title: Tenascin-C, a Prognostic Determinant of Esophageal Squamous Cell Carcinoma.
abstract: BACKGROUND
  Tenascin-C, an adhesion modulatory extracellular matrix molecule, is highly expressed in numerous human malignancies; thus, it may contribute to carcinogenesis and tumor progression. We explored the clinicopathological significance of Tenascin-C as a prognostic determinant of esophageal squamous cell carcinoma (ESCC).
  
  
  METHODS
  In ESCC patient tissues and cell lines, the presence of isoforms were examined using western blotting. We then investigated Tenascin-C immunohistochemical expression in 136 ESCC tissue samples. The clinical relevance of Tenascin-C expression and the correlation between Tenascin-C expression and expression of other factors related to cancer-associated fibroblasts (CAFs) were also determined.
  
  
  RESULTS
  Both 250 and 350 kDa sized isoforms of Tenascin-C were expressed only in esophageal cancer tissue not in normal tissue. Furthermore, both isoforms were also identified in all of four CAFs derived from esophageal cancer tissues. Tenascin-C expression was remarkably higher in ESCC than in adjacent non-tumor esophageal epithelium (p < 0.001). Tenascin-C expression in ESCC stromal fibroblasts was associated with patient's age, tumor (pT) stage, lymph node metastasis, clinical stage, and cancer recurrence. Tenascin-C expression in cancer cells was correlated with an increase in tumor-associated macrophage (TAM) population, cancer recurrence, and hypoxia inducible factor1α (HIF1α) expression. Moreover, Tenascin-C overexpression in cancer cells and stromal fibroblasts was an independent poor prognostic factor for overall survival (OS) and disease-free survival (DFS). In the Cox proportional hazard regression model, Tenascin-C overexpression in cancer cells and stromal fibroblasts was a significant independent hazard factor for OS and DFS in ESCC patients in both univariate and multivariate analyses. Furthermore, Tenascin-C expression in stromal fibroblasts of the ESCC patients was positively correlated with platelet-derived growth factor α (PDGFRα), PDGFRβ, and smooth muscle actin (SMA) expression. The 5-year OS and DFS rates were remarkably lower in patients with positive expressions of both Tenascin-C and PDGFRα (p < 0.001), Tenascin-C and PDGFRβ (p < 0.001), Tenascin-C and SMA (p < 0.001), Tenascin-C and fibroblast activation protein (FAP) (p < 0.001), and Tenascin-C and fibroblast-stimulating protein-1 (FSP1) (p < 0.001) in ESCC stromal fibroblasts than in patients with negative expressions of both Tenascin-C and one of the abovementioned CAF markers.
  
  
  CONCLUSIONS
  Our results show that Tenascin-C is a reliable and significant prognostic factor in ESCC. Tenascin-C may thus be a potent ESCC therapeutic target.
authors.affiliation: Key Laboratory of Natural Resources of the Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University, Yanji (133002), China.|Department of Pathology, Yanbian University College of Medicine, Yanji (133002), China.
authors.forename: Zhao-Ting
authors.initials: ZT
authors.lastname: Yang
authors.affiliation: Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea.|Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (110-745), South Korea.
authors.forename: So-Young
authors.initials: SY
authors.lastname: Yeo
authors.affiliation: Key Laboratory of Natural Resources of the Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University, Yanji (133002), China.|Department of Mathematics, Yanbian University College of Science, Yanji (133002), China.
authors.forename: Yong-Xue
authors.initials: YX
authors.lastname: Yin
authors.affiliation: Key Laboratory of Natural Resources of the Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University, Yanji (133002), China.|Department of Pathology, Yanbian University College of Medicine, Yanji (133002), China.
authors.forename: Zhen-Hua
authors.initials: ZH
authors.lastname: Lin
authors.affiliation: Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea.|Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (110-745), South Korea.
authors.forename: Hak-Min
authors.initials: HM
authors.lastname: Lee
authors.affiliation: Key Laboratory of Natural Resources of the Changbai Mountain and Functional Molecules, Ministry of Education, Yanbian University, Yanji (133002), China.|Department of Pathology, Yanbian University College of Medicine, Yanji (133002), China.
authors.forename: Yan-Hua
authors.initials: YH
authors.lastname: Xuan
authors.affiliation: Department of Oncology, Affiliated Hospital of Yanbian University, Yanji, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Cui
authors.affiliation: Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Republic of Korea.|Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul (110-745), South Korea.
authors.forename: Seok-Hyung
authors.initials: SH
authors.lastname: Kim
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis* / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000175:diagnosis* / Q000473:pathology; D000077277:Esophageal Squamous Cell Carcinoma; D004947:Esophagus / Q000473:pathology*; D005260:Female; D005347:Fibroblasts / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D019063:Tenascin / Q000032:analysis*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D019063:Tenascin