PATTERNS OF EXPRESSION OF METALLOPROTEINASES AND THEIR INHIBITORS IN HUMAN-MALIGNANT LYMPHOMAS

Forty-two cases of malignant lymphomas were studied for the expression of matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMP s) by Northern blot and in situ hybridization. The lymphomas were clas sified according to Working Formulation classification (25 high grade, 15 low grade, and 2 intermediate grade). The MMPs studied included: 7 2-kDa and 92-kDa gelatinases (type IV collagenases), interstitial coll agenase, PUMP-1 (MMP-7), and stromelysins 1 and 3. TIMPs included TIMP -1 and TIMP-2. All but one case expressed TIMP-1, and TIMP-2 transcrip ts were detected in 35 cases. Among the MMPs, 92-kDa gelatinase was ex pressed most consistently (35 cases), whereas mRNA transcripts of 72-k Da gelatinase, interstitial collagenase, and PUMP-1 were detected in o nly a few cases. Stromelysins 1 and 3 mRNAs were not detected in any o f the tumors studied. However, marked differences in the level of expr ession of certain MMPs and TIMPs were found among different grades of malignant lymphomas. The low grade tumors expressed low and relatively constant levels of TIMP-1, TIMP-2, and 92-kDa gelatinase transcripts, whereas high grade lymphomas displayed variable amounts of mRNAs for TIMPs and MMPs, with a trend toward elevated TIMP-1 and 92-kDa gelatin ase mRNA levels. In situ hybridization localized TIMP-1 transcripts to stromal cells, while 92-kDa gelatinase transcripts were most abundant in ''starry sky'' macrophages and large lymphoma cells. Zymography sh owed that active 92-kDa gelatinase is present in tumor protein extract s and differences in the level of the enzymatic activity were seen bet ween low and high grade lymphomas. Our data indicate that 92-kDa gelat inase and TIMP-1 expression by human malignant lymphomas may play an i mportant role in controlling their biologic aggressiveness.