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EXPRESSION OF HER-2 CORRELATED
PROTEINS IN ILEAL CARCINOIDS
Azzoni C., Giordano G., Bottarelli L., Tamburini E.,
D’Adda T., Pizzi S., Rindi G., Bordi C.
Department of Pathology and Laboratory Medicine,
Section of Pathological Anatomy, Parma University,
Parma - Italy
BACKGROUND
In a previous study of our laboratory we found a high
HER-2/neu immunohistochemical expression in ileal
midgut carcinoids (see data in Patients) at variance
with other gastroenteropancreatic endocrine tumors
HER-2/neu overexpression may be involved in the
carcinogenetic process of malignant ileal carcinoids
?
Involvement of metastasis-related proteins c-MET,
MTA-1 and VEGF activated by HER-2/neu
C-MET
 chromosome 7q31
 tyrosine kinase receptor for Scatter Factor (also
known as Hepatocyte Growth Factor)
 stimulating cell proliferation, dissociation, motility,
extracellular matrix invasion and metastatic
behavior of a large array of neoplasms
 overexpressed in several type of tumors, including
thyroid,
pancreatic,
colorectal
and
breast
carcinomas
 in endocrine pancreatic tumors the expression of
MET was found to be higher in tumors with
metastases and worse prognosis
MTA-1
 chromosome 14q32
 nuclear regulatory protein that interacts with
specific genes involved in cellular regulation,
invasion and progression
 expression of MTA-1 gene was increased four-times
in cerbB2/neu stable transfectants cells compared
to untransfected cells
 MTA-1 is overexpressed in a variety of human
cancers including cancers of the breast, ovary,
lung, gastrointestinal system and colorectum
VEGF
 chromosome 6p12
 highly specific mitogen for vascular endothelial cells
 clinical importance for tumor growth of solid
malignancies in various organs including breast,
lung, prostate and colon
 preclinical and clinical findings support VEGF as a
promising target for anticancer therapy
 VEGF has been demonstrated to be highly
expressed in midgut ileal carcinoids whereas it is
focally expressed in other gastroenteropancreatic
neuroendocrine tumors, suggesting the possible use
of this protein as a serum marker for ileal carcinoid
EXPERIMENTAL DESIGN
c-MET, MTA-1 and VEGF were examined
by immunohistochemistry in 35 primary
ileal carcinoids and in 5 metastatic
tissues
We also determined the association of
these proteins with the status of Her2/neu expression
PATIENTS
PRIMARY TUMORS
METASTASES
Legend: F, female; M, male;
nd: not determined
METHODS
Antibody
Clone
Retrieval
Dilution
Incubation
Positivity
c-MET
sc-161
EDTA ph 9
1:50
overnight
membrane,
cytoplasmic
EDTA ph 9
1:50
overnight
nuclear
EDTA ph 9
1:100
overnight
cytoplasmic
Santa Cruz,
Biotechology
MTA-1
Sc-17773
VEGF
Sc-7269
Santa Cruz,
Biotechology
Santa Cruz,
Biotechology
Semiquantitative analisys
intensity and positivity of immunohistochemical staining
c-MET, MTA-1, VEGF : 4-point scale:
0: no staining, 1: mild staining, 2: moderate staining,
3: intense staining
c-MET
MTA-1
VEGF
Intense staining of
metastasis- related
proteins in ileal
carcinoids
RESULTS
Increased expressions
of c-MET and MTA-1
proteins in 78% and
79% of cases,
respectively
100
80
60
40
Increased expression
of VEGF in 11% of
cases
20
0
c-MET
MTA-1
NORMAL: score 0-2
OVEREXPRESSED: score 3
VEGF
No expression
variations between
primary and metastatic
tumors
CONCLUSIONS
The proteins c-Met and MTA-1 likely have a specific
role in the malignant progression of ileal carcinoids
Overexpression of VEGF could not be confirmed
in our study
The increased levels of the c-MET and MTA-1 proteins
may depend on the Her-2/neu overexpression already
documented in ileal carcinoids