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

BACKGROUNDBACKGROUNDIn 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, Involvement of metastasis-related proteins c-MET, MTA-1 and VEGF activated by HER-2/MTA-1 and VEGF activated by HER-2/neuneu

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C-METC-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-1MTA-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

VEGFVEGF 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 DESIGNEXPERIMENTAL 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 Her-2/neu expression

PATIENTSPATIENTSPRIMARY TUMORSPRIMARY TUMORS METASTASESMETASTASES

Legend: F, female; M, male; nd: not determined

METHODSMETHODSAntibodyAntibody CloneClone RetrievalRetrieval DilutionDilution IncubationIncubation PositivityPositivity

c-MET sc-161Santa Cruz,

Biotechology

EDTA ph 9 1:50 overnight membrane, cytoplasmic

MTA-1 Sc-17773Santa Cruz,

Biotechology

EDTA ph 9 1:50 overnight nuclear

VEGF Sc-7269Santa Cruz,

Biotechology

EDTA ph 9 1:100 overnight cytoplasmic

Semiquantitative analisysSemiquantitative analisys

intensity and positivity of immunohistochemical stainingintensity 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

MTA-1c-MET

VEGF

Intense staining of Intense staining of metastasis- related metastasis- related proteins in ileal proteins in ileal carcinoidscarcinoids

RESULTSRESULTSIncreased expressions of c-MET and MTA-1 proteins in 78% and 79% of cases, respectively

Increased expression of VEGF in 11% of cases

No expression variations between primary and metastatic tumors

0

20

40

60

80

100

c-MET MTA-1 VEGF

NORMAL: score 0-2OVEREXPRESSED: score 3

CONCLUSIONSCONCLUSIONS

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