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Journal of Hepato-Biliary-Pancreatic Sciences

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01-03-2013 | Original article

Tumoral epithelial and stromal expression of SMAD proteins in pancreatic ductal adenocarcinomas

Authors: Adriana Handra-Luca, Pascal Hammel, Alain Sauvanet, Philippe Ruszniewski, Anne Couvelard

Published in: Journal of Hepato-Biliary-Pancreatic Sciences | Issue 3/2013

Abstract

Background

SMAD proteins, intracellular mediators of the transforming growth factor (TGF)-beta pathway, function within two axes, the SMAD1/5/8 and SMAD2/3, connected to TGF-beta and bone morphogenetic protein (BMP) ligands. The SMAD proteins of these two axes dimerize with SMAD4 and translocate to the nucleus. SMAD signaling is characterized by a dichotomic functioning, with tumor-suppressive functions and with loss of normal growth inhibitory responses, depending on the carcinogenesis stage. SMAD proteins also have pro-tumor effects including abnormal extracellular matrix production. Among tumors, pancreatic cancers harbor SMAD4 inactivation the most frequently and the SMAD proteins are considered to be key factors in pancreatic carcinogenesis.

Methods

Our aims were to study the expression patterns of the different types of SMAD proteins in pancreatic ductal adenocarcinomas treated by surgical resection (without neoadjuvant treatment) and their correlations with morphological and clinical characteristics. We examined the immunohistochemical expression of SMAD4, SMAD1/5/8, and SMAD2/3 in 99 pancreatic ductal adenocarcinomas. Antibodies directed against the activated, phosphorylated forms of proteins were used when appropriate (SMAD1/5/8, SMAD2/3). Protein expression in the epithelial tumor cells and in stromal fibroblasts was analyzed with regard to morphological and clinical data.

Results

Epithelial tumor cells showed SMAD1/5/8, SMAD2/3, and, SMAD4 expression in 13, 93, and 45 tumors, respectively, and stromal fibroblast expression in 5, 11, and 22 tumors, respectively. Epithelial SMAD4 was associated with a low, T1 or T2, TNM stage, and with the presence of an abundant stroma (p = 0.05 and <0.01, respectively). Activated stromal fibroblast SMAD2/3 expression was correlated with the presence of a fibrotic focus (p = 0.01), whereas fibroblast SMAD4 was related to a tendency for shorter postsurgical overall survival (p = 0.07). The relationship of stromal, fibroblast SMAD4 to a worse outcome attained statistical significance in the group of patients with T1 and with N1 stage tumors (p < 0.01 and p = 0.04, respectively).

Conclusion

In pancreatic ductal adenocarcinomas, SMAD protein expression in epithelial tumor cells or in stromal fibroblasts was related to stromal features and to a shorter postsurgical overall survival. Our results point out that the SMAD proteins play a role in the microenvironment of this highly fibrotic tumor type.

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Title: Tumoral epithelial and stromal expression of SMAD proteins in pancreatic ductal adenocarcinomas
Authors: Adriana Handra-Luca
Pascal Hammel
Alain Sauvanet
Philippe Ruszniewski
Anne Couvelard
Publication date: 01-03-2013
Publisher: Springer Japan
Published in: Journal of Hepato-Biliary-Pancreatic Sciences / Issue 3/2013
Print ISSN: 1868-6974
Electronic ISSN: 1868-6982
DOI: https://doi.org/10.1007/s00534-012-0518-6

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Springer Medicine

Tumoral epithelial and stromal expression of SMAD proteins in pancreatic ductal adenocarcinomas

Abstract

Background

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

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