Overexpression of the BMP4/SMAD signaling pathway in skull base chordomas is associated with poor prognosis.
Chordomas are rare, locally invasive tumors with characteristic expression of the T-box transcription factor Brachyury. Little is yet known of the molecular events involved in the development of these tumors. Bone morphogenesis protein 4 (BMP4) signaling, which acts upstream of Brachyury in embryonic development, has been implicated in carcinogenesis in multiple malignancies. To explore the role of the canonical BMP4/SMAD signaling pathway in the pathogenesis of chordoma, we investigated, in 40 skull base chordomas, the expression of three major components of the signaling axis: BMP4, phospho-SMAD5 and SMAD4. Immunostaining revealed positive expression in 70%, 52.5% and 90% of cases, respectively. Eighteen (45%) of patients exhibited concurrent positive expression of these markers, which we defined as "high" expression of the BMP4/SMAD signaling pathway. Interestingly, when we compared the pattern of expression with clinicopathological parameters, we found that high expression of the pathway was more often observed in larger tumors (≥ 4 cm) than smaller ones (P = 0.010), and correlated significantly with dural invasion (P = 0.024). The Kaplan-Meier log-rank test showed that the 5-year overall survival rate for patients with high expression of the pathway was significantly lower than those with low expression (71.4% vs. 90.2%, P = 0.010). In conclusion, our results demonstrate for the first time that overexpression of the BMP4/SMAD signaling pathway could predict poor clinical outcome in skull base chordomas, suggesting activation of this pathway is involved in chordoma pathogenesis.
Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University Beijing 100053, P. R. China.
Yanjun
Y
Feng
Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University Beijing 100053, P. R. China.
Qiuhang
Q
Zhang
Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University Beijing 100053, P. R. China.
Zhenlin
Z
Wang
Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University Beijing 100053, P. R. China.
Bo
B
Yan
Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University Beijing 100053, P. R. China.
Wei
W
Wei
Department of Otolaryngology, Head and Neck Surgery, Skull Base Surgery Center, Xuanwu Hospital, Capital Medical University Beijing 100053, P. R. China.
Pu
P
Li
D014408:Biomarkers, Tumor / Q000032:analysis*; D055415:Bone Morphogenetic Protein 4 / Q000032:analysis*; D002817:Chordoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D015398:Signal Transduction; D019292:Skull Base Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology / Q000628:therapy; D051901:Smad4 Protein / Q000032:analysis*; D051902:Smad5 Protein / Q000032:analysis*; D047368:Tumor Burden; D015854:Up-Regulation
C525809:BMP4 protein, human; D014408:Biomarkers, Tumor; D055415:Bone Morphogenetic Protein 4; C497796:SMAD4 protein, human; C497797:SMAD5 protein, human; D051901:Smad4 Protein; D051902:Smad5 Protein
Chordoma; SMAD; bone morphogenesis protein 4 (BMP4); prognosis; skull base