Lipid phosphate phosphatases (LPPs) are a group of enzymes that belong to a phosphatase/phosphotransferase family. Mammalian LPPs consist of three isoforms: LPP1, LPP2 and LPP3. They share highly conserved catalytic domains and catalyze the dephosphorylation of a variety of lipid phosphates, including phosphatidate, lysophosphatidate, sphingosine 1-phosphate, ceramide 1-phosphate and diacylglycerol pyrophosphate. LPPs are integral membrane proteins, which are localized on plasma membranes with the active site on the outer leaflet. This enables the LPPs to degrade extracellular lysophosphatidate and sphingosine 1-phosphate thereby attenuating their effects on the activation of surface receptors. LPP3 also exhibits non-catalytic effects at the cell surface. LPP expression on internal membranes such as endoplasmic reticulum and Golgi facilitates the metabolism of internal lipid phosphates, presumably on the luminal surface of these organelles. This action probably explains the signaling effects of the LPPs, which occur downstream of receptor activation. The three isoforms of LPPs show distinct and non-redundant effects in several physiological and pathological processes including embryo development, vascular function and tumor progression. This review is intended to present an up-to-date understanding of the physiological and pathological consequences of changing the activities of the different LPPs, especially in relation to cell signaling by lysophosphatidate and sphingosine 1-phosphate.

Signet ring cell adenocarcinomas (SRCCs) are a rare histological subtype of adenocarcinomas with a poor prognosis, typically due to advanced disease at diagnosis. A signet ring cell, mimicking its moniker, contains abundant intracytoplasmic mucin that pushes the nucleus to the periphery. In these cancers, this cell feature comprises more than 50% of the tumor. Despite predilection for the gastrointestinal tract, and in particular the stomach, primary SRCCs are also described in other sites, typically in case reports. This literature, however, lacks a standardized overview of the SRCC disease entity. Using a retrospective cohort approach, we summarize the clinicodemographic and mortality outcomes of SRCCs in thirteen primary sites, comprising 95% of all SRCCs in the Surveillance, Epidemiology, and End Results Program (SEER), a population-level cancer database covering nearly one-third of the United States population. SRCCs general trends compared to matching nonvariant adenocarcinomas are earlier age of onset, with initial presentation favoring higher rates of regional or distant disease presentation and poor tumor differentiation. After multivariable analysis, SRCCs typically have worse overall survivals, but substantial variances exist depending on tumor location. Identifying SRCCs at earlier disease stages is likely the single most important intervention to improving outcomes for these patients.

Tamoxifen is the accepted therapy for patients with estrogen receptor-α (ERα)-positive breast cancer. However, clinical resistance to tamoxifen, as demonstrated by recurrence or progression on therapy, is frequent and precedes death from metastases. To improve breast cancer treatment it is vital to understand the mechanisms that result in tamoxifen resistance. This study shows that concentrations of tamoxifen and its metabolites, which accumulate in tumors of patients, killed both ERα-positive and ERα-negative breast cancer cells. This depended on oxidative damage and anti-oxidants rescued the cancer cells from tamoxifen-induced apoptosis. Breast cancer cells responded to tamoxifen-induced oxidation by increasing Nrf2 expression and subsequent activation of the anti-oxidant response element (ARE). This increased the transcription of anti-oxidant genes and multidrug resistance transporters. As a result, breast cancer cells are able to destroy or export toxic oxidation products leading to increased survival from tamoxifen-induced oxidative damage. These responses in cancer cells also occur in breast tumors of tamoxifen-treated mice. Additionally, high levels of expression of Nrf2, ABCC1, ABCC3 plus NAD(P)H dehydrogenase quinone-1 in breast tumors of patients at the time of diagnosis were prognostic of poor survival after tamoxifen therapy. Therefore, overcoming tamoxifen-induced activation of the ARE could increase the efficacy of tamoxifen in treating breast cancer.

Autotaxin is a secreted enzyme, which produces extracellular lysophosphatidate from lysophosphatidylcholine. Lysophosphatidate activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. Autotaxin is also involved in wound healing, inflammation and in tumor growth, metastasis and chemo-resistance. It is, therefore, important to understand how autotaxin is regulated. It was proposed that autotaxin activity is inhibited by its product lysophosphatidate, or a related lipid called sphingosine-1-phosphate. We now show that this apparent inhibition is ineffective at high concentrations of lysophosphatidylcholine that occur in vivo. Instead, feedback regulation by lysophosphatidate and sphingosine-1-phosphate is mediated by inhibition of autotaxin expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting autotaxin activity in mice with ONO-8430506 severely decreased plasma lysophosphatidate concentrations and increased autotaxin mRNA in adipose tissue, which is a major site of autotaxin production. Consequently, the amount of inhibitor-bound autotaxin protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of lysophosphatidate in the circulation decreases autotaxin production. However, this feedback regulation can be overcome by the inflammatory cytokines, TNF-α or IL-1β. This enables high lysophosphatidate and autotaxin levels to co-exist in inflammatory conditions. The results are discussed in terms autotaxin regulation in wound healing and cancer.

Autotaxin is a secreted enzyme that produces most extracellular lysophosphatidate, which stimulates 6 G‐protein‐coupled receptors. Lysophosphatidate promotes cancer cell survival, growth, migration, invasion, metastasis, and resistance to chemotherapy and radiotherapy. The present work investigated whether inhibiting autotaxin could decrease breast tumor growth and metastasis. We used a new autotaxin inhibitor (ONO‐8430506; IC ₉₀ =100 nM), which decreased plasma autotaxin activity by >60% and concentrations of unsaturated lysophosphatidates by >75% for 24 h compared with vehicle‐treated mice. The effects of ONO‐8430506 on tumor growth were determined in a syngeneic orthotopic mouse model of breast cancer following injection of 20,000 BALB/c mouse 4T1 or 4T1‐12B cancer cells. We show for the first time that inhibiting autotaxin decreases initial tumor growth and subsequent lung metastatic nodules both by 60% compared with vehicle‐treated mice. Significantly, 4T1 cells express negligible autotaxin compared with the mammary fat pad. Autotaxin activity in the fat pad of nontreated mice was increased 2‐fold by tumor growth. Our results emphasize the importance of tumor interaction with its environment and the role of autotaxin in promoting breast cancer growth and metastasis. We also established that autotaxin inhibition could provide a novel therapeutic approach to blocking the adverse effects of lysophosphatidate in cancer.—Benesch, M. G. K., Tang, X., Maeda, T., Ohhata, A., Zhao, Y. Y., Kok, B. P. C., Dewald, J., Hitt, M., Curtis, J. M., McMullen, T. P. W., Brindley, D. N. Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice. FASEB J . 28, 2655–2666 (2014). www.fasebj.org