title: GDF15 is a potential predictive biomarker for TPF induction chemotherapy and promotes tumorigenesis and progression in oral squamous cell carcinoma.
abstract: BACKGROUND
  Randomized trials have not shown major survival benefits when induction chemotherapy plus standard therapy is compared with standard therapy alone in patients with oral squamous cell carcinoma (OSCC). Induction chemotherapy is likely to be effective for biologically distinct subgroups and biomarker development may lead to identification of patients whose tumors are likely to respond to a particular treatment.
  
  
  METHODS
  We evaluated immunohistochemical staining for GDF15 in pretreatment biopsy specimens of 230 of 256 OSCC patients who were treated in a prospective, randomized, phase III trial on induction chemotherapy including docetaxel, cisplatin and 5-fluorouracil (TPF). Relationship between GDF15 intervention and cell proliferation, migration, invasion, colony formation and tumorigenicity was analyzed using in vitro and in vivo OSCC models.
  
  
  RESULTS
  Low GDF15 expression predicted a better survival in OSCC patients, especially overall survival [P = 0.049, hazard ratio (HR) = 0.597] and distant metastasis-free survival (DMFS; P = 0.031, HR = 0.562). cN+ patients with low GDF15 expression benefitted from induction TPF in overall survival (P = 0.039, HR = 0.247) and DMFS (P = 0.039, HR = 0.247), cN- patients with high GDF15 expression benefitted from induction TPF in overall survival (P = 0.019, HR = 0.231), disease-free survival (P = 0.011, HR = 0.281), locoregional recurrence-free survival (P = 0.035, HR = 0.347) and DMFS (P = 0.009, HR = 0.197). Decreased GDF15 expression in OSCC lines significantly inhibited cell proliferation, migration, invasion, colony formation and tumorigenesis through increased phosphorylation of AKT and ERK1/2 (P < 0.05). Likewise, overexpression of GDF15 significantly promoted cell proliferation, migration, invasion and colony formation through decreased phosphorylation of AKT and ERK1/2 (P < 0.05).
  
  
  CONCLUSIONS
  GDF15 expression can be used as a prognostic biomarker for OSCC, and as a predictive biomarker for benefitting from TPF induction chemotherapy. GDF15 promotes tumorigenesis and progression through phosphorylation of AKT and ERK1/2 in OSCC. The clinical trial in this study was registered with www.ClinicalTrials.gov (NCT01542931).
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: C Z
authors.initials: CZ
authors.lastname: Yang
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: D W
authors.initials: DW
authors.lastname: Zhu
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Liu
authors.affiliation: University of Missouri, Kansas City School of Medicine, Kansas City, USA.
authors.forename: B
authors.initials: B
authors.lastname: Montgomery
authors.affiliation: Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: L Z
authors.initials: LZ
authors.lastname: Wang
authors.affiliation: Department of Oral Pathology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: Z Y
authors.initials: ZY
authors.lastname: Zhang
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
authors.forename: C P
authors.initials: CP
authors.lastname: Zhang
authors.affiliation: Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China zhonglp@hotmail.com.
authors.forename: L P
authors.initials: LP
authors.lastname: Zhong
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis*; D063646:Carcinogenesis / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000008:administration & dosage; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D055436:Growth Differentiation Factor 15 / Q000096:biosynthesis*; D006801:Humans; D007150:Immunohistochemistry; D060828:Induction Chemotherapy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009062:Mouth Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D043823:Taxoids / Q000008:administration & dosage
chemical_list: D014408:Biomarkers, Tumor; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D043823:Taxoids; D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil
keywords: growth differentiation factor 15; induction chemotherapy; oral squamous cell carcinoma; prognosis; tumorigenesis