One of the problematic features of hepatocellular carci-Background. Matrix metalloproteinase 9 (MMP-9), a noma (HCC) is its rapid invasion into the portal venous sys-92-kd gelatinase/type IV collagenase, has been implitem. Even in small HCCs, microscopic vascular invasion is cated as playing an important role in cancer invasion found in more than 40% of the nodules. 1,2 Macroscopic portal and metastasis. A previous study showed that serum venous invasion is reported to be the worst single prognostic type IV collagenase activity correlated with metastasis factor, after partial hepatectomy, for HCC. 3 Thus the detecby hepatocellular carcinoma (HCC). The aims of this tion of vascular invasion and its potential is important in study were to determine the plasma levels of immunoredetermining therapy and prognosis. At present, there is no active MMP-9 in patients with HCC and to compare the clinical laboratory test to predict the potential for or the ongolevels with the clinical features including vascular invaing activity of vascular invasion by HCC. Theoretically, the sion. Patients and Methods. This study included 100 pameasurement of the plasma levels of specific proteins that tients with HCC, 21 patients with chronic hepatitis (CH), are released by cancer cells and that are necessary for the 24 patients with liver cirrhosis (LC), and 138 healthy invasive process is a feasible approach to predict the tumor control subjects. Plasma MMP-9 levels were measured behavior. with a specific one-step sandwich enzyme immunoassay.
Invasive tumor growth and metastasis involve complex Results. Plasma MMP-9 levels in HCC (62 [33 to 130 ng/ steps. 4,5 The initial steps include the degradation of stromal mL] median [25%, 75%], 13 to 660 ng/mL, minimum, maxiarchitecture and of basement membrane components, espemum) were significantly elevated compared with those cially type IV collagen. Two kinds of type IV collagenase in in normal controls (36 [25 to 45], range, 2.8-70 ng/mL), in the matrix metalloproteinases family, 6 matrix metallopro-CH (28 [18 to 30], 13 to 66 ng/mL) and in LC (35 [26 to teinase 9 (MMP-9) (92-kd gelatinase/type IV collagenase) and 58], 16 to 86 ng/mL) (P รต .0000001; P ร
.0000003; and P ร
matrix metalloproteinase 2 (MMP-2) (72-kd gelatinase/type .00205, respectively). When the cut-off level was defined IV collagenase), have been implicated as playing a major role as 60 ng/mL from a receiver operating characteristic in the degradation of the basement membrane in cancer invacurve, plasma MMP-9 concentrations had a sensitivity sion and metastasis. 4,5 A correlation between the tumor secreof 53% and a specificity of 89% for the detection of HCC tion of MMP-9 7 as well as MMP-2, 8 and experimental metasfrom CH and LC. The levels were significantly higher in tasis has been reported.
HCC patients with macroscopic portal venous invasion
Previously, type IV collagenase activity (probably a mix-(79 [36 to 160], 15-660 ng/mL) than those without the invature of MMP-2 and MMP-9 activity) in the tissue homogenate sion (44 [27 to 80], 13 to 210 ng/mL) (P ร
.00726). Plasma of HCC was measured using a substrate degradation assay MMP-9 levels in patients with HCC were not correlated and was found to be the highest in HCC with metastasis. 9 with tumor number, size, volume, or serum a-fetoprotein Furthermore, elevated serum levels of type IV collagenase levels. Conclusions. The present data suggest that activity were reported in patients with HCC with metastaplasma MMP-9 levels can be a candidate for a novel sis. 10 These data indicated that aggressive HCC had high marker for HCC. The levels appear to reflect its potential levels of type IV collagenase in the tissue, and that the overand ongoing activity of vascular invasion. A long-term production correlated with elevated serum type IV collagenfollow-up of the patients will be necessary to determine ase activity. Thus, the circulating levels of type IV collagenwhether increased plasma MMP-9 levels are predictive ase must be a good marker of HCC, of its metastases, or of more invasive and metastatic HCC. (HEPATOLOGY possibly of the metastatic potential. 1996;24:1058-1062.)
Recently, we developed a one-step sandwich enzyme immunoassay for The assays developed by us and others 12,13 made it possible to evaluate the circulating MMP-9 levels in various physiological and pathophysiological conditions more easily than before. Therefore, we attempted to Abbreviations: HCC, hepatocellular carcinoma; MMP-9, matrix metalloproteinase 9; MMP-2, matrix metalloproteinase 2; CH, chronic hepatitis; LC, liver cirrhosis; mRNA, determine the utility of plasma MMP-9 levels in patients messenger RNA.