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    Elevated growth differentiating factor 15 expression predicts long-term benefit of docetaxel, cisplatin and 5-fluorouracil induction chemotherapy in patients with oral cancer. Tang Xiao,Hu Yong-Jie,Ju Wu-Tong,Fu Yong,Sun Wen-Wen,Liu Ying,Tan Yi-Ran,Wang Li-Zhen,Li Jiang,Tu Yao-Yao,Zhang Chen-Ping,Zhang Zhi-Yuan,Zhong Lai-Ping Oncology letters Our previous phase 3 trial (NCT01542931) failed to demonstrate improved survival when docetaxel, cisplatin and 5-fluorouracil (TPF) induction chemotherapy was introduced prior to surgery and postoperative radiotherapy in patients with locally advanced oral squamous cell carcinoma (OSCC). The aim of the present study was to investigate the long-term predictive value of GDF15 expression for potential personalized treatment strategies in OSCC. A total of 256 patients with stage III/IVA OSCC from our phase 3 trial were enrolled in the present study. Immunohistochemical staining against GDF15 was performed in the biopsy samples from 230/256 patients. Kaplan-Meier analysis, followed by the log-rank test, and the Cox proportional hazards model were used for outcome analysis using the statistical SPSS 18.0 software package for Windows. Among the 230 patients, low GDF15 expression was detected in 68 patients and high GDF15 expression was detected in 162 patients. With a median follow-up period of 67 months, the patients with low GDF15 expression exhibited a higher survival rate than those with high GDF15 expression, including 5-year overall survival (73.4 vs. 57.7%; P=0.059), 5-year disease-free survival (64.5 vs. 49.2%; P=0.033), 5-year locoregional recurrence-free survival (66.0 vs. 51.5%; P=0.043) and 5-year distant metastasis-free survival (73.4 vs. 56.6%; P=0.038) rates. Furthermore, the cT3/4N0M0 patients with high GDF15 expression benefited significantly from TPF induction chemotherapy, including overall survival (HR=0.233; P=0.02), disease-free survival (HR=0.296; P=0.014), locoregional recurrence-free survival (HR=0.347; P=0.035) and distant metastasis-free survival (HR=0.212; P=0.013) rates. The results of the present study suggested that elevated GDF15 expression may be used as a long-term prognostic biomarker for poor clinical outcomes in patients with locally advanced OSCC. Elevated GDF15 expression in cT3/4N0M0 patients predicts significant long-term benefit of survival from TPF induction chemotherapy. 10.3892/ol.2018.8324
    Growth differentiation factor 15 as a radiation-induced marker in oral carcinoma increasing radiation resistance. Schiegnitz Eik,Kämmerer Peer W,Rode Katharina,Schorn Thomas,Brieger Jürgen,Al-Nawas Bilal Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology BACKGROUND:Growth differentiation factor 15 (GDF15) is involved in tumor pathogenesis of oral squamous cell carcinoma (OSCC). The aim of this study was an investigation of the potential influence of GDF15 on radioresistance of OSCC cells in vitro. METHODS:Oral squamous cell carcinoma cell lines were irradiated with 0, 2, or 6 Gy, and GDF15 expression in the supernatant per survived cell colony was examined with ELISA. Non-irradiated and OSCC cell lines irradiated with 6 Gy were evaluated for GDF15 expression using immunofluorescent staining. For further investigation of GDF15 effects on radioresistance, a GDF15 knockdown model in a human OSCC cell line was established, and apoptotic activity after radiation was measured using the Caspase-Glo 3/7 system. RESULTS:ELISA and immunofluorescent staining indicated an increased GDF15 expression in 5 OSCC cell lines compared with human gingival epithelial cells. Irradiation with two and six gray resulted in a significant elevation of GDF15 expression per survived cell colony in the irradiated OSCC cell lines (P < 0.001). Furthermore, a dose-dependent expression of GDF15 was seen. Immunofluorescent staining confirmed an elevated GDF15 expression in irradiated OSCC cell lines (n = 10; P ≤ 0.001). Apoptotic activity was significantly increased after irradiation in the GDF15 knockdown group compared with control cells (n = 24; P < 0.001). CONCLUSION:This study describes for the first time the vital role of GDF15 both in tumorigenesis and in radioresistance of OSCC cells. With its anti-apoptotic effects, GDF15 possibly promotes tumor progression and might protect carcinoma cells against irradiation effects. Consequently, GDF15 may be a promising therapeutic target in oral cancer. 10.1111/jop.12323
