Plasma levels of matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 correlate with disease stage and survival in colorectal cancer patients.
OBJECTIVE
The matrix metalloproteinases and their inhibitors are known to be involved in the process of tumor invasion and progression. Our objective was to investigate the potential diagnostic and prognostic value of plasma matrix metalloproteinase-2 and -9 and tissue inhibitor of metalloproteinase-1 in colorectal cancer.


METHODS
Gelatinase bioactivity and immunoreactivity of pro-matrix metalloproteinase-2 and -9, tissue inhibitor of metalloproteinase-1, and carcinoembryonic antigen were determined simultaneously in preoperative plasma and serum of colorectal cancer patients (n = 94) and in healthy controls (n = 51).


RESULTS
Plasma pro-matrix metalloproteinase-2 levels were lower in colorectal cancer patients (P < 0.0001) than in controls, and its gelatinolytic activity revealed an inverse correlation with adverse clinicopathologic parameters, such as lymph node involvement (P = 0.017), stage (0, I, II vs. III, IV; P = 0.012), and the carcinoembryonic antigen level (P = 0.016). Pro-matrix metalloproteinase-9 levels did not differ between patients and controls. Pro-matrix metalloproteinase-2 gelatinolytic activity showed potential value in colorectal cancer diagnosis, identifying patients with 70 percent sensitivity at 95 percent specificity. Pro-matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1, and carcinoembryonic antigen all showed lower sensitivities. Combining pro-matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-1 measurements increased the sensitivity significantly to 84 percent. With respect to prognosis, tissue inhibitor of metalloproteinase-1 showed value in predicting disease outcome in our patient group, whereas pro-matrix metalloproteinase-2 and -9 did not. The combination of tissue inhibitor of metalloproteinase-1 and carcinoembryonic antigen was better in predicting three-year survival than tissue inhibitor of metalloproteinase-1 alone, but it remains to be determined if the combination would be a better marker for survival than carcinoembryonic antigen alone.


CONCLUSIONS
Low pro-matrix metalloproteinase-2 levels and high tissue inhibitor of metalloproteinase-1 levels correlate with parameters of colorectal cancer disease. These correlations may be used in the search for new markers in colorectal cancer diagnosis and prognosis.
Waas
Erwin T
ET
Department of Surgery, University Medical Center Nijmegen, Nijmegen, The Netherlands.
Hendriks
Thijs
T
Lomme
Roger M L M
RM
Wobbes
Theo
T
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D002272:Carcinoembryonic Antigen / Q000097:blood; D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000473:pathology* / Q000532:radiotherapy / Q000601:surgery; D005260:Female; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000097:blood*; D008875:Middle Aged; D009367:Neoplasm Staging / Q000379:methods*; D011237:Predictive Value of Tests; D011379:Prognosis; D011446:Prospective Studies; D011480:Protease Inhibitors / Q000097:blood*; D016019:Survival Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood*
D014408:Biomarkers, Tumor; D002272:Carcinoembryonic Antigen; D011480:Protease Inhibitors; D019715:Tissue Inhibitor of Metalloproteinase-1; D020778:Matrix Metalloproteinase 2