title: CXCL12 expression promotes esophageal squamous cell carcinoma proliferation and worsens the prognosis.
abstract: The chemokine CXCL12 and its corresponding receptor CXCR4 are key players in the development of several cancers. Therefore, we hypothesized that there is a functional causality between CXCL12 expression and tumor progression in patients with esophageal squamous cell carcinoma (ESCC).
  
  
  
  We performed an immunohistochemical analysis in 79 consecutive patients with ESCC. We performed in vitro and in vivo cell proliferation assays using ESCC cell lines and a newly established transfectant stably overexpressing CXCL12.
  
  
  
  Immunohistochemistry revealed positive CXCR4 and CXCL12 expression in 48 (61 %) and 62 (78 %) patients, respectively. Additionally, the expression levels did not significantly correlate with any clinicopathological factors. The MIB-1 proliferation index was markedly higher in ESCC with a positive expression of CXCR4 or CXCL12. Positive CXCL12 expression was significantly correlated with lower recurrence-free survival (RFS, p = 0.02). Cox's hazard models revealed CXCL12 expression as an independent predictive factor for recurrence. In vitro, CXCL12 exposure or overexpression enhanced ESCC proliferation; and AMD3100, a specific inhibitor of CXCR4, equally decreased proliferation irrespective of CXCL12 exposure or overexpression. In the mouse model, AMD3100 significantly decreased ESCC tumor size (p = 0.03).
  
  
  
  CXCL12 stimulates ESCC proliferation, and its expression levels are related to lower RFS in patients with ESCC. Our findings indicate that positive CXCL12 expression may be a useful marker for predicting the outcome in patients with ESCC and is a potentially new therapeutic target for ESCC.
authors.affiliation: Department of Surgery, Keio University School of Medicine, 160-0016, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Uchi
authors.affiliation: Department of Surgery, Keio University School of Medicine, 160-0016, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan. htakeuchi@a6.keio.jp.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Department of Surgery, Keio University School of Medicine, 160-0016, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Matsuda
authors.affiliation: Department of Surgery, Keio University School of Medicine, 160-0016, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saikawa
authors.affiliation: Department of Surgery, Keio University School of Medicine, 160-0016, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Kawakubo
authors.affiliation: Department of Surgery, Keio University School of Medicine, 160-0016, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Wada
authors.affiliation: Department of Surgery, Keio University School of Medicine, 160-0016, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Surgery, Keio University School of Medicine, 160-0016, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Department of Surgery, Keio University School of Medicine, 160-0016, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Department of Surgery, Keio University School of Medicine, 160-0016, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Tai
authors.initials: T
authors.lastname: Omori
authors.affiliation: Department of Surgery, Keio University School of Medicine, 160-0016, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000096:biosynthesis*; D018572:Disease-Free Survival; D004938:Esophageal Neoplasms / Q000378:metabolism / Q000473:pathology*; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D011379:Prognosis; D016016:Proportional Hazards Models; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D014408:Biomarkers, Tumor; C515255:CXCL12 protein, human; D054377:Chemokine CXCL12
keywords: CXCL12; CXCR4; Chemokine; Chemokine receptor; Esophageal squamous cell carcinoma