    Expression of growth differentiation factor 15 is positively correlated with histopathological malignant grade and in vitro cell proliferation in oral squamous cell carcinoma. Zhang Lei,Yang Xiao,Pan Hong-ya,Zhou Xiao-jian,Li Jiang,Chen Wan-tao,Zhong Lai-ping,Zhang Zhi-yuan Oral oncology Previously, we established an in vitro cellular carcinogenesis model of oral squamous cell carcinoma (OSCC) and expression microarray analysis showed that the gene encoding growth differentiation factor 15 (GDF15) was significantly upregulated in this model. In this study, we confirmed that expression of GDF15 was increased both at mRNA and protein levels in a panel of OSCC lines and clinical samples from primary OSCC patients. We also observed that expression of GDF15 was positively correlated with the malignancy of the disease: a higher level of GDF15 expression indicates a higher malignant grade of OSCC. Treatment of OSCC cell line (Tca3118) with siRNA against GDF15 significantly inhibited cellular proliferation and colony formation. Based on these observations, we conclude that GDF15 is a positive gene of OSCC development and progression and GDF15 can be used as an additional marker for histopathologic evaluation of OSCC differentiation. 10.1016/j.oraloncology.2008.07.017
    Elevated level of serum growth differentiation factor 15 is associated with oral leukoplakia and oral squamous cell carcinoma. Yang Cheng-Zhe,Ma Jie,Luo Qing-Qiong,Neskey David M,Zhu Dong-Wang,Liu Ying,Myers Jeffrey N,Zhang Chen-Ping,Zhang Zhi-Yuan,Zhong Lai-Ping Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology BACKGROUND:Although molecular mechanism of growth differentiation factor 15 (GDF15) in tumorigenesis of oral squamous cell carcinoma (OSCC) is not clear, the diagnostic and prognostic value of serum GDF15 detection has been noticed. However, serum GDF15 levels in patients with oral leukoplakia and GDF15 as a potential predictive biomarker for response to induction chemotherapy in patients with OSCC have not been reported. METHODS:Pretreatment serum GDF15 concentration was detected using an enzyme-linked immunosorbent assay in 30 healthy persons, 24 patients with oral leukoplakia, and 60 patients with OSCC. RESULTS:Serum GDF15 concentration was significantly higher in patients with oral leukoplakia and OSCC, compared with healthy controls (F = 13.701, df = 2, P < 0.001). From a diagnostic standpoint, a cutoff value of 346.9 ng/l of serum GDF15 concentration was calculated using receiver operating characteristic curve, with a sensitivity of 0.750, specificity of 0.867, Youden's Index of 0.617, and area under curve of 0.863. From a prognostic standpoint, patients with serum GDF15 concentration <346.9 ng/l had an improved 3-year disease-free survival rate (64.3% vs 56.5%) compared with those above 346.9 ng/l, but the difference was not statistically significant. A decreased concentration of GDF15 (<346.9 ng/l) showed a predictive trend toward an improved response to induction chemotherapy compared with elevated concentration with clinical response rates of 100% and 71.4%, respectively, but the difference was not significant. CONCLUSION:Elevated GDF15 level may be not only a diagnostic biomarker for oral leukoplakia, but also a prognostic/predictive biomarker associated with decreased survival and diminished response to induction chemotherapy for patients with OSCC. 10.1111/jop.12091
