Studies of tissue inhibitors of metalloproteinases (TIMPs) suggest that one of their main functions is to inhibit metalloproteinase (MMP) activity and thus prevent tumor invasion by preserving extracellular matrix (ECM) integrity. In the present study we examined the distribution of transcripts for TIMP-1, MMP-2 and MMP-9 in monkey hepatocellular carcinoma tissues. In situ hybridization demonstrated elevated levels of TIMP-1 transcripts in fibrous tissue septa, tumor inflammatory infiltrate, tumor blood vessels and in expanded portal areas. However, elevated transcripts for MMP-2 and MMP-9 were found only in tumor inflammatory infiltrate. In lung metastasis high levels of TIMP-1 transcripts were found in the stromal cells surrounding necrotic tumor nodules, in tumor blood vessels, and in mesothelial cells. MMP-9 transcripts were elevated at the periphery of the necrotic tumor nodules. These findings suggest that TIMP-1 and type IV collagenases/gelatinases can be independently regulated in vivo and that TIMP-1 may have functions in ECM remodeling which are unrelated to inhibition of MMP activity.
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Mareel MM, De Baetselier P and Van Roy FM, 1991, Cellular activities implicated in invasion and metastasis. In: Mechanisms of Invasion and Metastasis. Boca Raton, Ann Arbor: CRC Press, pp. 73–219.
Turpeenniemi-Hujanen T, Thorgeirsson UP, Hart IR, Grant SS and Liotta LA, 1985, Expression of collagenase IV (basement membrane collagenase) activity in murine tumor cell hybrids that differ in metastatic potential. J Natl Cancer Inst, 75, 99–103.
Ballin M, Gomez DE, Sinha CC and Thorgeirsson UP, 1988, Ras oncogene mediated induction of a 92 kDa metalloproteinase; strong correlation with the malignant phenotype. Biochem Biophys Res Commun, 154, 832–8.
Pyke C, Ralfkiaer E, Huhtala P, Hurskainen T, Dano K and Tryggvason K, 1992, Localization of messenger RNA for Mr 72,000 and 92,000 type IV collagenases in human skin cancers by in situ hybridization. Cancer Res, 52, 1336–41.
Van Der Stappen JWJ, Hendriks T and Wobbes T, 1990, Correlation between collagenolytic activity and grade of histological differentiation in colorectal tumors. Int J Cancer, 45, 1071–8.
Hewitt RE, Leach IH, Powe DG, Clark IM, Cawston TE and Turner DR, 1991, Distribution of collagenase and tissue inhibitor of metalloproteinases (TIMP) in colorectal tumors. Int J Cancer, 49, 666–72.
Kossakowska AE, Urbanski SJ and Edwards DR, 1991, Tissue inhibitor of metalloproteinases-1 (TIM P-1) RNA is expressed at elevated levels in malignant nonHodgkin's lymphomas. Blood, 77, 2475–81.
Kossakowska AE, Urbanski SJ, Watson A, Hayden LJ and Edwards DR, 1993, Patterns of expression of metalloproteinases and their inhibitors in human malignant lymphomas. Oncol Res, 5, 19–28.
Poulsom R, Hanby AM, Pignatelli M, et al. 1993, Expression of gelatinase A and TIMP-2 mRNAs in desmoplastic fibroblasts in both mammary carcinomas and basal cell carcinomas of the skin. J Clin Pathol, 46, 429–36.
Hicks NJ, Ward RV and Reynolds JJ, 1984, A fibrosarcoma model derived from mouse embryo cells: growth properties and secretion of collagenase and metalloproteinase inhibitor (TIMP) by tumor cell lines. Int J Cancer, 33, 835–44.
Khokha R, Waterhouse P, Yagel S, et al. 1989, Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells. Science, 243, 947–50.
Clavel C, Polette M, Doco M, Binninger I and Birembaut P, 1992, Immunolocalization of matrixmetalloproteinases and their tissue inhibitor in human mammary pathology. Bull Cancer, 79, 261–70.
Polette M, Clavel C, Birembaut P and De Clerk YA, 1993, Localization by in situ hybridization of mRNAs encoding stromelysin 3 and tissue inhibitors of metalloproteinases TIMP-1 and TIMP-2 in human head and neck carcinomas. Path Res Pract, 189, 1052–7.
Nakatsukasa H, 1986, Type IV collagen-degrading enzyme activity in hepatocellular carcinoma. Acta Med Okayama, 40, 183–91.
Fukada Y, Imoto M, Koyama Y, et al. 1991, Immunohistochemical study on tissue inhibitors of metalloproteinases in normal and pathological human livers. Gastroenterologica Japonica, 26, 37–41.
Muzillo DA, Imoto M, Fukada Y, et al. 1993, Clinical evaluation of serum tissue inhibitor of metalloproteinases-1 levels in patients with liver disease. J Gastroenterol Hepatol, 8, 437–41.
Adamson RH, Takayama S, Sugimura T and Thorgeirsson UP, 1994, Induction of hepatocellular carcinoma in non-human primates by the food mutagen 2-amino-3methylimidazo[4,5-f]quinoline. Envir Hlth Perspect, 102, 190–3.
