Lysophosphatidic acids, cyclic phosphatidic acids and autotaxin as promising targets in therapies of cancer and other diseases.

Gendaszewska‐Darmach, Edyta

doi:10.18388/abp.2008_3070

Cited by 45 publications

(29 citation statements)

References 84 publications

(110 reference statements)

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“…( 223 )]. PPAR γ , which resides intracellularly and counters TGF-β fibrogenesis, is also an additional receptor for LPA ( 224 ). In addition to S1P being able to “disarm” Foxp3 Tregs mentioned above, S1P and LPA regulate the function, migration, and trafficking of all lymphoid cells and monocyte/macrophage/dendritic cells with S1P also being able to sequester T cells in the thymus and peripheral lymphoid organs, resulting in some instances in lymphopenia, which is frequently found in patients with SSc ( 225 – 227 ).…”

Section: Immune System In Ssc Pathogenesismentioning

confidence: 99%

Pathogenesis of Systemic Sclerosis

et al. 2015

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Systemic scleroderma (SSc) is one of the most complex systemic autoimmune diseases. It targets the vasculature, connective tissue-producing cells (namely fibroblasts/myofibroblasts), and components of the innate and adaptive immune systems. Clinical and pathologic manifestations of SSc are the result of: (1) innate/adaptive immune system abnormalities leading to production of autoantibodies and cell-mediated autoimmunity, (2) microvascular endothelial cell/small vessel fibroproliferative vasculopathy, and (3) fibroblast dysfunction generating excessive accumulation of collagen and other matrix components in skin and internal organs. All three of these processes interact and affect each other. The disease is heterogeneous in its clinical presentation that likely reflects different genetic or triggering factor (i.e., infection or environmental toxin) influences on the immune system, vasculature, and connective tissue cells. The roles played by other ubiquitous molecular entities (such as lysophospholipids, endocannabinoids, and their diverse receptors and vitamin D) in influencing the immune system, vasculature, and connective tissue cells are just beginning to be realized and studied and may provide insights into new therapeutic approaches to treat SSc.

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Section: Immune System In Ssc Pathogenesismentioning

confidence: 99%

Pathogenesis of Systemic Sclerosis

et al. 2015

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“…Despite all the literature on the mechanisms of LPA‐mediated signaling in cancer [34–43], the regulation of ATX expression is poorly understood, although some progress has been made. Galectin‐3, a β‐galactoside binding protein known to increase the invasive potential of cancer cells, increases ATX expression at the transcriptional level by modulating the expression of the transcription factor Nuclear Factor of Activated T‐cell 1 (NFAT1) [155].…”

Section: Recent Insights Into Atx and Cancermentioning

confidence: 99%

“…The initial relation of ATX/LPA signaling with melanoma cells resulted in much of the early research into ATX being concentrated in the cancer field, and progress has been regularly reviewed [34–43]. In short, LPA signaling through at least six known G‐protein‐coupled receptors (LPA 1‐6 ) stimulates cell survival and migration through the relative activations of phosphatidylinositol 3‐kinase (PI3K), ERK 1/2 , mTOR, Ca 2+ ‐transients, Rac, Rho and Ras (Fig.…”

Section: Introduction and Overviewmentioning

confidence: 99%

Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions

et al. 2014

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a b s t r a c tAutotaxin is a secreted enzyme that produces most of the extracellular lysophosphatidate from lysophosphatidylcholine, the most abundant phospholipid in blood plasma. Lysophosphatidate mediates many physiological and pathological processes by signaling through at least six G-protein coupled receptors to promote cell survival, proliferation and migration. The autotaxin/lysophosphatidate signaling axis is involved in wound healing and tissue remodeling, and it drives many chronic inflammatory conditions from fibrosis to colitis, asthma and cancer. In cancer, lysophosphatidate signaling promotes resistance to chemotherapy and radiotherapy, and increases both angiogenesis and metastasis. Research into autotaxin inhibitors is accelerating, both as primary and adjuvant therapy. Historically, autotaxin inhibitors had poor bioavailability profiles and thus had limited efficacy in vivo. This situation is now changing, especially since the recent crystal structure of autotaxin is now enabling rational inhibitor design. In this review, we will summarize current knowledge on autotaxin-mediated disease processes including cancer, and discuss recent advancements in the development of autotaxin-targeting strategies. We will also provide new insights into autotaxin as an inflammatory mediator in the tumor microenvironment that promotes cancer progression and therapy resistance.

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“…ATX is among the top 40 upregulated genes in metastatic cancer [108] and this is explained by the effects of LPA, which signals through at least six and putatively eight G-protein-coupled receptors. Through these receptors, LPA stimulates cell motility, cell survival/viability, cell proliferation, morphological changes, contraction, wound healing and invasion [109][110][111][112][113][114][115][116][117][118]. LPA achieves these effects by signaling through the relative activations of phosphatidylinositol 3kinase (PI3K), ERK 1/2 , mTOR, Ca 2+ -transients, Rac, Rho and Ras [119].…”

Section: Atx In Malignancy: Metastasis and Angiogenesismentioning

confidence: 99%

Autotaxin – An Enzymatic Augmenter of Malignant Progression Linked to Inflammation

Brindley¹,

Benesch²,

Murph³

2015

Melanoma - Current Clinical Management and Future Therapeutics

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Malignant melanoma cells are incredibly hardy, stemming from their intrinsic defensive nature. These cells inherit unique characteristics, which allowed their non-malignant predecessors, melanocytes, to survive solar ultraviolet radiation and simultaneously provide protection to neighboring cells. Most other cell types would die after such harsh exposure. Unsurprisingly, melanoma cells, which survive ultraviolet radiation, are intrinsically resistant to most chemotherapy. Although there are numerous molecular reasons for this reality, herein we focus on the causal role of autotaxin (ATX) in melanoma. ATX is a 125 kDa glycoprotein enzyme that was initially discovered in the serum-free medium of A2058 human melanoma cells by Stracke et al. in 1992 [1] (Figure 1). Today, we know much more about this glycoprotein enzyme and how it affects melanoma. Indeed, ATX is highly overexpressed among primary melanomas and metastatic melanomas, in comparison to melanoma in situ and in normal skin [2]. In fact, "autotaxin" derived its name based on its initial property as an "autocrine motility factor". The rationale is that A2058 melanoma cells secrete ATX into culture medium and then respond to it with self-stimulated random and directed motility. Even though the amount of ATX in conditioned medium is less than 0.005% of total protein, only miniscule amounts, detected in picomolar and nanomolar concentrations, are needed to promote motility. [1] This suggests a large role for a low-abundant secreted enzyme. There are five alternatively-spliced isoforms of ATX that are catalytically active [3,4]. The original ATX protein described in 1992 is termed ATXα, whereas the most abundant isoform is ATXβ and is the same isoform responsible for plasma lysoPLD activity [5]. Full length ATX

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Lysophosphatidic acids, cyclic phosphatidic acids and autotaxin as promising targets in therapies of cancer and other diseases.

Cited by 45 publications

References 84 publications

Pathogenesis of Systemic Sclerosis

Pathogenesis of Systemic Sclerosis

Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions

Autotaxin – An Enzymatic Augmenter of Malignant Progression Linked to Inflammation

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