Department of Oral and Maxillofacial-Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
University of Missouri, Kansas City School of Medicine, Kansas City, USA.
Ann Oncol. 2014 Jun;25(6):1215-22. doi: 10.1093/annonc/mdu120. Epub 2014 Mar 24.
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.
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.
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).
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).
在口腔鳞状细胞癌（OSCC）患者中，与单独标准治疗相比，诱导化疗加标准治疗并未显示出主要的生存获益。诱导化疗可能对生物学上不同的亚组有效，生物标志物的发展可能会确定哪些患者的肿瘤可能对特定治疗有反应。
我们评估了 256 例 OSCC 患者中 230 例患者的预处理活检标本中的 GDF15 免疫组织化学染色，这些患者参加了一项前瞻性、随机、III 期试验，接受包括多西紫杉醇、顺铂和 5-氟尿嘧啶（TPF）的诱导化疗。使用体外和体内 OSCC 模型分析 GDF15 干预与细胞增殖、迁移、侵袭、集落形成和肿瘤发生之间的关系。
低 GDF15 表达预测 OSCC 患者的生存更好，尤其是总生存[P=0.049，风险比（HR）=0.597]和无远处转移生存（DMFS；P=0.031，HR=0.562）。低 GDF15 表达的 cN+患者从总生存（P=0.039，HR=0.247）和 DMFS（P=0.039，HR=0.247）中受益于诱导 TPF，高 GDF15 表达的 cN-患者从总生存（P=0.019，HR=0.231）、无病生存（P=0.011，HR=0.281）、局部区域复发无生存（P=0.035，HR=0.347）和 DMFS（P=0.009，HR=0.197）中受益于诱导 TPF。OSCC 系中 GDF15 表达的降低通过增加 AKT 和 ERK1/2 的磷酸化显著抑制细胞增殖、迁移、侵袭、集落形成和肿瘤发生（P<0.05）。同样，GDF15 的过表达通过降低 AKT 和 ERK1/2 的磷酸化显著促进细胞增殖、迁移、侵袭和集落形成（P<0.05）。
GDF15 表达可用作 OSCC 的预后生物标志物，也可用作从 TPF 诱导化疗中获益的预测生物标志物。GDF15 通过 OSCC 中的 AKT 和 ERK1/2 的磷酸化促进肿瘤发生和进展。本研究中的临床试验在 www.ClinicalTrials.gov 上注册（NCT01542931）。
