Tissue inhibitor of metalloproteinases-1 (TIMP-1) RNA is expressed at elevated levels in malignant non-Hodgkin's lymphomas.
Secreted metalloproteinases (MPs) and their specific inhibitors (TIMPs, tissue inhibitors of MPs) are important mediators of extracellular matrix metabolism. Previous studies have linked either excessive MP release or reduced TIMP-1 production to the invasive and metastatic phenotypes of cancer cells. In the present study we investigated the relationship between the expression of TIMP-1 and the clinical behavior of 28 non-Hodgkin's lymphomas. Northern blot analysis showed that levels of TIMP-1 mRNAs correlated directly with clinical aggressiveness: tumors in the high-grade category contained the highest levels of TIMP-1 transcripts approaching those found in maximally growth factor-stimulated fibroblasts in vitro. In situ hybridization localized the TIMP-1 expression to stromal cells of endothelial and fibroblastic origin. In contrast, transcripts hybridizing with metalloproteinase gene probes (interstitial collagenase and 72-Kd type IV collagenase) were expressed at very low levels in malignant lymphomas and their expression was not coordinately regulated with that of TIMP-1. The majority of tumors expressed either interstitial collagenase or 72-Kd type IV collagenase, and only a small number expressed both. Interstitial collagenase transcripts were only detected in high-grade tumors. The relative levels of TIMP-1 expression did not correlate with the degree of fibrosis of the tumors. Our data suggest the importance of tumor-stromal interactions in non-Hodgkin's lymphomas, and moreover, our results indicate a possible relationship between high-level, localized expression of TIMP-1 and the malignant phenotype of high-grade advanced-stage lymphomas.
Kossakowska
A E
AE
Department of Pathology, University of Calgary, Alberta, Canada.
Urbanski
S J
SJ
Edwards
D R
DR
D015152:Blotting, Northern; D015342:DNA Probes; D015870:Gene Expression; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000235:genetics* / Q000473:pathology; D003012:Microbial Collagenase / Q000235:genetics; D009693:Nucleic Acid Hybridization; D015347:RNA Probes; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics* / Q000302:isolation & purification; D019714:Tissue Inhibitor of Metalloproteinases; D014158:Transcription, Genetic
D015342:DNA Probes; D006023:Glycoproteins; D015347:RNA Probes; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D019714:Tissue Inhibitor of Metalloproteinases; D003012:Microbial Collagenase