    GDF15 derived from both tumor-associated macrophages and esophageal squamous cell carcinomas contributes to tumor progression via Akt and Erk pathways. Urakawa Naoki,Utsunomiya Soken,Nishio Mari,Shigeoka Manabu,Takase Nobuhisa,Arai Noriaki,Kakeji Yoshihiro,Koma Yu-ichiro,Yokozaki Hiroshi Laboratory investigation; a journal of technical methods and pathology Tumor-associated macrophages (TAMs) are known to be involved in the progression, angiogenesis, and motility of various cancers. We previously reported the association between an increased number of infiltrating TAMs with tumor progression and poor prognosis in esophageal squamous cell carcinomas (ESCCs). To study the roles of TAMs in ESCC, we first exposed peripheral blood monocyte (PBMo)-derived macrophages from healthy volunteers to conditioned media of TE series human ESCC cell line (TECM) and confirmed the induction of the expression of the M2 macrophage marker CD204 and the protumorigenic factors interleukin (IL)-10, VEGFA, and MMPs. Next, we compared gene expression profiles between PBMo-derived macrophages stimulated with or without TECM by cDNA microarray and focused on growth differentiation factor 15 (GDF15) among the highly expressed genes including IL-6, IL-8, and CXCL1. Our immunohistochemical study of 70 surgically resected ESCCs revealed that GDF15 was present not only in cancer cells but also in macrophages. The high expression of GDF15 in the ESCCs was significantly correlated with several more malignant phenotypes including vessel invasion, lymph node metastasis, and clinical stages. Patients with high GDF15 expression showed significantly poorer disease-free survival (P=0.011) and overall survival (P=0.041). We also found that recombinant human GDF15 promotes cell proliferation and the phosphorylation of both Akt and Erk1/2 in ESCC cell lines in vitro. These results indicate that GDF15 is secreted by both TAMs and cancer cells in the tumor microenvironment and is associated with aberrant growth and a poor prognosis in human ESCC. 10.1038/labinvest.2015.36
    GDF15 is a potential predictive biomarker for TPF induction chemotherapy and promotes tumorigenesis and progression in oral squamous cell carcinoma. Yang C Z,Ma J,Zhu D W,Liu Y,Montgomery B,Wang L Z,Li J,Zhang Z Y,Zhang C P,Zhong L P Annals of oncology : official journal of the European Society for Medical Oncology 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. PATIENTS AND 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). 10.1093/annonc/mdu120
    Mutant GDF15 presents a poor prognostic outcome for patients with oral squamous cell carcinoma. Ma Jie,Tang Xiao,Sun Wen-Wen,Liu Ying,Tan Yi-Ran,Ma Hai-Long,Zhu Dong-Wang,Wang Min,Wang Li-Zhen,Li Jiang,Tu Yao-Yao,Zhang Chen-Ping,Zhang Zhi-Yuan,Zhong Lai-Ping Oncotarget PURPOSE:To investigate the mutation status of growth differentiation factor 15 (GDF15) in patients with oral squamous cell carcinoma (OSCC), as well as the prognostic value of missense GDF15 mutations. PATIENTS AND METHODS:Formalin-fixed paraffin-embedded biopsy samples from 46 OSCC patients were involved in this study. GDF15 and TP53 mutations were sequenced using the Ion Torrent Personal Genome Machine, GDF15 protein expression was detected using immunohistochemistry. Torrent Suite Software v.3.6, Integrative Genomics Viewer; v.2.3, statistical software SPSS18.0 for Windows were used for analysis. All hypothesis-generating tests were two-sided at a significance level of 0.05. RESULTS:Twenty-nine GDF15 mutations were identified in 19 out of 46 patients (41.3%), including eighteen missense mutations, two nonsense mutations and nine synonymous mutations. The patients with missense GDF15 mutations had poorer prognostic outcomes than those with wild-type GDF15, including overall survival (P = 0.035), disease-free survival (P = 0.032), locoregional recurrence-free survival (P = 0.015), and distant metastasis-free survival (P = 0.070). Missense GDF15mutations was an independent increased risk factor of overall survival (HR = 5.993, 95% CI:1.856-19.346, P = 0.003), disease-free survival (HR = 3.764, 95% CI:1.295-10.945, P = 0.015), locoregional recurrence-free survival (HR = 4.555, 95% CI:1.494-13.889, P = 0.008), and distant metastasis-free survival (HR = 4.420, 95% CI:1.145-13.433, P = 0.009). CONCLUSIONS:Patients with missense GDF15 mutations have significantly poorer outcomes than those with wild-type GDF15, missense GDF15 mutations could be used as an independent increased risk factor of poor prognosis in OSCC patients. 10.18632/oncotarget.6017