Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice

Benesch, Matthew G.K.; Tang, Xiaoyun; Maeda, Takeyasu; Ohhata, Akira; Zhao, Yuan; Kok, Beverley; Dewald, Jay; Hitt, Mary; Curtis, Jonathan M.; McMullen, Todd; Brindley, David N.

doi:10.1096/fj.13-248641

Cited by 100 publications

(177 citation statements)

References 61 publications

Supporting

Mentioning

162

Contrasting

Order By: Relevance

“…Following trypsinization and washing, cells were suspended in phenol red-free DMEM/ Matrigel (1:1, v/v). A syngeneic orthotopic mouse breast tumor model was established as before ( 13 ) were injected sub cutaneously into the fl ank. Expression of exogenous proteins was maintained by adding 2 mg/ml doxycycline to the drinking water.…”

Section: Mouse Tumor Modelsmentioning

confidence: 99%

“…Expression of exogenous proteins was maintained by adding 2 mg/ml doxycycline to the drinking water. Tumor growth was monitored as before ( 13 ). To establish a metastatic model, 4T1 cells (1.5 × 10 5 , in PBS) were injected into BALB/c mice through the tail vein.…”

Section: Mouse Tumor Modelsmentioning

confidence: 99%

“…S1P and LPA molecular species were measured in plasma and tumors by mass spectrometry ( 13 ). Phosphatidate and diacylglycerol were measured in cells after labeling for 2 h with 20 µCi of carrier-free [ …”

Section: Assays For Lpp1 Lpa Phosphatidate and Diacylglycerolmentioning

confidence: 99%

See 2 more Smart Citations

Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice

Tang

Benesch

Dewald

et al. 2014

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

The bioactive lipid lysophosphatidate (LPA) is produced mainly by the secreted enzyme autotaxin (ATX) ( 1-3 ). The ATX gene is among the 40 most upregulated genes in metastatic cancers ( 4 ). LPA signals through at least six G-proteincoupled receptors to increase cell division, survival, migration, and angiogenesis ( 1-3 ). Overexpression of ATX, LPA 1 , LPA 2 , or LPA 3 receptors in mammary cells causes spontaneous development of mammary tumors in mice ( 5 ). Women with breast carcinomas that express high levels of LPA 3 receptors in cancer epithelial cells, or ATX in stromal cells, have larger tumors, nodal involvement, and higher stage disease ( 6 ). LPA produces resistance to the cytotoxic effects of paclitaxel ( 2, 7-9 ), carboplatin ( 10 ), and radiation-induced cell death ( 2,11,12 ). Inhibiting ATX activity and lowering LPA concentrations in plasma and tumors decreases the initial phase of breast tumor growth and subsequent lung metastasis by ‫ف‬ 60% in a mouse model ( 13 ). These combined results provide strong evidence that increased LPA signaling in cancer cells promotes the growth and metastasis of breast tumors.The present studies focus on a different approach to attenuating LPA signaling. This involves increasing the expression of lipid phosphate phosphatase-1 (LPP1), which is a member of a family of three phosphatases that dephosphorylate bioactive lipid phosphates and pyrophosphates ( 14-16 ). Despite this broad specifi city for lipid phosphates that is observed with cell-free systems, changing the expression of the different LPPs in animal models produces different

show abstract

Section: Mouse Tumor Modelsmentioning

confidence: 99%

Section: Mouse Tumor Modelsmentioning

confidence: 99%

See 1 more Smart Citation

Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice

Tang

Benesch

Dewald

et al. 2014

Journal of Lipid Research

Self Cite

View full text Add to dashboard Cite

show abstract

“…This growth reduction is synergic with doxorubicin and the combined therapy decreases tumor growth by >70﹪ for about 17 days (Table 1). Subsequent lung and liver metastases were also reduced by about 50﹪-60﹪ with ATX inhibition [76,148] . In the same studies, we showed for first time that activation of LPA 1 receptors increases the stabilization of the transcription factor, Nrf2, and induces its nuclear translocation [148] .…”

