Abstract
Oesophageal adenocarcinoma is believed to arise from metaplastic mucosa in the distal oesophagus, a condition also known as Barrett's oesophagus (BE). BE develops as a result of injury caused by refluxing gastric and duodenal contents and is associated with increased risk of malignant transformation. Matrix metalloproteinases (MMPs) have been implicated in all aspects of tumour progression; tumour growth, basement membrane degradation, invasion and metastatic spread. Using in situ hybridization, we investigated the expression patterns of collagenases-1 and -3, stromelysin-2, matrilysin, metalloelastase and TIMPs-1 and -3 in BE, adenocarcinoma and lymph-node metastases. Matrilysin was expressed abundantly in 12/15 tumours and in 4/6 lymph-node metastases and its expression correlated with the histological aggressiveness of tumour. Matrilysin and metalloelastase were upregulated already in BE. Stromelysin-2 and collagenase-3 expression was detected only in a few tumours. Collagenase-1 was expressed by cancer and stromal cells in 9/15 tumours. Tumour-infiltrating macrophages expressed metalloelastase in 13/15 cancers. TIMPs-1 and -3 were expressed in 12/15 and 11/15 tumours, respectively. Laminin-5 and tenascin were abundantly expressed at the invasive front of poorly differentiated tumours, but not in BE. Our results indicate that matrilysin is the principal MMP expressed by tumour cells in oesophageal adenocarcinoma, and further studies are needed to investigate whether matrilysin or tenascin-C could be used as a predictive marker for progression of BE to cancer. © 2001 Cancer Research Campaign
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References
Adachi Y, Yamamoto H, Itoh F, Hinoda Y, Okada Y and Imai K (1999) Contribution of matrilysin (MMP-7) to the metastatic pathway of human colorectal cancers. Gut 45: 252–258
Ahonen M, Baker AH and Kahari VM (1998) Adenovirus-mediated gene delivery of tissue inhibitor of metalloproteinases-3 inhibits invasion and induces apoptosis in melanoma cells. Cancer Res 58: 2310–2315
Airola K, Ahonen M, Johansson N, Heikkilä P, Kere J, Kähäri V-M and Saarialho-Kere UK (1998) Human TIMP-3 is expressed during fetal development, hair growth cycle and cancer progression. J Histochem Cytochem 46: 437–448
Airola K, Karonen T, Vaalamo M, Lehti K, Lohi J, Kariniemi AL, Keski-Oja J and Saarialho-Kere UK (1999) Expression of collagenases-1 and -3 and their inhibitors TIMP-1 and -3 correlates with the level of invasion in malignant melanomas. Br J Cancer 80: 733–743
Anand-Apte B, Pepper MS, Voest E, Montesano R, Olsen B, Murphy G, Apte SS and Zetter B (1997) Inhibition of angiogenesis by tissue inhibitor of metalloproteinase-3. Invest Ophthalmol Vis Sci 38: 817–823
Antonioli DA and Wang HH (1997) Morphology of Barrett's esophagus and Barrett's-associated dysplasia and adenocarcinoma. Gastroenterol Clin North Am 26: 495–506
Apte SS, Olsen BR and Murphy G (1996) The gene structure of tissue inhibitor of metalloproteinases (TIMP)-3 and its inhibitory activities define the distinct TIMP gene family. J Biol Chem 270: 14313–14318
Bonelli L (1993) Barrett's esophagus: results of a multicentric survey. G.O.S.P.E. (Gruppo Operativo per lo Studio delle Precancerosi Esofagee). Endoscopy 25: 652–654
