title: LOXL2 Is Highly Expressed in Cancer-Associated Fibroblasts and Associates to Poor Colon Cancer Survival.
abstract: OBJECTIVE
  Cancer-associated fibroblasts (CAF) are major mediators in tumor microenvironment. We investigated the changes in protein expression in colon cancer-associated fibroblasts compared with normal fibroblasts (NF) in the context of searching for prognostic biomarkers, particularly for stage II patients.
  
  
  METHODS
  CAFs and NFs isolated from colon cancer patients were used to identify differentially expressed proteins using quantitative proteomics. Stromal expression of deregulated proteins was analyzed by IHC. Prognostic impact was studied using external gene-expression datasets for training, then quantitative PCR and IHC for validation in different cohorts of patients. Combined datasets were used for prediction of risk assessment at stages II and III.
  
  
  RESULTS
  A desmoplastic signature composed of 32 proteins, highly specific for stromal components in colon cancer, was identified. These proteins were enriched for extracellular matrix organization components, TGFβ signaling pathway, fibrosis, and wound-healing proteins. The expression in CAFs of 11 upregulated proteins and four downregulated proteins, selected for biomarker validation, was verified by orthogonal techniques. LOXL2 displayed a high prognostic impact by using external independent datasets and further validation in two different cohorts of patients. High expression of LOXL2 was associated with higher recurrence P = 0.001 HR, 5.38 [95% confidence interval (CI), 1.70-17.01] and overall survival P = 0.001 HR, 8.52 (95% CI, 1.90-38.29). IHC analysis revealed a prognostic value for LOXL2 in stage II patients.
  
  
  CONCLUSIONS
  We identified LOXL2 to be associated with the outcome of colon cancer patients. Furthermore, it can be used to stratify patients at stages II and III for further therapeutic decisions.
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: Sofía
authors.initials: S
authors.lastname: Torres
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Garcia-Palmero
authors.affiliation: Department of Medical Oncology, Hospital Puerta de Hierro Majadahonda, Madrid, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Herrera
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: Rubén A
authors.initials: RA
authors.lastname: Bartolomé
authors.affiliation: Department of Medical Oncology, Hospital Puerta de Hierro Majadahonda, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Peña
authors.affiliation: Department of Pathology, Fundación Jiménez Díaz, Madrid, Spain.
authors.forename: M Jesús
authors.initials: MJ
authors.lastname: Fernandez-Aceñero
authors.affiliation: Core facilities, CIB-CSIC, Madrid, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Padilla
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain.
authors.forename: Alberto
authors.initials: A
authors.lastname: Peláez-García
authors.affiliation: Core facilities, CIB-CSIC, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Lopez-Lucendo
authors.affiliation: Department of Pathology, Hospital Virgen de la Salud, Toledo, Spain.
authors.forename: Rufo
authors.initials: R
authors.lastname: Rodriguez-Merlo
authors.affiliation: IMIM-Hospital del Mar, Barcelona, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: García de Herreros
authors.affiliation: Department of Medical Oncology, Hospital Puerta de Hierro Majadahonda, Madrid, Spain.
authors.forename: Félix
authors.initials: F
authors.lastname: Bonilla
authors.affiliation: Department of Cellular and Molecular Medicine, Centro de Investigaciones Biológicas (CIB-CSIC), Madrid, Spain. icasal@cib.csic.es.
authors.forename: J Ignacio
authors.initials: JI
authors.lastname: Casal
mesh_terms: D000594:Amino Acid Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D015415:Biomarkers; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D003110:Colonic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D009367:Neoplasm Staging; D011379:Prognosis; D025941:Protein Interaction Mapping; D060066:Protein Interaction Maps; D040901:Proteomics / Q000379:methods; D015203:Reproducibility of Results; D017154:Stromal Cells / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D059016:Tumor Microenvironment / Q000235:genetics
chemical_list: D015415:Biomarkers; D008840:Microfilament Proteins; D009124:Muscle Proteins; D016212:Transforming Growth Factor beta; C051615:transgelin; D000594:Amino Acid Oxidoreductases; C119091:LOXL2 protein, human