Distinct endobronchial expression of matrix-metalloproteinases (MMP) and their endogenous inhibitors in lung cancer.
BACKGROUND
Degradation of extracellular matrix (ECM) and basement membranes is required for tumour cell invasion and metastasis. The ECM is degraded by matrix metalloproteinases (MMP) which are counteracted by tissue inhibitors of metalloproteinases (TIMP). In aggressive tumours the balance of proteolysis and antiproteolysis is disrupted, resulting in fast tumour progression and invasiveness. We examined MMP and TIMP expression patterns in bronchial washings of 58 consecutive lung tumour patients and 10 controls. Pathohistological investigations revealed squamous cell carcinoma (n = 23), adenocarcinoma (n = 18), small cell lung carcinoma (n = 9), and pulmonary metastases of extrapulmonary tumours (n = 8). MMP/TIMP expression was correlated to histology, location, or staging of tumours.


METHODS
Expression and activity of MMP was identified by zymography and Western blotting. Expression of TIMP-1 and TIMP-2 was analysed by Western blotting and enzyme-linked immunosorbent assays.


RESULTS
We identified MMP-1, MMP-2 and MMP-9, but not MMP-3 or MMP-8 in bronchial washings. All MMPs were expressed in the tumour-affected and the tumour-free parts of the lung. While MMP-1 and MMP-9 were present in all samples, the inactive precursor of MMP-2 was specifically expressed in adenocarcinoma or lung metastases of extrapulmonary tumours. No MMP-2 was found in controls. While TIMP-1 was expressed in all samples, TIMP-2 was not detectable.


CONCLUSIONS
The tumour type-specific expression of the MMP-2 precursor in adenocarcinoma and lung metastases suggests that MMP-2 in the absence of TIMP-2 correlates with aggressive tumour progression and may serve as an indicator for poor prognosis.
Reichenberger
F
F
Pulmonary Division, Department of Internal Medicine and Research, University Hospital, Basel, Switzerland.
Eickelberg
O
O
Wyser
C
C
Perruchoud
A P
AP
Roth
M
M
Tamm
M
M
D000230:Adenocarcinoma / Q000201:enzymology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001992:Bronchoalveolar Lavage Fluid; D018288:Carcinoma, Small Cell / Q000201:enzymology; D002294:Carcinoma, Squamous Cell / Q000201:enzymology; D004797:Enzyme-Linked Immunosorbent Assay; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology* / Q000556:secondary; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism* / Q000494:pharmacology; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism* / Q000494:pharmacology
D000970:Antineoplastic Agents; D019715:Tissue Inhibitor of Metalloproteinase-1; D019716:Tissue Inhibitor of Metalloproteinase-2; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2