Brabletz T, Jung A, Dag S, Hlubek F and Kirchner T (1999) Beta-catenin regulates the expression of the matrix metalloproteinase-7 in human colorectal cancer. Am J Pathol 155: 1033–1038
Cazorla M, Hernandez L, Nadal A, Balbin M, Lopez JM, Vizoso F, Fernandez PL, Iwata K, Cardesa A, Lopez-Otin C and Campo E (1998) Collagenase-3 expression is associated with advanced local invasion in human squamous cell carcinomas of the larynx. J Pathol 186: 144–150
Chambers AF and Matrisian LM (1997) Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 89: 1260–1270
Chandler S, Cossins J, Lury J and Wells G (1996) Macrophage metalloelastase degrades matrix and myelin proteins and processes a tumour necrosis factor-alpha fusion protein. Biochem Biophys Res Commun 228: 421–429
Etoh T, Inoue H, Yoshikawa Y, Barnard GF, Kitano S and Mori M (2000) Increased expression of collagenase-3 (MMP-13) and MT1-MMP in oesophageal cancer is related to cancer aggressiveness. Gut 47: 50–56
Feinberg MW, Jain MK, Werner F, Sibinga NE, Wiesel P, Wang H, Topper JN, Perrella MA and Lee ME (2000) Transforming growth factor-beta 1 inhibits cytokine-mediated induction of human metalloelastase in macrophages. J Biol Chem 275: 25766–25773
Fingleton BM, Heppner Goss KJ, Crawford HC and Matrisian LM (1999) Matrilysin in early stage intestinal tumorigenesis. APMIS 107: 102–110
Gronski TJ Jr, Martin RL, Kobayashi DK, Walsh BC, Holman MC, Huber M, Van Wart HE and Shapiro SD (1997) Hydrolysis of a broad spectrum of extracellular matrix proteins by human macrophage elastase. J Biol Chem 272: 12189–12194
Heppner KJ, Lynn MM, Jensen RA and Rodgers WH (1996) Expression of most matrix metalloproteinase family members in breast cancer represents a tumor-induced host response. Am J Pathol 149: 273–282
Jahkola T, Toivonen T, von Smitten K, Blomqvist C and Virtanen I (1996) Expression of tenascin in invasion border of early breast cancer correlates with higher risk of distant metastasis. Int J Cancer 69: 445–447
Jankowski JA, Wright NA, Meltzer SJ, Triadafilopoulos G, Geboes K, Casson AG, Kerr D and Young LS (1999) Molecular evolution of the metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. Am J Pathol 154: 965–973
Johansson N, Airola K, Grenman R, Kariniemi AL, Saarialho-Kere U and Kahari VM (1997) Expression of collagenase-3 (matrix metalloproteinase- 13) in squamous cell carcinomas of the head and neck. Am J Pathol 151: 499–508
Johansson N, Vaalamo M, Grenman S, Hietanen S, Klemi P, Saarialho-Kere U and Kahari VM (1999) Collagenase-3 (MMP-13) is expressed by tumor cells in invasive vulvar squamous cell carcinomas. Am J Pathol 154: 469–480
Kahari VM and Saarialho-Kere U (1999) Matrix metalloproteinases and their inhibitors in tumour growth and invasion. Ann Med 31: 34–45
Kerkela E, Ala-aho R, Jeskanen L, Lohi J, Grenman R, Kahari VM and Saarialho-Kere U (2001) Differential patterns of stromelysin-2 (MMP-10) and MT1-MMP (MMP-14) expression in epithelial skin cancers. Br J Cancer 84: 659–669
Koshikawa N, Giannelli G, Cirulli V, Miyazaki K and Quaranta V (2000) Role of cell surface metalloprotease MT1-MMP in epithelial cell migration over laminin-5. J Cell Biol 148: 615–624
Kusukawa J, Harada H, Shima I, Sasaguri Y, Kameyama T and Morimatsu M (1996) The significance of epidermal growth factor receptor and matrix metalloproteinase-3 in squamous cell carcinoma of the oral cavity. Eur J Cancer B Oral Oncol 32B: 217–221
