ABSTRACT
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. PATIENTS AND 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. CONCLUSION: 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.
Subject(s)
Colorectal Neoplasms/pathology , Metalloproteases/metabolism , Microsatellite Instability , Tissue Inhibitor of Metalloproteinases/metabolism , Aged , Colorectal Neoplasms/genetics , Colorectal Neoplasms/metabolism , Electrophoresis, Polyacrylamide Gel , Female , Humans , Intestinal Mucosa/metabolism , Intestinal Mucosa/pathology , Male , Matrix Metalloproteinase 14/metabolism , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Middle Aged , Tissue Inhibitor of Metalloproteinase-1/metabolism , Tissue Inhibitor of Metalloproteinase-2/metabolismABSTRACT
OBJECTIVE: The aim of this retrospective study was to compare clinical, biological, and histological features and treatment response in 115 patients with overlap syndrome (OS), autoimmune hepatitis (AIH) or primary biliary cirrhosis (PBC). METHODS: Consecutive patients with AIH, PBC or OS followed between 1984 and 2005 in five different centers were included. All data were re-evaluated using current diagnostic criteria of each disease. RESULTS: Fifteen patients had OS (13 females), 48 AIH (40 females) and 52 PBC (49 females). Patients with OS were significantly younger than patients with PBC (median age: 44 vs 59 years). Jaundice (20%) and pruritus (20%) were the main initial symptoms in OS. Patients with OS had serum transaminase and gammaglobulin levels significantly higher than patients with PBC; serum alkaline phosphatase, gamma-glutamyl-transpeptidase and IgM levels were significantly higher in OS than in patients with AIH. Histological analysis showed moderate or severe piecemeal necrosis in 86% and destructive cholangitis in 93% in OS group. Among 11 patients with OS treated with ursodeoxycholic acid (UDCA) or immunosuppressors alone, only 6 had a complete biochemical response. In contrast, all patients with OS receiving combined therapy, as first or second line, responded, 5 patients to the combination corticosteroids-azathioprine-UDCA and 2 to the combination cyclosporine-UDCA. CONCLUSION: OS is not rare and accounts for 13.9% of patients with autoimmune liver disease in our series. Combination of immunosuppressors and UDCA appears the most efficient treatment in these patients.