance. In this review, we will summarize recent advances made in understanding LPA signaling with respect to chronic inflammation and cancer. We will also provide perspectives on the applications of inhibitors of LPA signaling in preventing cancer initiation, as adjuncts extending the efficacy of current cancer treatments by blocking inflammation caused by either the cancer or the cancer therapy itself, and by disruption of the tumor microenvironment. Overall, LPA, a simple molecule that mediates a plethora of biological effects, can be targeted at its levels of production by autotaxin, LPA receptors or through LPA degradation by lipid phosphate phosphatases. Drugs for these applications will soon be entering clinical practice.

Keywords: adjuvant therapy; chemoresistance; chronic inflammation; fibrosis; hallmarks of cancer; lipid phosphate phosphatases; lysophosphatidic acid; metastasis; radiotherapy.

Figure 1

General overview of cancer initiation and the role of autotaxin/lysophosphatidate (ATX/LPA). A convergence of extrinsic and intrinsic pathways leads to sustained inflammatory and survival signaling that involves upregulation of ATX/LPA signaling through both increases in ATX and LPA concentrations with concurrent decreases in eco-lipid phosphate phosphatase (LPP) activity. The establishment of this vicious cycle leads to cancer initiation and progression as often described by the hallmarks of cancer (sustained proliferative signaling, evasion of growth suppressors, replicative immortality, angiogenesis, resistance to cell death, deregulation of cellular genetics, avoidance of the immune system, and invasion and metastasis) [3,6,7].

Figure 2

Overview of the LPA signaling axis. Extracellular LPA is produced from LPC by the lysophospholipase D activity of ATX. LPA then signals through at least six known G-protein coupled LPA receptors to mediate its host of physiological and pathological effects. LPA is rapidly turned over by the eco-activity of LPP1-3 into inorganic phosphate and monoacylglycerol (MAG), which apart from 2-arachidonoylglycerol, does not affect signaling.

Figure 3

Overview of γ-radiation-induced inflammation in adipose tissue. γ-radiation, upon inducing double strand DNA breaks, activates the proteins ATM, ATR, and PARP-1. These in turn activate NFκB, facilitating the expression of COX-2, ATX, LPA_1–2 and numerous inflammatory mediators, which in concert lead to repair and survival of tissues.