Angerer LM and Angerer RC, 1992, In situ hybridization to cellular RNA with radiolabelled RNA probes. In: Wilkinson DG, ed. In Situ Hybridization: A Practical Approach. Oxford: IRL Press at Oxford University Press, pp. 15–32.
Mackay AR, Ballin M, Pelina MD, et al. 1992, Effect of phorbol ester and cytokines on matrix metalloproteinase and tissue inhibitor of metalloproteinase expression in tumor and normal cell lines. Invasion Met, 12, 168–84.
Edwards DR, Murphy G, Reynolds JJ, et al. 1987, Transforming growth factor beta modulates the expression of collagenase and metalloproteinase inhibitor. EMBO J, 6, 1899–904.
Overall CM, Wrana JL and Sodek J, 1989, Independent regulation of collagenase, 72-kDa progelatinase and metalloproteinase inhibitor expression in human fibro blasts by transforming growth factor-beta. J Biol Chem, 264, 1860–9.
Lotz M and Guerne P-A, 1991, Interleukin-6 induces the synthesis of tissue inhibitor of metalloproteinases-1/erythroid potentiating activity (TIMP-1/EPA). J Biol Chem, 266, 2017–20.
Campbell EJ, Cury JD, Shapiro SD, Goldberg GI and Welgus HG, 1991, Neutral proteinases of human mononuclear phagocytes. Cellular differentiation markedly alters cell phenotype for serine proteinases, metalloproteinases and tissue inhibitor of metalloproteinases. J Immunol, 146, 1286–93.
Visscher DW, Hoyhtya M, Ottosen SK, et al. 1994, Enhanced expression of tissue inhibitor of metalloproteinase-2 (TIMP-2) in the stroma of breast carcinomas correlates with tumor recurrence. Int J Cancer, 59, 339–44.
Okazaki I and Maruyama K, 1974, Collagenase activity in experimental hepatic fibrosis. Nature, 252, 49–50.
Montfort I, Perez-Tamayo R, Alvizouri AM and Tello E, 1990, Collagenase of hepatocytes and sinusoidal liver cells in the reversibility of experimental cirrhosis of the liver. Virchows Archiv B Cell Pathol, 59, 281–9.
Milani S, Herbst H, Schuppan D, et al. 1994, Differential expression of matrix-metalloproteinase-1 and -2 genes in normal and fibrotic human liver. Am J Pathol, 144, 528–37.
Montfort I and Perez-Tamayo R, 1978, Collagenase in experimental carbon tetrachloride cirrhosis of the liver. Am J Pathol, 92, 411–20.
Emonard HP, Remacle AG, Noel AG, Grimaud J-A, Stetler-Stevenson WG and Foidart J-M, 1992, Tumor cell surface-associated binding site for the Mr 72,000 type IV collagenase. Cancer Res, 52, 5845–8.
Zucker S, Wieman JM, Lysik RM, et al. 1987, Enrichment of collagen and gelatin degrading activities in the plasma membranes of human cancer cells. Cancer Res, 47, 1608–14.
Zucker S, Moll VM, Lysik RM, et al. 1990, Extraction of type-IV collagenase/gelatinase from plasma membranes of human cancer cells. Int J Cancer, 45, 1137–42.
Docherty AJP, Lyons A, Smith BJ, Wright EM, Stephens PE and Harris TJR, 1985, Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid potentiating activity. Nature, 315, 764–7.
Bertaux B, Hornebeck W, Eisen AZ and Dubertret L, 1991, Growth stimulation of human keratinocytes by tissue inhibitor of metalloproteinases. J Invest Dermatol, 97, 679–85.
Gauldie J, Richards C, Harnish D, Lansdorp P and Baumann H, 1987, Interferon-beta 2/B cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte stimulating factor and regulates the major acute phase protein response in liver cells. Proc Natl Acad Sci, 84, 7251–5.
Kordula T, Guttgemann I, Rose-John S, et al. 1992, Synthesis of tissue inhibitor of metalloproteinase-1 (TIMP-1) in human hepatoma cells (HepG2). Upregulation by interleukin-6 and transforming growth factor-beta 1. FEBS Lett, 313, 143–7.
Takigawa M, Nishida Y, Suzuki F, Kishi J-I, Yamashita K and Hayakawa T, 1990, Induction of angiogenesis in chick yolk-sac membrane by polyamines and its inhibition by tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2). Biochem Biophys Res Commun, 172, 1264–71.
Johnson MD, Kim H-RC, Chester L, Tsao-Wu G, Bouk N and Polverini PJ, 1994, Inhibition of angiogenesis by tissue inhibitor of metalloproteinase. J Cell Physiol, 160, 194–202.
Saarialho-Kere UK, Chang ES, Welgus HG and Parks WC, 1992, Distinct localization of collagenase and tissue inhibitor of metalloproteinases expression in wound healing associated with ulcerative pyogenic granuloma. J Clin Invest, 90, 1952–7.
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Lindsay, C.K., Thorgeirsson, U.P. Localization of messenger RNA for tissue inhibitor of metalloproteinases-1 and type IV collagenases/gelatinases in monkey hepatocellular carcinomas. Clin Exp Metast 13, 381–388 (1995). https://doi.org/10.1007/BF00121914
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DOI: https://doi.org/10.1007/BF00121914