title: Autotaxin-lysophosphatidic acid signaling axis mediates tumorigenesis and development of acquired resistance to sunitinib in renal cell carcinoma.
abstract: OBJECTIVE
  Sunitinib is currently considered as the standard treatment for advanced renal cell carcinoma (RCC). We aimed to better understand the mechanisms of sunitinib action in kidney cancer treatment and in the development of acquired resistance.
  
  
  METHODS
  Gene expression profiles of RCC tumor endothelium in sunitinib-treated and -untreated patients were analyzed and verified by quantitative PCR and immunohistochemistry. The functional role of the target gene identified was investigated in RCC cell lines and primary cultures in vitro and in preclinical animal models in vivo.
  
  
  RESULTS
  Altered expression of autotaxin, an extracellular lysophospholipase D, was detected in sunitinib-treated tumor vasculature of human RCC and in the tumor endothelial cells of RCC xenograft models when adapting to sunitinib. ATX and its catalytic product, lysophosphatidic acid (LPA), regulated the signaling pathways and cell motility of RCC in vitro. However, no marked in vitro effect of ATX-LPA signaling on endothelial cells was observed. Functional blockage of LPA receptor 1 (LPA1) using an LPA1 antagonist, Ki16425, or gene silencing of LPA1 in RCC cells attenuated LPA-mediated intracellular signaling and invasion responses in vitro. Ki16425 treatment also dampened RCC tumorigenesis in vivo. In addition, coadministration of Ki16425 with sunitinib prolonged the sensitivity of RCC to sunitinib in xenograft models, suggesting that ATX-LPA signaling in part mediates the acquired resistance against sunitinib in RCC.
  
  
  CONCLUSIONS
  Our results reveal that endothelial ATX acts through LPA signaling to promote renal tumorigenesis and is functionally involved in the acquired resistance of RCC to sunitinib.
authors.affiliation: Authors' Affiliations: Departments of Urology and Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas; and Institue of Medicine, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Shih-Chi
authors.initials: SC
authors.lastname: Su
authors.forename: Xiaoxiao
authors.initials: X
authors.lastname: Hu
authors.forename: Patrick A
authors.initials: PA
authors.lastname: Kenney
authors.forename: Megan M
authors.initials: MM
authors.lastname: Merrill
authors.forename: Kara N
authors.initials: KN
authors.lastname: Babaian
authors.forename: Xiu-Ying
authors.initials: XY
authors.lastname: Zhang
authors.forename: Tapati
authors.initials: T
authors.lastname: Maity
authors.forename: Shun-Fa
authors.initials: SF
authors.lastname: Yang
authors.forename: Xin
authors.initials: X
authors.lastname: Lin
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Wood
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D002292:Carcinoma, Renal Cell / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D019008:Drug Resistance, Neoplasm; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D007680:Kidney Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055806:Microvessels / Q000187:drug effects / Q000473:pathology; D009361:Neoplasm Invasiveness; D010727:Phosphoric Diester Hydrolases / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D000077210:Sunitinib; D059467:Transcriptome; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000099189:Lysophospholipase D
chemical_list: D020533:Angiogenesis Inhibitors; D007211:Indoles; D008246:Lysophospholipids; D010727:Phosphoric Diester Hydrolases; D011758:Pyrroles; D000077210:Sunitinib; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid