Correlation of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinase expression in ileal carcinoids, lymph nodes and liver metastasis with prognosis and survival.
OBJECTIVE
Ileal carcinoids are gut epithelial tumors originating from serotonin-containing enterochromaffin (EC) cells. Therapeutic options for effectively inhibiting the growth and spread of metastatic carcinoids are still limited. We aimed to identify the role of matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) during tumor development and metastasis.


METHODS
Tissue samples were obtained from surgically treated patients. Expression of the EC-cell marker, vesicular monoamine transporter-1 (VMAT-1), was used to verify ileal carcinoids. We investigated the differential expression of MMP-2, 7, 9, 11, and 13 and their endogenous inhibitors (TIMP-1, 2, and 3) by quantitative real-time RT-PCR in 25 primary tumors, their corresponding lymph node metastases and/or liver metastases and matched normal mucosa.


RESULTS
Significantly increased expression of VMAT-1, MMP-2, MMP-11, TIMP-1 and TIMP-3 was determined by quantitative RT-PCR in EC-cell carcinoids compared to normal intestinal mucosa (p < 0.05). In contrast, MMP-2 and MMP-9 as well as TIMP-1, TIMP-2, and TIMP-3 expression in primary tumors of patients with liver metastases (M1) was significantly lower than in patients lacking liver metastases (M0). EC-cell tumors were significantly larger in the M1 group of tumors, while VMAT-1 expression was significantly decreased. We found an inverse correlation between tumor size and prognosis. Univariate analysis further revealed that decreased expression of VMAT-1, MMP-2 and TIMP-3 in primary tumors was significantly associated with a reduced survival time of the patients.


CONCLUSIONS
Our data reveal that MMP-2 and TIMP-3 expression together with VMAT-1 expression are of potential prognostic and clinical value in ileal carcinoids.
Voland
Petra
P
II. Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany.
Besig
Sophie
S
Rad
Roland
R
Braun
Thomas
T
Baur
Dorothee M
DM
Perren
Aurel
A
Langer
Rupert
R
Höfler
Heinz
H
Prinz
Christian
C
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D002276:Carcinoid Tumor / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004759:Enterochromaffin Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D007078:Ileal Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism / Q000556:secondary*; D008207:Lymphatic Metastasis; D008297:Male; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011379:Prognosis; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D050493:Vesicular Monoamine Transport Proteins / Q000378:metabolism
D014408:Biomarkers, Tumor; C493449:SLC18A1 protein, human; D019714:Tissue Inhibitor of Metalloproteinases; D050493:Vesicular Monoamine Transport Proteins; D020782:Matrix Metalloproteinases