ELEVATED TISSUE INHIBITOR OF METALLOPROTEINASE-1 RNA IN COLORECTAL-CANCER STROMA CORRELATES WITH LYMPH-NODE AND DISTANT METASTASES

Tissue inhibitor of metalloproteinase (TIMP) inhibits the proteolytic activity of several matrix metalloproteinases centrally involved in tu mor invasion and metastases, The purpose of this study was to determin e the origin of TIMP-1 mRNA production in both human colorectal cancer (CRC) and metastatic liver lesions as well as define the relationship s between TIMP-1 RNA expression and standard clinicopathological varia bles of CRC, Total cellular RNA, extracted from 56 CRC and 10 liver me tastases, were examined by Northern blot hybridization, The mean/norma l mucosa fold increase of TIMP-1 RNA was significantly elevated in bot h CRC (12.1 +/- 1.7) and liver metastases (10.0 +/- 3.6), No relations hip was noted between TIMP-1 expression and tumor size, location nor d ifferentiation. Based on lymph node metastases status, significantly h igher TIMP-1 RNA levels were found in CRC with metastases than in thos e without metastases (15.6 +/- 3.3 versus 7.9 +/- 1.3) (P = 0.04), Sim ilarly, TIMP-1 RNA levels were higher in primary CRC with distant meta stases than those without distant metastases (17.6 +/- 4.1 versus 9.3 +/- 1.9) (P = 0.04), In situ hybridization localized TIMP-1 mRNA predo minantly in tumor stroma within spindle fibroblast-like cells rather t han in cancer cells themselves, The correlation between the increased TIMP-1 mRNA level and advanced CRC stage noted in this study reflects a possible growth-promoting function for TIMP-1 in human CRC.