Hypoxia Enhances Lysophosphatidic Acid Responsiveness in Ovarian Cancer Cells and Lysophosphatidic Acid Induces Ovarian Tumor Metastasis In vivo
Kwan Sik Kim,Saubhik Sengupta,Michael Berk,Yong Geun Kwak,Pedro F. Escobar,Jerome L. Belinson,Samuel C. Mok,Yan Xu,Yan Xu +8 more
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TLDR
It is shown for the first time that exogenous LPA enhances tumor metastasis in an orthotopic ovarian cancer model and HIF alpha expression in tumors and hypoxia conditions indicate that hypoxic conditions are likely to be pathologically important for ovarian cancer development.Abstract:
Lysophosphatidic acid (LPA) is elevated in ascites of ovarian cancer patients and stimulates growth and other activities of ovarian cancer cells in vitro . Tissue hypoxia is a critical factor for tumor aggressiveness and metastasis in cancers. We tested whether the ascites of ovarian cancer is hypoxic and whether hypoxia influences the effects of LPA on ovarian cancer cells. We found that ovarian ascitic fluids were hypoxic in vivo . Enhanced cellular responsiveness to LPA, including migration and/or invasion of ovarian cancer cells, was observed under hypoxic conditions. This enhancement could be completely blocked by geldanamycin or a small interfering RNA targeting hypoxia-inducible factor 1α (HIF1α). LPA-induced cell migration required cytosolic phospholipase A 2 (cPLA 2 ) and LPA stimulates cPLA 2 phosphorylation in a HIF1α-dependent manner under hypoxia conditions. Furthermore, we show for the first time that exogenous LPA enhances tumor metastasis in an orthotopic ovarian cancer model and HIFα expression in tumors. 17-Dimethylaminoethylamino-17-demethoxygeldanamycin (an inhibitor of the heat shock protein 90) effectively blocked LPA-induced tumor metastasis in vivo. Together, our data indicate that hypoxic conditions are likely to be pathologically important for ovarian cancer development. HIF1α plays a critical role in enhancing and/or sensitizing the role of LPA on cell migration and invasion under hypoxic conditions, where cPLA 2 is required for LPA-induced cell migration. (Cancer Res 2006; 66(16): 7983-90)read more
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LPA Receptors: Subtypes and Biological Actions
Ji Woong Choi,Deron R. Herr,Kyoko Noguchi,Yun C. Yung,Chang-Wook Lee,Tetsuji Mutoh,Mu-En Lin,Siew T. Teo,Kristine E. Park,Alycia N. Mosley,Jerold Chun +10 more
TL;DR: This work has provided valuable proof-of-concept data to support LPA receptors and LPA metabolic enzymes as targets for the treatment of medically important diseases that include neuropsychiatric disorders, neuropathic pain, infertility, cardiovascular disease, inflammation, fibrosis, and cancer.
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IRE1α–XBP1 controls T cell function in ovarian cancer by regulating mitochondrial activity
Minkyung Song,Tito A. Sandoval,Chang-Suk Chae,Sahil Chopra,Chen Tan,Melanie R. Rutkowski,Mahesh Raundhal,Mahesh Raundhal,Ricardo A. Chaurio,Kyle K. Payne,Csaba Konrad,Sarah E. Bettigole,Hee Rae Shin,Michael J. Crowley,Juan P. Cerliani,Andrew V. Kossenkov,Ievgen Motorykin,Sheng Zhang,Giovanni Manfredi,Dmitriy Zamarin,Kevin Holcomb,Paulo C. Rodriguez,Gabriel A. Rabinovich,Gabriel A. Rabinovich,Jose R. Conejo-Garcia,Laurie H. Glimcher,Laurie H. Glimcher,Juan R. Cubillos-Ruiz +27 more
TL;DR: Ov ovarian cancer—an aggressive malignancy that is refractory to standard treatments and current immunotherapies—induces endoplasmic reticulum stress and activates the IRE1α–XBP1 arm of the unfolded protein response in T cells to control their mitochondrial respiration and anti-tumour function.
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Lysophosphatidic Acid Receptors Determine Tumorigenicity and Aggressiveness of Ovarian Cancer Cells
Shuangxing Yu,Mandi M. Murph,Yiling Lu,Shuying Liu,Hassan Hall,Jinsong Liu,Clifton Stephens,Xianjun Fang,Gordon B. Mills +8 more
TL;DR: Exposure to LPA2 or LPA3 during ovarian carcinogenesis contributes to ovarian cancer aggressiveness, suggesting that the targeting of LPA production and action may have potential for the treatment of ovarian cancer.
Journal ArticleDOI
Plasma Lysophosphatidylcholine Levels: Potential Biomarkers for Colorectal Cancer
Zhenwen Zhao,Yijin Xiao,Paul Elson,Haiyan Tan,Sarah J. Plummer,Michael Berk,Phyu P. Aung,Ian C. Lavery,Jean P. Achkar,Li Li,Graham Casey,Yan Xu +11 more
TL;DR: In this article, the authors evaluated the lysophosphatidylcholines (LPCs) as potential biomarkers for colorectal cancer (CRC), where a highly reliable and minimally invasive blood test is lacking.
Journal ArticleDOI
The Unique Molecular and Cellular Microenvironment of Ovarian Cancer.
Thomas Worzfeld,Elke Pogge von Strandmann,Magdalena Huber,Till Adhikary,Uwe Wagner,Silke Reinartz,Rolf Müller +6 more
TL;DR: Current knowledge is summarized and discussed on signaling networks formed by cytokines, lipids, and extracellular vesicles; the pathophysiologial roles of TAMs and T cells; the mechanism of transcoelomic metastasis; and the cell type selective processing of signals from the TME.
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