Diseases of the Colon & Rectum

, Volume 44, Issue 9, pp 1290–1296 | Cite as

Tissue inhibitor of metalloproteinase-3 is a basement membrane-associated protein that is significantly decreased in human colorectal cancer

  • ZhaoShi Zeng
  • Yi Sun
  • WeiPing Shu
  • Jose G. Guillem
Original Contributions
  • 19 Downloads

Abstract

PURPOSE: The balance between local levels of matrix metalloproteinases and tissue inhibitor of metalloproteinases is believed to play a key role in tumor invasion and metastases. Because tissue inhibitor of metalloproteinase-3 suppresses tumorigenicity and tumor invasionin vitro, the aim of this study was to determine its expression in human colorectal cancer. METHODS: Thirty-nine human colorectal cancer specimens, three adenomas, and matched normal adjacent mucosa from 39 colorectal cancer patients were analyzed. Tissue inhibitor of metalloproteinase-3 ribonucleic acid and protein expression were analyzed by Northern blot hybridization and Western blot analysis, respectively. The cellular localizations of tissue inhibitor of metalloproteinase-3 ribonucleic acid and protein were determined byin situ hybridization and immunolocalization. RESULTS: Tissue inhibitor of metalloproteinase-3 ribonucleic acid expression was increased in colorectal cancer compared with paired normal mucosa. In contrast, tissue inhibitor of metalloproteinase-3 protein level was higher in normal mucosa than in the corresponding colorectal cancer. In addition, tissue inhibitor of metalloproteinase-3 protein levels progressively decreased with advancing colorectal cancer stages. Tissue inhibitor of metalloproteinase-3 protein tumor to normal mucosa ratio was 0.74 ± 0.12, 0.51 ± 0.18, 0.48 ± 0.12, and 0.45 ± 0.2 for Dukes A (n=8), B (n=9), C (n=9), and D (n=13) stages, respectively. Both tissue inhibitor of metalloproteinase-3 messenger ribonucleic acid and protein were located predominantly within spindle-shaped and round stromal cells. Furthermore, in colonic epithelium, tissue inhibitor of metalloproteinase-3 and type IV collagen protein were similarly concentrated in the basal region. CONCLUSIONS: These data provide the first detailed description of the cellular expression of tissue inhibitor of metalloproteinase-3 in colorectal cancer and identify it as a basement membrane-associated protein. This is an important observation, because the presence of tissue inhibitor of metalloproteinase-3 protein near the basement membrane supports its role in preventing proteolytic degradation, angiogenesis, and apoptosis.

Key words

Colorectal cancer Matrix metalloproteinases Tissue inhibitor of metalloproteinase 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Liotta LA, Steeg PS, Stetler-Stevenson WG. Cancer metastasis and angiogenesis: an imbalance of positive and negative regulation. Cell 1991;64:327–36.Google Scholar
  2. 2.
    Sato H, Takino T, Okada Y,et al. A matrix metalloproteinase expressed on the surface of invasive tumour cells. Nature 1994;370:61–5.Google Scholar
  3. 3.
    Murphy G, Cawston TE, Reynolds JJ. An inhibitor of collagenase from human amniotic fluid: purification, characterization and action on metalloproteinases. Biochem J 1981;195:167–70.Google Scholar
  4. 4.
    Stetler-Stevenson WG, Krutzsch HC, Liotta LA. Tissue inhibitor of metalloproteinase (TIMP-2): a new member of the metalloproteinase inhibitor family. J Biol Chem 1989;264:17374–8.Google Scholar
  5. 5.
    Pavloff N, Staskus PW, Kishnani NS, Hawkes SP. A new inhibitor of metalloproteinases from chicken: ChIMP-3. A third member of the TIMP family. J Biol Chem 1992;267:17321–6.Google Scholar
  6. 6.
    Greene J, Wang M, Liu YE,et al. Molecular cloning and characterization of human tissue inhibitor of metalloproteinase 4. J Biol Chem 1996;271:30375–80.Google Scholar
  7. 7.
    Gasson JC, Golde DW, Kaufman SE,et al. Molecular characterization and expression of the gene encoding human erythroid-potentiating activity. Nature 1985;315:768–71.Google Scholar
  8. 8.
    Hill PA, Reynolds JJ, Meikle MC. Inhibition of stimulated bone resorption in vitro by TIMP-1 and TIMP-2. Biochim Biophys Acta 1993;1177:71–4.Google Scholar
  9. 9.
    Curry TE Jr, Mann JS, Estes RS, Jones PB. Alpha 2-macroglobulin and tissue inhibitor of metalloproteinases: collagenase inhibitors in human preovulatory ovaries. Endocrinology 1990;127:63–8.Google Scholar
  10. 10.
    Graham CH, Lala PK. Mechanism of control of trophoblast invasion in situ. J Cell Physiol 1991;148:228–34.Google Scholar
  11. 11.
    Zafarullah M, Pelletier JP, Cloutier JM, Martel-Pelletier J. Elevated metalloproteinase and tissue inhibitor of metalloproteinase mRNA in human osteoarthritic synovia. J Rheumatol 1993;20:693–7.Google Scholar
  12. 12.
    Khokha R, Waterhouse P, Yagel S,et al. Antisense RNA-induced reduction in murine TIMP levels confers oncogenicity on Swiss 3T3 cells. Science 1989;243:947–50.Google Scholar
  13. 13.
    Albini A, Melchiori A, Santi L,et al. Tumor cell invasion inhibited by TIMP-2. J Natl Cancer Inst 1991;83:775–9.Google Scholar
  14. 14.
    Montgomery AM, Mueller BM, Reisfeld RA, Taylor SM, DeClerck YA. Effect of tissue inhibitor of the matrix metalloproteinases-2 expression on the growth and spontaneous metastasis of a human melanoma cell line. Cancer Res 1994;54:5467–73.Google Scholar
  15. 15.
    Alvarez OA, Carmichael DF, DeClerck YA. Inhibition of collagenolytic activity and metastasis of tumor cells by a recombinant human tissue inhibitor of metalloproteinases. J Natl Cancer Inst 1990;82:589–95.Google Scholar
  16. 16.
    Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K. Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells: a possible new growth factor in serum. FEBS Lett 1992;298:29–32.Google Scholar
  17. 17.
    Stetler-Stevenson WG, Bersch N, Golde DW. Tissue inhibitor of metalloproteinase-2(TIMP-2) has erythroidpotentiating activity. FEBS Lett 1992;296:231–4.Google Scholar
  18. 18.
    Harvey MB, Leco KJ, Arcellana-Panlilio MY,et al. Proteinase expression in early mouse embryos is regulated by leukaemia inhibitory factor and epidermal growth factor. Development 1995;121:1005–14.Google Scholar
  19. 19.
    Apte SS, Hayashi K, Seldin MF,et al. Gene encoding a novel murine tissue inhibitor of metalloproteinases (TIMP), TIMP-3, is expressed in developing mouse epithelia, cartilage, and muscle, and is located on mouse chromosome 10. Dev Dyn 1994;200:177–97.Google Scholar
  20. 20.
    Airola K, Ahonen M, Johansson N,et al. Human TIMP-3 is expressed during fetal development, hair growth cycle, and cancer progression. J Histochem Cytochem 1998;46:437–47.Google Scholar
  21. 21.
    Apte SS, Mattei MG, Olsen BR. Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Genomics 1994;19:86–90.Google Scholar
  22. 22.
    Wick M, Haronen R, Mumberg D,et al. Structure of the human TIMP-3 gene and its cell cycle-regulated promoter. Biochem J 1995;311:549–54.Google Scholar
  23. 23.
