title: Intratumor stromal proportion predicts aggressive phenotype of gastric signet ring cell carcinomas.
abstract: OBJECTIVE
  The aim of this study was to evaluate the prognostic significance of the intratumor stromal proportion in gastric signet ring cell (SRC) carcinomas.
  
  
  BACKGROUND
  Cancer stroma, as exemplified by cancer-associated fibroblasts (CAFs), plays critical roles in cancer proliferation, invasion, and metastasis.
  
  
  METHODS
  One hundred seventy-five SRC carcinoma cases were classified according to the intratumor desmoplastic stromal proportion to then analyze the clinicopathologic characteristics of stroma-rich cases. We also investigated the impact of CAFs on the migration as well as on the phenotypic changes of gastric SRC carcinomas in vitro. Furthermore, we performed RNA sequencing of a pair of CAFs and normal-tissue-associated fibroblasts.
  
  
  RESULTS
  Stroma-rich SRC carcinomas (64 of 175 cases, 36.5%) were associated with female patients (P = 0.045), large tumor size (P = 0.007), higher T category (P < 0.001), and the presence of perineural invasion (P = 0.018). Patients with stroma-rich SRC carcinomas had a significantly shorter disease-free survival (P < 0.001) and overall survival (P < 0.001). However, in a subgroup analysis, the prognostic significance of the stromal proportion correlated only with patients with T3/4 disease. From multivariate analysis, the high stromal proportion is an independent prognostic factor to predict worse disease-free survival (hazard ratio 2.288; P = 0.001) and overall survival (hazard ratio 2.503; P = 0.001). We found that CAFs enhanced the migratory abilities of cancer cells through the epithelial-mesenchymal transition, and RNA sequencing results confirmed these findings.
  
  
  CONCLUSIONS
  The intratumor stromal proportion could be a useful prognostic biomarker and a potential therapeutic target in gastric SRC carcinomas.
authors.affiliation: Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea. dakeun@gmail.com.
authors.forename: Dakeun
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea.|Brain Korea 21 Plus Research Center for Biomedical Sciences, Ajou University, Suwon, Republic of Korea.
authors.forename: In-Hye
authors.initials: IH
authors.lastname: Ham
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Sang Yong
authors.initials: SY
authors.lastname: Son
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea.
authors.forename: Sang-Uk
authors.initials: SU
authors.lastname: Han
authors.affiliation: Department of Pathology, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea.
authors.forename: Young-Bae
authors.initials: YB
authors.lastname: Kim
authors.affiliation: Department of Surgery, Ajou University School of Medicine, Suwon, Republic of Korea. hhcmc75@naver.com.|Brain Korea 21 Plus Research Center for Biomedical Sciences, Ajou University, Suwon, Republic of Korea. hhcmc75@naver.com.|Division of Gastrointestinal Surgery, Department of Surgery, Ajou University School of Medicine, 164, Worldcup-ro, Yeongtong-gu, Suwon, Gyeonggi-do, 16499, Republic of Korea. hhcmc75@naver.com.
authors.forename: Hoon
authors.identifier: http://orcid.org/0000-0002-5435-5363
authors.initials: H
authors.lastname: Hur
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000072645:Cancer-Associated Fibroblasts / Q000473:pathology*; D018279:Carcinoma, Signet Ring Cell / Q000401:mortality / Q000473:pathology*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011379:Prognosis; D013274:Stomach Neoplasms / Q000401:mortality / Q000473:pathology*; D059016:Tumor Microenvironment; D055815:Young Adult
keywords: Cancer-associated fibroblast; Gastric cancer; Intratumor stromal proportion; Prognosis; Signet ring cell carcinoma