title: Stromal fibroblasts are predictors of disease-related mortality in esophageal squamous cell carcinoma.
abstract: The growth, invasiveness and metastasis of human cancers are determined not only by cancer cells, but also by their microenvironment. Activated stromal fibroblasts promote tumor progression by secreting growth factors. In the present study, we focused on interrelations between cancer and fibroblasts, the main component of tumor stroma. We retrospectively analyzed the relations of mortality to clinical, pathological, and α-smooth muscle actin (α-SMA) characteristics in 97 consecutive patients with esophageal squamous cell carcinoma (ESCC). In vitro, we used TE-11, KYSE150 and KYSE220 ESCC cell lines and isolated esophageal stromal fibroblasts, some of which were immortalized. Migration assays were conducted to assess the effects of fibroblasts on cancer-cell migration and 3-dimensional organotypic cultures. In vivo, TE-11 and KYSE220 cells plus immortalized fibroblasts were co-transplanted subcutaneously in Nod/Scid mice to assess the effects of fibroblasts on tumorigenicity. Clinicopathologically, the α-SMA expression of cancer stroma was correlated with venous invasion (p<0.01), nodal involvement (p=0.02), recurrence (p=0.01), and was a predictor of survival in patients with stage I and II ESCC (p=0.04). In vitro, the presence of fibroblasts strongly promoted the migration of TE-11, KYSE150 and KYSE220 cells. On organotypic culture, stromal invasion was observed only in the presence of immortalized fibroblasts. In vivo, tumors developed or grew in a fibroblast‑dependent manner after implantation. Our findings provide evidence that stromal fibroblasts and tumor cells interact to promote tumor progression in ESCC. In patients with earlier stage ESCC, α-SMA may be a predictor of mortality. Inhibition of paracrine systems associated with tumor fibroblasts may slow or reverse tumor progression, potentially leading to the development of new targeted therapies.
authors.affiliation: Department of Surgery, Jichi Medical University, Shimotsuke-City, Tochigi 329-0498, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Surgery, Jichi Medical University, Shimotsuke-City, Tochigi 329-0498, Japan.
authors.forename: Kazue
authors.initials: K
authors.lastname: Morishima
authors.affiliation: Department of Surgery, Jichi Medical University, Shimotsuke-City, Tochigi 329-0498, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ui
authors.affiliation: Department of Integrative Pathology, Jichi Medical University, Shimotsuke-City, Tochigi 329-0498, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Matsubara
authors.affiliation: Department of Integrative Pathology, Jichi Medical University, Shimotsuke-City, Tochigi 329-0498, Japan.
authors.forename: Tomoko
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Integrative Pathology, Jichi Medical University, Shimotsuke-City, Tochigi 329-0498, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Oguni
authors.affiliation: Department of Surgery, Jichi Medical University, Shimotsuke-City, Tochigi 329-0498, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Hosoya
authors.affiliation: Department of Surgery, Jichi Medical University, Shimotsuke-City, Tochigi 329-0498, Japan.
authors.forename: Naohiro
authors.initials: N
authors.lastname: Sata
authors.affiliation: Department of Surgery, Jichi Medical University, Shimotsuke-City, Tochigi 329-0498, Japan.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Lefor
authors.affiliation: Department of Surgery, Jichi Medical University, Shimotsuke-City, Tochigi 329-0498, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Yasuda
authors.affiliation: Department of Integrative Pathology, Jichi Medical University, Shimotsuke-City, Tochigi 329-0498, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Niki
mesh_terms: D000199:Actins / Q000378:metabolism*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000401:mortality* / Q000473:pathology*; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000401:mortality* / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D004947:Esophagus / Q000166:cytology* / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D009361:Neoplasm Invasiveness / Q000473:pathology; D009362:Neoplasm Metastasis / Q000473:pathology; D009374:Neoplasms, Experimental; D017154:Stromal Cells / Q000378:metabolism
chemical_list: D000199:Actins