Abstract
Autotaxin (ATX) is a secreted enzyme that produces lysophosphatidate (LPA), which signals through six G-protein coupled receptors, promoting tumor growth, metastasis, and survival from chemotherapy and radiotherapy. Many cancer cells produce ATX, but breast cancer cells express little ATX. In breast tumors, ATX is produced by tumor-associated stroma. Breast tumors are also surrounded by adipose tissue, which is a major bodily source of ATX. In mice, a high-fat diet increases adipocyte ATX production. ATX production in obesity is also increased because of low-level inflammation in the expanded adipose tissue. This increased ATX secretion and consequent LPA signaling is associated with decreased adiponectin production, which results in adverse metabolic profiles and glucose homeostasis. Increased ATX production by inflamed adipose tissue may explain the obesity-breast cancer association. Breast tumors produce inflammatory mediators that stimulate ATX transcription in tumor-adjacent adipose tissue. This drives a feedforward inflammatory cycle since increased LPA signaling increases production of more inflammatory mediators and cyclooxygenase-2. Inhibiting ATX activity, which has implications in breast cancer adjuvant treatments, attenuates this cycle. Targeting ATX activity and LPA signaling may potentially increase chemotherapy and radiotherapy efficacy, and decrease radiation-induced fibrosis morbidity independently of breast cancer type because most ATX is not derived from breast cancer cells.
Highlights
ATX acts as the “gatekeeper” to control LPA signaling through a family of six G protein-coupled receptors (Figure 1)
The negative regulation of ATX transcription by LPA and S1P is overcome by the effects of inflammatory cytokines and chemokines, which increase ATX production and secretion [23]
It was concluded that ATX-LPA signaling proteins are highly expressed in breast tumors with adipose tissue-rich stroma and this is associated with macrophage infiltration and poorer patient outcomes [96]
Summary
Autotaxin (ATX) belongs to a family of ectonucleotide pyrophosphatase/phosphodiesterases (ENPPs) and its gene name is ENPP2 [1]. ATX acts as the “gatekeeper” to control LPA signaling through a family of six G protein-coupled receptors (Figure 1). The negative regulation of ATX transcription by LPA and S1P is overcome by the effects of inflammatory cytokines and chemokines, which increase ATX production and secretion [23] This explains why there is increased expression of ATX together with high LPA concentrations in inflammatory diseases including cancers. ATX secretion and the production of LPA1 receptors and by increasing the expression of LPP1 [28]. LPA signaling is generally increased in cancers because of the high secretion of ATX and the low expressions of LPP1 and LPP3 [51]. Antagonizing the actions of the LPA5 receptor has been proposed as an essential target for the immunological control of cancer progression [60]
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