title: AXL is a potential therapeutic target in dedifferentiated and pleomorphic liposarcomas.
abstract: BACKGROUND
  AXL is a well-characterized, protumorigenic receptor tyrosine kinase that is highly expressed and activated in numerous human carcinomas and sarcomas, including aggressive subtypes of liposarcoma. However, the role of AXL in the pathogenesis of well-differentiated (WDLPS), dedifferentiated (DDLPS), and pleomorphic liposarcoma (PLS) has not yet been determined.
  
  
  METHODS
  Immunohistochemical analysis of AXL expression was conducted on two tissue microarrays containing patient WDLPS, DDLPS, and PLS samples. A panel of DDLPS and PLS cell lines were interrogated via western blot for AXL expression and activity and by ELISA for growth arrest-specific 6 (GAS6) production. AXL knockdown was achieved by siRNA or shRNA. The effects of AXL knockdown on cell proliferation, migration, and invasion were measured in vitro. In addition, AXL shRNA-containing DDLPS cells were assessed for their tumor-forming capacity in vivo.
  
  
  RESULTS
  In this study, we determined that AXL is expressed in a subset of WDLPS, DDLPS, and PLS patient tumor samples. In addition, AXL and its ligand GAS6 are expressed in a panel of DDLPS and PLS cell lines. We show that the in vitro activation of AXL via stimulation with exogenous GAS6 resulted in a significant increase in cell proliferation, migration, and invasion in DDLPS and PLS cell lines. Transient knockdown of AXL resulted in attenuation of these protumorigenic phenotypes in vitro. Stable AXL knockdown not only decreased migratory and invasive characteristics of DDLPS and PLS cells in vitro but also significantly diminished tumorigenicity of two dedifferentiated liposarcoma xenograft models in vivo.
  
  
  CONCLUSIONS
  Our results suggest that AXL signaling contributes to the aggressiveness of DDLPS and PLS, and that AXL is therefore a potential therapeutic target for treatment of these rare, yet devastating tumors.
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. caitlin.d.may@gmail.com.|The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, TX, USA. caitlin.d.may@gmail.com.
authors.forename: Caitlin D
authors.initials: CD
authors.lastname: May
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. jgarnett@mdanderson.org.
authors.forename: Jeannine
authors.initials: J
authors.lastname: Garnett
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. xiaoyan4@hotmail.com.
authors.forename: XiaoYan
authors.initials: X
authors.lastname: Ma
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. smlanders@mdanderson.org.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Landers
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. dringram@mdanderson.org.
authors.forename: Davis R
authors.initials: DR
authors.lastname: Ingram
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. elizabeth.demicco@mountsinai.org.
authors.forename: Elizabeth G
authors.initials: EG
authors.lastname: Demicco
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. gasannaa@hotmail.com.
authors.forename: Ghadah A
authors.initials: GA
authors.lastname: Al Sannaa
authors.affiliation: Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. tonavu@gmail.com.
authors.forename: Tona
authors.initials: T
authors.lastname: Vu
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. hlixia@mdanderson.org.|The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, TX, USA. hlixia@mdanderson.org.
authors.forename: Lixia
authors.initials: L
authors.lastname: Han
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. yizhang030@hotmail.com.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. cmkivlin@mdanderson.org.|The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, TX, USA. cmkivlin@mdanderson.org.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Kivlin
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. sbolshak@mdanderson.org.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Bolshakov
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. akazad@mdanderson.org.
authors.forename: Azad Abul
authors.initials: AA
authors.lastname: Kalam
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Juehui.Liu@uth.tmc.edu.
authors.forename: Juehui
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. fgzlzhou@gmail.com.
authors.forename: Fuguo
authors.initials: F
authors.lastname: Zhou
authors.affiliation: Curtis and Elizabeth Anderson Cancer Institute, Memorial University Medical Center, Savannah, GA, USA. broccdo1@memorialhealth.com.
authors.forename: Dominique
authors.initials: D
authors.lastname: Broccoli
authors.affiliation: Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. wlwang@mdanderson.org.
authors.forename: Wei-Lien
authors.initials: WL
authors.lastname: Wang
authors.affiliation: The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, TX, USA. alazar@mdanderson.org.|Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. alazar@mdanderson.org.
authors.forename: Alexander J
authors.initials: AJ
authors.lastname: Lazar
authors.affiliation: Department of Surgery, The Ohio State University, Columbus, OH, USA. Raphael.Pollock@osumc.edu.
authors.forename: Raphael E
authors.initials: RE
authors.lastname: Pollock
authors.affiliation: Department of Surgery, Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel. pollocklev@gmail.com.
authors.forename: Dina
authors.initials: D
authors.lastname: Lev
authors.affiliation: Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. ketorres@mdanderson.org.|The University of Texas Health Science Center at Houston Graduate School of Biomedical Sciences, Houston, TX, USA. ketorres@mdanderson.org.
authors.forename: Keila E
authors.initials: KE
authors.lastname: Torres
mesh_terms: D002454:Cell Differentiation / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008080:Liposarcoma / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism*; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D020794:Receptor Protein-Tyrosine Kinases; D000094963:Axl Receptor Tyrosine Kinase; D000099255:Growth Arrest-Specific Protein 6; C000722289:AXL protein, human