Section: Atx Inhibitorsmentioning

confidence: 98%

“…It was the first reported ATX inhibitor to reduce plasma LPA levels in vivo for an extended period [140] . In rat air-pouch models, 30 mg/kg PF-8380 inhibited inflammatory hyperalgesia with the same efficacy as 30 mg/kg naproxen, a routinely used nonsteroidal anti-inflammatory drug Inflammatory hyperalgesia [140] Radiotherapy sensitizer in glioblastoma [146] ONO-8430506 Autotaxin activity inhibitor (competitive) Preclinical IC 50 5 nmol/L 10-30 mg/kg Benign prostatic hyperplasia [147] Reduces breast tumor growth and metastasis and increases sensitization to doxorubicin [76,148] Lpathomab TM LPA monoclonal antibody Preclinical 25 mg/kg Traumatic brain injury [127] AM966 LPA 1 antagonist Preclinical IC 50 17 nmol/L 10 mg/kg Idiopathic pulmonary fibrosis [132] BMS-986020 LPA 1 antagonist Phase II 600 mg/day (patients) Idiopathic pulmonary fibrosis [133] BMS-986202/AM152 LPA 1 antagonist Phase I 20-40 mg/kg Idiopathic pulmonary fibrosis [134] SAR100842 LPA 1/3 antagonist Phase II 20-40 mg/kg Systemic sclerosis [135] Gene overexpression Induced LPP gene expression Preclinical Overexpressed in cancer cells LPP3 overexpression reduces ovarian cancer cell growth [118] LPP1 overexpression reduces tumor growth and metastasis in breast and thyroid cancers [116] (NSAID) [140] . At this concentration, PF-8380 maximally reduced LPA levels in both plasma and at the site of inflammation.…”

Section: Atx Inhibitorsmentioning

confidence: 99%

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

2016

J Biomed Res

View full text Add to dashboard Cite

Extracellular lysophosphatidate (LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin (ATX), and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases (LPPs). In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity. In cancers, LPA signaling drives tumor growth, angiogenesis, metastasis, resistance to chemotherapy and decreased efficacy of radiotherapy. Hence, targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options. In this review, we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity, LPA receptor antagonists, LPA monoclonal antibodies, and increasing low LPP expression. Some of these agents are already in clinical trials and have applications beyond cancer, including chronic inflammatory diseases.

show abstract

Osteoclast‐Derived Autotaxin, a Distinguishing Factor for Inflammatory Bone Loss

Flammier

Peyruchaud

Bourguillault

et al. 2019

Arthritis & Rheumatology

View full text Add to dashboard Cite

Objective The severity of rheumatoid arthritis (RA) correlates directly with bone erosions arising from osteoclast (OC) hyperactivity. Despite the fact that inflammation may be controlled in patients with RA, those in a state of sustained clinical remission or low disease activity may continue to accrue erosions, which supports the need for treatments that would be suitable for long‐lasting inhibition of OC activity without altering the physiologic function of OCs in bone remodeling. Autotaxin (ATX) contributes to inflammation, but its role in bone erosion is unknown. Methods ATX was targeted by inhibitory treatment with pharmacologic drugs and also by conditional inactivation of the ATX gene Ennp2 in murine OCs (ΔATXCtsk). Arthritic and erosive diseases were studied in human tumor necrosis factor–transgenic (hTNF+/−) mice and mice with K/BxN serum transfer–induced arthritis. Systemic bone loss was also analyzed in mice with lipopolysaccharide (LPS)–induced inflammation and estrogen deprivation. Joint inflammation and bone erosion were assessed by histology and micro–computed tomography. The role of ATX in RA was also examined in OC differentiation and activity assays. Results OCs present at sites of inflammation overexpressed ATX. Pharmacologic inhibition of ATX in hTNF+/− mice, as compared to vehicle‐treated controls, significantly mitigated focal bone erosion (36% decrease; P < 0.05) and systemic bone loss (43% decrease; P < 0.05), without affecting synovial inflammation. OC‐derived ATX was revealed to be instrumental in OC bone resorptive activity and was up‐regulated by the inflammation elicited in the presence of TNF or LPS. Specific loss of ATX in OCs from mice subjected to ovariectomy significantly protected against the systemic bone loss and erosion that had been induced with LPS and K/BxN serum treatments (30% reversal of systemic bone loss [P < 0.01]; 55% reversal of erosion [P < 0.001]), without conferring bone‐protective properties. Conclusion Our results identify ATX as a novel OC factor that specifically controls inflammation‐induced bone erosions and systemic bone loss. Therefore, ATX inhibition offers a novel therapeutic approach for potentially preventing bone erosion in patients with RA.

show abstract

Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice

Cited by 100 publications

References 61 publications

Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice

Lipid phosphate phosphatase-1 expression in cancer cells attenuates tumor growth and metastasis in mice

Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo

Osteoclast‐Derived Autotaxin, a Distinguishing Factor for Inflammatory Bone Loss

Contact Info

Product

Resources

About