title: Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients.
abstract: BACKGROUND
  For stage I-II colon cancer a significant number (5-25%) of patients has recurrent disease within 5 years. There is need to identify these high-risk patients as they might benefit from additional treatment. Stroma-tissue surrounding the cancer cells plays an important role in the tumor behavior. The proportion of intra-tumor stroma was evaluated for the identification of high-risk patients. In addition, protein expression of markers involved in pathways related to stroma production and epithelial-to-mesenchymal transition (EMT) was analyzed: beta-catenin, TGF-beta-R2 and SMAD4.
  
  
  METHODS
  In a retrospective study of 135 patients with stage I-II colon cancer, the amount of stroma was estimated on routine haematoxylin-eosin stained histological sections. Sections were also immunohistochemically stained for beta-catenin, TGF-beta-R2 and SMAD4.
  
  
  RESULTS
  Of 135 analyzed patients 34 (25.2%) showed a high proportion of stroma (stroma-high) and 101 (74.8%) a low proportion (stroma-low). Significant differences in overall-survival and disease-free-survival were observed between the two groups, with stroma-high patients showing poor survival (OS p<0.001, HZ 2.73, CI 1.73-4.30; DFS p<0.001, HZ 2.43, CI 1.55-3.82). A high-risk group was identified with stroma-high and SMAD4 loss (OS p=0.008, HZ 7.98, CI 4.12-15.44, DFS p=0.005, HZ 6.57, CI 3.43-12.56); 12 of 14 (85.7%) patients died within 3 years. In a logistic-regression analysis a high proportion of stroma and SMAD4 loss were strongly related (HZ 5.42, CI 2.13-13.82, p<0.001).
  
  
  CONCLUSIONS
  Conventional haematoxylin-eosin stained tumor slides contain more prognostic information than previously fathomed. This can be unleashed by assessing the tumor-stroma ratio. The combination of analyzing the tumor-stroma ratio and staining for SMAD4 results in an independent parameter for confident prediction of clinical outcome.
authors.affiliation: Department of Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands.
authors.forename: Wilma E
authors.initials: WE
authors.lastname: Mesker
authors.forename: Gerrit-Jan
authors.initials: GJ
authors.lastname: Liefers
authors.forename: Jan M C
authors.initials: JM
authors.lastname: Junggeburt
authors.forename: Gabi W
authors.initials: GW
authors.lastname: van Pelt
authors.forename: Paola
authors.initials: P
authors.lastname: Alberici
authors.forename: Peter J K
authors.initials: PJ
authors.lastname: Kuppen
authors.forename: Noel F
authors.initials: NF
authors.lastname: Miranda
authors.forename: Karin A M
authors.initials: KA
authors.lastname: van Leeuwen
authors.forename: Hans
authors.initials: H
authors.lastname: Morreau
authors.forename: Karoly
authors.initials: K
authors.lastname: Szuhai
authors.forename: Rob A E M
authors.initials: RA
authors.lastname: Tollenaar
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Tanke
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D012189:Retrospective Studies; D051901:Smad4 Protein / Q000235:genetics* / Q000378:metabolism; D017154:Stromal Cells / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D051901:Smad4 Protein