Tissue MMP-2 and MMP-9 [corrected] are better prognostic factors than serum MMP-2/TIMP-2--complex or TIMP-1 [corrected] in stage [corrected] I-III lung carcinoma.
Matrix metalloproteinases (MMPs) are involved in tumor growth and spreading. Here, we investigated the tumor immunoreactive protein of MMP-2, MMP-9 and TIMP-1 as well as the levels of circulating total TIMP-1 and MMP-2/TIMP-2-complex as prognostic factors in lung cancer patients. The material included 59 patients, 30 with a squamous cell carcinoma, 21 with an adenocarcinoma and eight with other histology. Circulating antigens were measured by ELISA assay and the protein expression in primary tumors was analyzed by streptavidin-biotin immunohistochemical staining using specific monoclonal antibodies. The strong positivity for MMP-2 or MMP-9 in tumor predicted poor prognosis. The 5-year survival rates were 83 or 85% in patients negative for MMP-2 or MMP-9, respectively. Only 17% of the patients with a tumor highly positive for MMP-2 and 43% of those with a high positivity for MMP-9 survived at that time (Cox regression P=0.042 for MMP-2 and log rank P=0.046 for MMP-9). On the contrary, strong tissue positivity for TIMP-1 demonstrated a tendency for a favorable survival, although the difference did not reach statistical significance. In patients with a squamous cell carcinoma Stage I, low serum TIMP-1 (<or=300 ng/ml) also predicted unfavorable survival (log rank P=0.033). Further in subgroup of patients treated by lobectomy (n=29), the high levels of circulating MMP-2/TIMP-2-complex (>or=300 ng/ml) associated with an increased survival rate, the 5-year survival being 81 versus 34% (log rank P=0.069) in patients with high or low serum levels for MMP-2/TIMP-2-complex, respectively. Tissue MMP-2 correlated to high expression of MMP-9 immunoreactive protein (P=0.003), but the serum levels of MMP-2/TIMP-2-complex or TIMP-1 did not correlate to the immunostaining of the corresponding tumors. We conclude that in lung carcinoma the best prognostic value is achieved by using immunohistochemistry for MMP-2 and MMP-9. In early disease, however, serum TIMP-1 or MMP-2/TIMP-2-complex could offer some further prognostic value.
Department of Oncology and Radiotherapy, Oulu University Hospital, University of Oulu, P.O. Box 22, FIN-90029 OYS, Finland.
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S
Hoikkala
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Pääkkö
Y
Y
Soini
R
R
Mäkitaro
V
V
Kinnula
T
T
Turpeenniemi-Hujanen
D000230:Adenocarcinoma / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000097:blood*; D002294:Carcinoma, Squamous Cell / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis* / Q000097:blood*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D016019:Survival Analysis; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000032:analysis* / Q000097:blood*
D014408:Biomarkers, Tumor; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9