TY - JOUR
T1 - Involvement of HER-2/neu and metastasis-related proteins in the development of ileal neuroendocrine tumors
AU - Azzoni, C
AU - Bottarelli, L
AU - Cecchini, S
AU - Lagrasta, C
AU - Pizzi, S
AU - D'Adda, T
AU - Tamburini, E
AU - Rindi, Guido
AU - Bordi, C.
PY - 2011
Y1 - 2011
N2 - HER-2/neu overexpression and/or gene amplification occurs in several human malignancies, frequently correlates with tumor aggressiveness, and provides the basis for treatment with trastuzumab. Among neuroendocrine neoplasms (NEN) of the gastroenteropancreatic (GEP) tract, ileal neuroendocrine tumors show peculiar features of malignancy with frequent metastases at the diagnosis. We investigated the overexpression and/or amplification of HER-2/neu and the involvement of the metastasis-related proteins c-Met, MTA-1, and VEGF in 24 primary ileal NEN by immunohistochemistry and fluorescence in situ hybridization (FISH). Data were compared with those of 43 GEP endocrine tumors of other sites. All primary ileal NEN showed an intense membranous and cytoplasmic immunostaining for HER-2/neu. According to the breast cancer scoring system, 17% of ileal carcinoids showed a score of 3+ and 71% with a score of 2+ with a significant difference respect the non-ileal GEP endocrine tumors (p < 0.0000). FISH analysis revealed chromosome 17 polysomy in 33% of 2+/3+ ileal tumors but not HER-2/neu gene amplification. The c-Met and MTA-1 but not VEGF were overexpressed in almost all ileal NEN, whereas VEGF presented more frequently a normal staining. The comparisons with the other GEP NEN demonstrated significant differences for all the three proteins (p < 0.0000, p < 0.0002, and p < 0.001, respectively). These findings suggest that in ileal NEN, HER-2/neu overexpression plays a role in the carcinogenetic process and by triggering the altered expression of c-Met and MTA-1, may activate the molecular pathway(s) promoting tumor progression and metastasis development. Ileal HER-2/neu overexpressing neuroendrocrine tumors may constitute potential candidates for target therapy with specific humanized monoclonal antibodies.
AB - HER-2/neu overexpression and/or gene amplification occurs in several human malignancies, frequently correlates with tumor aggressiveness, and provides the basis for treatment with trastuzumab. Among neuroendocrine neoplasms (NEN) of the gastroenteropancreatic (GEP) tract, ileal neuroendocrine tumors show peculiar features of malignancy with frequent metastases at the diagnosis. We investigated the overexpression and/or amplification of HER-2/neu and the involvement of the metastasis-related proteins c-Met, MTA-1, and VEGF in 24 primary ileal NEN by immunohistochemistry and fluorescence in situ hybridization (FISH). Data were compared with those of 43 GEP endocrine tumors of other sites. All primary ileal NEN showed an intense membranous and cytoplasmic immunostaining for HER-2/neu. According to the breast cancer scoring system, 17% of ileal carcinoids showed a score of 3+ and 71% with a score of 2+ with a significant difference respect the non-ileal GEP endocrine tumors (p < 0.0000). FISH analysis revealed chromosome 17 polysomy in 33% of 2+/3+ ileal tumors but not HER-2/neu gene amplification. The c-Met and MTA-1 but not VEGF were overexpressed in almost all ileal NEN, whereas VEGF presented more frequently a normal staining. The comparisons with the other GEP NEN demonstrated significant differences for all the three proteins (p < 0.0000, p < 0.0002, and p < 0.001, respectively). These findings suggest that in ileal NEN, HER-2/neu overexpression plays a role in the carcinogenetic process and by triggering the altered expression of c-Met and MTA-1, may activate the molecular pathway(s) promoting tumor progression and metastasis development. Ileal HER-2/neu overexpressing neuroendrocrine tumors may constitute potential candidates for target therapy with specific humanized monoclonal antibodies.
KW - Antibodies, Monoclonal
KW - Antibodies, Monoclonal, Humanized
KW - Gene Amplification
KW - Genes, erbB-2
KW - Histone Deacetylases
KW - Humans
KW - Ileal Neoplasms
KW - In Situ Hybridization, Fluorescence
KW - Neuroendocrine Tumors
KW - Proto-Oncogene Proteins c-met
KW - Receptor, erbB-2
KW - Repressor Proteins
KW - Vascular Endothelial Growth Factor A
KW - Antibodies, Monoclonal
KW - Antibodies, Monoclonal, Humanized
KW - Gene Amplification
KW - Genes, erbB-2
KW - Histone Deacetylases
KW - Humans
KW - Ileal Neoplasms
KW - In Situ Hybridization, Fluorescence
KW - Neuroendocrine Tumors
KW - Proto-Oncogene Proteins c-met
KW - Receptor, erbB-2
KW - Repressor Proteins
KW - Vascular Endothelial Growth Factor A
UR - http://hdl.handle.net/10807/5864
U2 - 10.1007/s00428-011-1069-y
DO - 10.1007/s00428-011-1069-y
M3 - Article
VL - 458
SP - 525
EP - 536
JO - Virchows Archiv : an international journal of pathology
JF - Virchows Archiv : an international journal of pathology
ER -