The predictive value of genes of the TGF-beta1 pathway in multimodally treated squamous cell carcinoma of the esophagus.
OBJECTIVE
Pretherapeutic identification of esophageal squamous cell carcinomas (ESCCs) that are likely to respond to neoadjuvant chemoradiotherapy is important in the attempt to improve the prognosis for patients. In the present study, expression of members of the transforming growth factor-beta1 (TGF-beta1) signaling pathway was investigated in pretherapeutic biopsies from 97 ESCCs (cT3, cN0/+, cM0) in patients who underwent neoadjuvant chemoradiotherapy (45 Gy plus cisplatin and 5-fluorouracil) and subsequent esophagectomy in the setting of a single-center prospective treatment trial.


METHODS
Expression of TGF-beta1 and its downstream effectors Smad4 and Smad7 was assessed using quantitative reverse transcription polymerase chain reaction from RNA prepared from pretherapeutic tumor biopsies. The presence of phosphorylated Smad2 was assessed immunohistochemically.


RESULTS
Expression of TGF-beta1 (mean 7.8; range 0.0-25.7 arb. units), Smad4 (mean 0.1; range 0.0-0.4 arb. units), and Smad7 (mean 1.6; range 0.4-16.1 arb. units) varied substantially between the patients. Tumors with total or subtotal regression, as determined by histopathological examination after neoadjuvant chemoradiotherapy, showed significantly higher levels of Smad4 mRNA expression than tumors with minor or no regression (P = 0.032). TGF-beta1 and Smad7 mRNA expression as well as Smad2 protein expression were of no prognostic value. Expression of the four genes under analysis also showed no impact on the overall survival. In contrast, the overall survival correlated significantly with histopathological regression (P < 0.0001) and to a minor degree also with clinical regression grading (P = 0.0254).


CONCLUSIONS
Among the parameters analyzed, only Smad4 was found to have possible predictive value for esophageal squamous cell carcinoma in patients receiving neoadjuvant chemoradiotherapy.
Pühringer-Oppermann
Franziska
F
Department of Pathology, Technical University of Munich, Munich, Germany.
Sarbia
Mario
M
Ott
Nicola
N
Brücher
Björn L D M
BL
D000328:Adult; D000368:Aged; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000628:therapy; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms / Q000235:genetics / Q000628:therapy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010766:Phosphorylation; D011237:Predictive Value of Tests; D012333:RNA, Messenger / Q000032:analysis; D015398:Signal Transduction / Q000235:genetics*; D051899:Smad2 Protein / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics*; D051906:Smad7 Protein / Q000235:genetics; D016019:Survival Analysis; D053773:Transforming Growth Factor beta1 / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
D012333:RNA, Messenger; C497782:SMAD2 protein, human; C497806:SMAD7 protein, human; D051899:Smad2 Protein; D051901:Smad4 Protein; D051906:Smad7 Protein; D053773:Transforming Growth Factor beta1