title: Receptor of activated protein C promotes metastasis and correlates with clinical outcome in lung adenocarcinoma.
abstract: BACKGROUND
  Efficient metastasis requires survival and adaptation of tumor cells to stringent conditions imposed by the extracellular milieu. Identification of critical survival signaling pathways in tumor cells might unveil novel targets relevant in disease progression.
  
  
  OBJECTIVE
  To investigate the contribution of activated protein C (APC) and its receptor (endothelial protein C receptor [EPCR]) in animal models of lung cancer metastasis and in patients with lung adenocarcinoma.
  
  
  METHODS
  Signaling pathway triggered by APC/EPCR and its relevance in apoptosis was studied in vitro. Functional significance was assessed by silencing and blocking antibodies in several in vivo models of lung cancer metastasis in athymic nude Foxn1(nu) mice. We examined EPCR levels using a microarray dataset of 107 patients. Immunohistochemical analysis was performed in an independent cohort of 295 patients with lung adenocarcinoma.
  
  
  RESULTS
  The effects of APC binding to EPCR rapidly triggered Akt and extracellular signal-regulated kinase signaling pathways, leading to attenuated in vitro apoptosis. In vivo, silencing of EPCR expression or blocking APC/EPCR interaction reduced infiltration in the target organ, resulting in impaired prometastatic activity. Moreover, overexpression of EPCR induced an increased metastatic activity to target organs. Analysis of clinical samples showed a robust association between high EPCR levels and poor prognosis, particularly in stage I patients.
  
  
  CONCLUSIONS
  EPCR and its ligand APC promote cell survival that contributes to tumor cell endurance to stress favoring prometastatic activity of lung adenocarcinoma. EPCR/APC is a novel target of relevance in the clinical outcome of early-stage lung cancer.
authors.affiliation: Division of Oncology, Adhesion and Metastasis Laboratory, Center for Applied Medical Research, University of Navarra, Pamplona, Spain.
authors.forename: Iker
authors.initials: I
authors.lastname: Antón
authors.forename: Eva
authors.initials: E
authors.lastname: Molina
authors.forename: Diego
authors.initials: D
authors.lastname: Luis-Ravelo
authors.forename: Carolina
authors.initials: C
authors.lastname: Zandueta
authors.forename: Karmele
authors.initials: K
authors.lastname: Valencia
authors.forename: Cristina
authors.initials: C
authors.lastname: Ormazabal
authors.forename: Susana
authors.initials: S
authors.lastname: Martínez-Canarias
authors.forename: Naiara
authors.initials: N
authors.lastname: Perurena
authors.forename: María José
authors.initials: MJ
authors.lastname: Pajares
authors.forename: Jackeline
authors.initials: J
authors.lastname: Agorreta
authors.forename: Luis M
authors.initials: LM
authors.lastname: Montuenga
authors.forename: Victor
authors.initials: V
authors.lastname: Segura
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
authors.forename: Javier
authors.initials: J
authors.lastname: De Las Rivas
authors.forename: José
authors.initials: J
authors.lastname: Hermida
authors.forename: Fernando
authors.initials: F
authors.lastname: Lecanda
mesh_terms: D000230:Adenocarcinoma / Q000556:secondary*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001779:Blood Coagulation Factors / Q000502:physiology*; D002470:Cell Survival; D060833:Cellular Microenvironment / Q000502:physiology; D004195:Disease Models, Animal; D005260:Female; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000473:pathology*; D051379:Mice; D011379:Prognosis; D040081:Protein Array Analysis; D011486:Protein C / Q000502:physiology*; D011956:Receptors, Cell Surface / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D001779:Blood Coagulation Factors; D011486:Protein C; D011956:Receptors, Cell Surface; C091963:activated protein C receptor