Lucas R, Holmgren L, Garcia I, Jimenez B, Mandriota SJ, Borlat F, Sim BK, Wu Z, Grau GE, Shing Y, Soff GA, Bouck N and Pepper MS (1998) Multiple forms of angiostatin induce apoptosis in endothelial cells. Blood 92: 4730–4741
Martin DC, Ruther U, Sanchez-Sweatman OH, Orr FW and Khokha R (1996) Inhibition of SV40 T antigen-induced hepatocellular carcinoma in TIMP-1 transgenic mice. Oncogene 13: 569–576
McDonnell S, Navre M, Coffey RJ and Matrisian LM (1991) Expression and localization of the matrix metalloproteinase Pump-1 (MMP-7) in human gastric and colon carcinomas. Mol Carcinog 4: 527–533
Mueller J, Werner M and Siewert JR (2000) Malignant progression in Barrett's esophagus: pathology and molecular biology. Recent Results Cancer Res 155: 29–41
Murphy G, Cockett MI, Ward RV and Docherty AJ (1991) Matrix metalloproteinase degradation of elastin, type IV collagen and proteoglycan. A quantitative comparison of the activities of 95 kDa and 72 kDa gelatinases, stromelysins-1 and -2 and punctuated metalloproteinase (PUMP). Biochem J 277: 277–279
Murray GI, Duncan ME, O'Neil P, McKay JA, Melvin WT and Fothergill JE (1998) Matrix metalloproteinase-1 is associated with poor prognosis in oesophageal cancer. J Pathol 185: 256–261
Nagase H and Woessner JF Jr (1999) Matrix metalloproteinases. J Biol Chem 274: 21491–21494
Ohashi K, Nemoto T, Nakamura K and Nemori R (2000) Increased expression of matrix metalloproteinase 7 and 9 and membrane type 1-matrix metalloproteinase in esophageal squamous cell carcinomas. Cancer 88: 2201–2209
Park HI, NI J, Gerkema FE, Liu D, Belozerov VE and Sang QX (2000) Identification and characterization of human endometase (Matrix metalloproteinase-26) from endometrial tumor. J Biol Chem 275: 20540–20544
Peters JH, Clark GW, Ireland AP, Chandrasoma P, Smyrk TC and DeMeester TR (1994) Outcome of adenocarcinoma arising in Barrett's esophagus in endoscopically surveyed and nonsurveyed patients. J Thorac Cardiovasc Surg 108: 813–821
Pyke C, Romer J, Kallunki P, Lund LR, Ralfkiaer E, Dano K and Tryggvason K (1994) The γ2-chain of kalinin/laminin-5 is preferentially expressed in invading malignant cells in human cancers. Am J Pathol 145: 782–791
Pyke C, Salo S, Ralfkiaer E, Romer J, Dano K and Tryggvason K (1995) Laminin-5 is a marker of invading cancer cells in some human carcinomas and is coexpressed with the receptor for urokinase plasminogen activator in budding cancer cells in colon adenocarcinomas. Cancer Res 55: 4132–4139
Saarialho-Kere U, Chang ES, Welgus HG and Parks WC (1992) Distinct localization of collagenase and TIMP expression in wound healing associated with ulcerative pyogenic granuloma. J Clin Invest 90: 1952–1957
Saarialho-Kere UK, Pentland AP, Birkedal-Hansen H, Parks WC and Welgus HG (1994) Distinct populations of basal keratinocytes express stromelysin-1 and stromelysin-2 in chronic wounds. J Clin Invest 94: 79–88
Saarialho-Kere U, Vaalamo M, Puolakkainen P, Airola K, Parks WC and Karjalainen-Lindsberg M-L (1996) Enhanced expression of matrilysin, collagenase and stromelysin-1 in gastrointestinal ulcers. Am J Pathol 148: 519–526
Shima I, Sasaguri Y, Kusukawa J, Yamana H, Fujita H, Kakegawa T and Morimatsu M (1992) Production of matrix metalloproteinase-2 and metalloproteinase-3 related to malignant behavior of esophageal carcinoma. A clinicopathologic study. Cancer 70: 2747–2753
