title: Effects of THBS3, SPARC and SPP1 expression on biological behavior and survival in patients with osteosarcoma.
abstract: BACKGROUND
  Osteosarcoma is a very aggressive tumor with a propensity to metastasize and invade surrounding tissue. Identification of the molecular determinants of invasion and metastatic potential may guide the development of a rational strategy for devising specific therapies that target the pathways leading to osteosarcoma.
  
  
  METHODS
  In this study, we used pathway-focused low density expression cDNA arrays to screen for candidate genes related to tumor progression. Expression patterns of the selected genes were validated by real time PCR on osteosarcoma patient tumor samples and correlated with clinical and pathological data.
  
  
  RESULTS
  THBS3, SPARC and SPP1 were identified as genes differentially expressed in osteosarcoma. In particular, THBS3 was expressed at significantly high levels (p = 0.0001) in biopsies from patients with metastasis at diagnosis, which is a predictor of worse overall survival, event-free survival and relapse free survival at diagnosis. After chemotherapy, patients with tumors over-expressing THBS3 have worse relapse free survival. High SPARC expression was found in 51/55 (96.3%) osteosarcoma samples derived from 43 patients, and correlated with the worst event-free survival (p = 0.03) and relapse free survival (p = 0.07). Overexpression of SPP1 was found in 47 of 53 (89%) osteosarcomas correlating with better overall survival, event-free survival and relapse free survival at diagnosis.
  
  
  CONCLUSIONS
  In this study three genes were identified with pattern of differential gene expression associated with a phenotypic role in metastasis and invasion. Interestingly all encode for proteins involved in extracellular remodeling suggesting potential roles in osteosarcoma progression. This is the first report on the THBS3 gene working as a stimulator of tumor progression. Higher levels of THBS3 maintain the capacity of angiogenesis. High levels of SPARC are not required for tumor progression but are necessary for tumor growth and maintenance. SPP1 is not necessary for tumor progression in osteosarcoma and may be associated with inflammatory response and bone remodeling, functioning as a good biomarker.
authors.affiliation: Department of Pediatrics, Instituto de Oncologia Pediátrica (IOP-GRAACC), Universidade Federal de São Paulo, Escola Paulista de Medicina, São Paulo 04023-062, Brazil. genetica@graacc.org.br
authors.forename: Cristiane A
authors.initials: CA
authors.lastname: Dalla-Torre
authors.forename: Maisa
authors.initials: M
authors.lastname: Yoshimoto
authors.forename: Chung-Hae
authors.initials: CH
authors.lastname: Lee
authors.forename: Anthony M
authors.initials: AM
authors.lastname: Joshua
authors.forename: Silvia R C
authors.initials: SR
authors.lastname: de Toledo
authors.forename: Antônio S
authors.initials: AS
authors.lastname: Petrilli
authors.forename: Joyce A D
authors.initials: JA
authors.lastname: Andrade
authors.forename: Susan
authors.initials: S
authors.lastname: Chilton-MacNeill
authors.forename: Maria
authors.initials: M
authors.lastname: Zielenska
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Squire
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016723:Bone Remodeling / Q000235:genetics; D049109:Cell Proliferation; D002648:Child; D002675:Child, Preschool; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D020411:Oligonucleotide Array Sequence Analysis; D015676:Osteonectin / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D053495:Osteopontin / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology; D012516:Osteosarcoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011446:Prospective Studies; D019699:Thrombospondins / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
chemical_list: D014408:Biomarkers, Tumor; D015676:Osteonectin; C506895:SPP1 protein, human; D019699:Thrombospondins; C101863:thrombospondin 3; D053495:Osteopontin