Role of MT-MMPs and MMP-2 in pancreatic cancer progression.
Activation of matrix metalloproteinase-2 (MMP-2) by the membrane-type matrix metalloproteinases (MT-MMPs) has been associated with tumor progression. In the present study, we examined the role of MMP-2 and its activators MT1-MMP, MT2-MMP and MT3-MMP in pancreatic tumor cell invasion and the development of the desmoplastic reaction characteristic of pancreatic cancer tissues. Northern blot analyses revealed that transcript levels of MT1-MMP and MT2-MMP, but not MT3-MMP, were enhanced in pancreatic cancer tissues (n = 18) compared with both chronic pancreatitis (n = 9) and healthy pancreas (n = 9). A good correlation was found between MT1-MMP and both MMP-2 expression (p < 0.01) and activity in pancreatic cancer tissues. In addition, expression and activation of MMP-2 were strongly associated with the extent of the desmoplastic reaction in pancreatic cancer tissues. Invasion assays showed a good correlation between MMP-2 expression and activity and the invasive potential of pancreatic cancer cell lines. In cell lines with high levels of MMP-2 expression and activity, the MMP inhibitor Batimastat led to significant reduction of the number of invading cells. Our results suggest that MT1-MMP is involved in the progression of pancreatic cancer via activation of MMP-2. MMP-2 itself plays an important role in tumor cell invasion and appears to be associated with the development of the characteristic desmoplastic reaction in pancreatic cancer.
Ellenrieder
V
V
Department of Internal Medicine, University of Ulm, Ulm, Germany.
Alber
B
B
Lacher
U
U
Hendler
S F
SF
Menke
A
A
Boeck
W
W
Wagner
M
M
Wilda
M
M
Friess
H
H
Büchler
M
M
Adler
G
G
Gress
T M
TM
D000230:Adenocarcinoma / Q000201:enzymology* / Q000473:pathology; D018450:Disease Progression; D005355:Fibrosis / Q000473:pathology; D005780:Gelatin / Q000378:metabolism; D006801:Humans; D053517:Matrix Metalloproteinase 15; D053513:Matrix Metalloproteinase 16; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000201:enzymology* / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis; D014407:Tumor Cells, Cultured
C507098:MMP15 protein, human; C507102:MMP16 protein, human; D012333:RNA, Messenger; D005780:Gelatin; D053517:Matrix Metalloproteinase 15; D053513:Matrix Metalloproteinase 16; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9