Tumoral Epithelial and Stromal Expression of SMAD Proteins in Pancreatic Ductal Adenocarcinomas
Adriana Handra-Luca, Pascal Hammel, Alain Sauvanet, Philippe Ruszniewski, Anne Couvelard. APHP Avicenne Universite Paris 13 Nord Medecine, Bobigny, France, Metropolitan; APHP Beaujon Universite Paris 7, Clichy, France, Metropolitan; APHP Bichat Claude Bernard Universite Paris 7, Paris, France, Metropolitan
Background: SMAD proteins, intracellular mediators of the TGFbeta pathway, function within two axis, the SMAD1/5/8 and SMAD2/3, connected to TGFbeta and BMP ligands. They dimerise 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 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 key factors in pancreatic carcinogenesis.
Design: We aimed to study the expression patterns of the different types of SMAD proteins in a large series of pancreatic ductal adenocarcinomas (PDAC) treated by surgical resection and their correlations to morphological and clinical characteristics. We examined the immunohistochemical expression of SMAD4, SMAD1/5/8 and SMAD2/3 in 99 PDAC. Antibodies directed against the activated, phosphorylated forms of proteins have been 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: The SMAD1/5/8, SMAD2/3 and, SMAD4 proteins were expressed in tumor epithelial cells in 13.5%, 96% and 49% of the tumors and in 5%, 11% and 23% PDAC in stromal fibroblasts. Epithelial SMAD4 was associated to a low, T1 or T2 TNM stage and to the presence of an abundant stroma (p=0.05 and <0.01, respectively). Activated stromal fibroblast SMAD2/3 expression was correlated to presence of a fibrotic focus (p=0.01), whereas fibroblast SMAD4 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 groups of patients with T1 and with N1 stage tumors (p<0.01 and p=0.04, respectively).
Conclusions: In PDAC, SMAD protein expression in epithelial tumor cells or in stromal fibroblasts was related to stroma features and to worse outcome. Our results point out that the SMAD proteins play a role in the microenvironment of this highly fibrotic tumor type.
Tuesday, March 20, 2012 1:00 PM
Poster Session IV # 289, Tuesday Afternoon