    Sun Y, Hegamyer G, Colburn NH. Molecular cloning of five messenger RNAs differentially expressed in preneoplastic or neoplastic JB6 mouse epidermal cells: one is homologous to human tissue inhibitor of metalloproteinases-3. Cancer Res 1994;54:1139–44.Google Scholar
  24. 24.
    Bian J, Wang Y, Smith MR,et al. Suppression of in vivo tumor growth and induction of suspension cell death by tissue inhibitor of metalloproteinases (TIMP)-3. Carcinogenesis 1996;17:1805–11.Google Scholar
  25. 25.
    Anand-Apte B, Bao L, Smith R,et al. A review of tissue inhibitor of metalloproteinases-3 (TIMP-3) and experimental analysis of its effect on primary tumor growth. Biochem Cell Biol 1996;74:853–62.Google Scholar
  26. 26.
    Uria JA, Ferrando AA, Velasco G, Freije JM, Lopez-Otin C. Structure and expression in breast tumors of human TIMP-3, a new member of the metalloproteinase inhibitor family. Cancer Res 1994;54:2091–4.Google Scholar
  27. 27.
    Byrne JA, Tomasetto C, Rouyer N,et al. The tissue inhibitor of metalloproteinases-3 gene in breast carcinoma: identification of multiple polyadenylation sites and a stromal pattern of expression. Mol Med 1995;1:418–27.Google Scholar
  28. 28.
    Powe DG, Brough JL, Carter GI,et al. TIMP-3 mRNA expression is regionally increased in moderately and poorly differentiated colorectal adenocarcinoma. Br J Cancer 1997;75:1678–83.Google Scholar
  29. 29.
    Ahonen M, Baker AH, Kahari VM. Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res 1998;58:2310–5.Google Scholar
  30. 30.
    Astler VB, Coller FA. The prognostic significance of direct extension of carcinoma of the colon and rectum. Ann Surg 1954;139:846–51.Google Scholar
  31. 31.
    Sun Y, Hegamyer G, Kim H,et al. Molecular cloning of mouse tissue inhibitor of metalloproteinases-3 and its promoter: specific lack of expression in neoplastic JB6 cells may reflect altered gene methylation. J Biol Chem 1995;270:19312–9.Google Scholar
  32. 32.
    Zeng ZS, Guillem JG. Distinct pattern of matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 mRNA expression in human colorectal cancer and liver metastases. Br J Cancer 1995;72:575–82.Google Scholar
  33. 33.
    Zeng ZS, Guillem JG. Colocalisation of matrix metalloproteinase-9-mRNA and protein in human colorectal cancer stromal cells. Br J Cancer 1996;74:1161–7.Google Scholar
  34. 34.
    Kohn EC, Liotta LA. Molecular insights into cancer invasion: strategies for prevention and intervention. Cancer Res 1995;55:1856–62.Google Scholar
  35. 35.
    Zeng ZS, Cohen AM, Guillem JG. Loss of basement membrane type IV collagen is associated with increased expression of metalloproteinases 2 and 9 (MMP-2 and MMP-9) during human colorectal tumorigenesis. Carcinogenesis 1999;20:749–55.Google Scholar
  36. 36.
    Kim H, Pennie WD, Sun Y, Colburn NH. Differential functional significance of AP-1 binding sites in the promoter of the gene encoding mouse tissue inhibitor of metalloproteinases-3. Biochem J 1997;324:547–53.Google Scholar
  37. 37.
    Tyagi SC, Kumar SG, Haas SJ,et al. Post-transcriptional regulation of extracellular matrix metalloproteinase in human heart end-stage failure secondary to ischemic cardiomyopathy. J Mol Cell Cardiol 1996;28:1415–28.Google Scholar
  38. 38.
    Zeng ZS, Guillem JG. Unique activation of matrix metalloproteinase-9 within human liver metastasis from colorectal cancer. Br J Cancer 1998;78:349–53.Google Scholar
  39. 39.
    Anand-Apte B, Pepper MS, Voest E,et al. Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Invest Ophthalmol Vis Sci 1997;38:817–23.Google Scholar
  40. 40.
    Yang TT, Hawkes SP. Role of the 21-kDa protein TIMP-3 in oncogenic transformation of cultured chicken embryo fibroblasts. Proc Natl Acad Sci U S A 1992;89:10676–80.Google Scholar
  41. 41.
    Baker AH, Zaltsman AB, George SJ, Newby AC. Divergent effects of tissue inhibitor of metalloproteinase-1, -2, or -3 overexpression on rat vascular smooth muscle cell invasion, proliferation, and death in vitro: TIMP-3 promotes apoptosis. J Clin Invest 1998;101:1478–87.Google Scholar

Copyright information

© The American Society of Colon and Rectal Surgeons 2001

Authors and Affiliations

  • ZhaoShi Zeng
    • 1
  • Yi Sun
    • 2
  • WeiPing Shu
    • 1
  • Jose G. Guillem
    • 1
  1. 1.From the Colorectal Service, Department of SurgeryMemorial Sloan-Kettering Cancer CenterNew York
  2. 2.Cancer Molecular Sciences, Pfizer Global Research & DevelopmentAnn Arbor LaboratoriesAnn Arbor

Personalised recommendations