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


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2012-05-12

AUTHORS

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

ABSTRACT

BackgroundSMAD 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.MethodsOur 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.ResultsEpithelial 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).ConclusionIn 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. More... »

PAGES

294-302

Identifiers

URI

http://scigraph.springernature.com/pub.10.1007/s00534-012-0518-6

DOI

http://dx.doi.org/10.1007/s00534-012-0518-6

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1045321845

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22581056


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37 ConclusionIn pancreatic ductal adenocarcinomas
38 Epithelial SMAD4
39 MethodsOurs
40 N1 stage tumors
41 ResultsEpithelial tumor cells
42 SMAD4
43 SMAD4 expression
44 SMAD4 inactivation
45 Smad protein expression
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47 Smad signaling
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83 fibrotic tumor type
84 focus
85 form
86 function
87 functioning
88 group
89 group of patients
90 growth factor
91 growth inhibitory response
92 immunohistochemical expression
93 inactivation
94 inhibitory responses
95 intracellular mediators
96 key factor
97 loss
98 matrix production
99 mediators
100 microenvironment
101 morphogenetic proteins
102 normal growth inhibitory responses
103 nucleus
104 outcomes
105 overall survival
106 pancreatic cancer
107 pancreatic carcinogenesis
108 pancreatic ductal adenocarcinoma
109 pathway
110 patients
111 patterns
112 phosphorylated form
113 postsurgical overall survival
114 presence
115 pro-tumor effects
116 production
117 protein
118 protein expression
119 regard
120 relationship
121 resection
122 response
123 results
124 role
125 shorter postsurgical overall survival
126 signaling
127 significance
128 stage
129 stage tumors
130 statistical significance
131 stroma
132 stromal expression
133 stromal features
134 stromal fibroblast SMAD2/3 expression
135 stromal fibroblast expression
136 stromal fibroblasts
137 surgical resection
138 survival
139 tendency
140 tumor cells
141 tumor types
142 tumor-suppressive function
143 tumors
144 types
145 worse outcomes
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