Beneficial influence of microsatellite instability on gelatinase-tissue inhibitors of metalloproteinase balance in colorectal cancer.
BACKGROUND
Colorectal cancers (CRC) with high level of microsatellite instability (MSI-H) are characterized by lower metastasis propensity and better prognosis than their stable microsatellite (MSS) counterpart. It was hypothesized that the difference in cancer progression might be related to distinct gelatinase-tissue inhibitors of metalloproteinase (TIMPs) balance in MSI-H and MSS sporadic CRC.


METHODS
Levels of gelatinase-A (MMP-2) and -B (MMP-9), TIMP-1 and -2 and membrane-type matrix metallo-proteinase-1 (MT1-MMP) were compared in tumors and normal mucosa from patients with MSI-H and MSS CRC.


RESULTS
Active levels of MMP-2 and -9, normalized to normal mucosa, were lower in MSI-H than MSS CRC. There was a trend for higher levels of TIMP-1 and TIMP-2 within MSI-H tumors compared with MSS tumors (p=0.08 and p=0.15, respectively), while TIMP-2 amounts were significantly higher in adjacent normal tissue (p<0.001) in patients with MSI-H vs. MSS cancers. There was also a trend for lower MT1-MMP activity in MSI-H than in MSS CRC.


CONCLUSIONS
Our data suggest that the distinct invasive and metastatic behaviors of MSI-H and MSS CRC may be related to different patterns of gelatinase secretion and regulation.
Thiéfin
Gérard
G
CHU Reims, Hôpital Robert Debré, Service d'Hépato-Gastroentérologie, Reims F-51092, France. gthiefin@chu-reims.fr
Dupont
Aurélie
A
Guillou
Pierre-José
PJ
Vitry
Fabien
F
Bouche
Olivier
O
Yaziji
Nahla
N
Lagarde
Stéphanie
S
Maquart
François-Xavier
FX
Palot
Jean-Pierre
JP
Hornebeck
William
W
Diebold
Marie-Danièle
MD
D000368:Aged; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D045726:Metalloproteases / Q000378:metabolism*; D053842:Microsatellite Instability; D008875:Middle Aged; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000378:metabolism*
D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D019716:Tissue Inhibitor of Metalloproteinase-2; D045726:Metalloproteases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14