Siri A, Knauper V, Veirana N, Caocci F, Murphy G and Zardi L (1995) Different susceptibility of small and large human tenascin-C isoforms to degradation by matrix metalloproteinases. J Biol Chem 270: 8650–8654
Skyldberg B, Salo S, Eriksson E, Aspenblad U, Moberger B, Tryggvason K and Auer G (1991) Laminin-5 as a marker of invasiveness in cervical lesions. J Natl Cancer Inst 91: 1882–1887
Sutinen M, Kainulainen T, Hurskainen T, Vesterlund E, Alexander JP, Overall CM, Sorsa T and Salo T (1998) Expression of matrix metalloproteinases (MMP-1 and -2) and their inhibitors (TIMP-1, -2 and -3) in oral lichen planus, dysplasia, squamous cell carcinoma and lymph node metastasis. Br J Cancer 77: 2239–2245
Tanaka M, Itai T, Adachi M and Nagata S (1998) Downregulation of Fas ligand by shedding. Nat Med 4: 31–36
Tani T, Lumme A, Linnala A, Kivilaakso E, Kiviluoto T, Burgeson RE, Kangas L, Leivo I and Virtanen I (1997) Pancreatic carcinomas deposit laminin-5, preferably adhere to laminin-5, and migrate on the newly deposited basement membrane. Am J Pathol 151: 1289–1302
Vaalamo M, Weckroth M, Puolakkainen P, Kere J, Saarinen P, Lauharanta J and Saarialho-Kere UK (1996) Patterns of matrix metalloproteinase and TIMP-1 expression in chronic and normally healing human cutaneous wounds. Br J Dermatol 135: 52–59
Vaalamo M, Mattila L, Johansson N, Kariniemi A-L, Karjalainen-Lindsberg M-L, Kähäri V-M and Saarialho-Kere UK (1997) Distinct populations of stromal cells express collagenase-3 (MMP-13) and collagenase-1 (MMP-1) in chronic ulcers but not in normally healing wounds. J Invest Dermatol 109: 96–101
Vaalamo M, Karjalainen-Lindsberg M-L, Puolakkainen P, Kere J and Saarialho-Kere U (1998) Distinct expression profiles of stromelysin-2 (MMP-10), collagenase-3 (MMP-13), macrophage metalloelastase (MMP-12), and tissue inhibitor of metalloproteinases-3 (TIMP-3) in intestinal ulcerations. Am J Pathol 152: 1005–1014
van Sandick JW, van Lanschot JJ, Kuiken BW, Tytgat GN, Offerhaus GJ and Obertop H (1998) Impact of endoscopic biopsy surveillance of Barrett's oesophagus on pathological stage and clinical outcome of Barrett's carcinoma. Gut 43: 216–222
Velasco G, Pendas AM, Fueyo A, Knauper V, Murphy G and Lopez-Otin C (1999) Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members. J Biol Chem 274: 4570–4576
Westermarck J and Kahari VM (1999) Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J 13: 781–792
Yamamoto H, Adachi Y, Itoh F, Iku S, Matsuno K, Kusano M, Arimura Y, Endo T, Hinoda Y, Hosokawa M and Imai K (1999) Association of matrilysin expression with recurrence and poor prognosis in human esophageal squamous cell carcinoma. Cancer Res 59: 3313–3316
Yamashita K, Mori M, Shiraishi T, Shibuta K and Sugimachi K (2000) Clinical significance of matrix metalloproteinase-7 expression in esophageal carcinoma. Clin Cancer Res 6: 1169–1174
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Salmela, M., Karjalainen-Lindsberg, ML., Puolakkainen, P. et al. Upregulation and differential expression of matrilysin (MMP-7) and metalloelastase (MMP-12) and their inhibitors TIMP-1 and TIMP-3 in Barrett's oesophageal adenocarcinoma. Br J Cancer 85, 383–392 (2001). https://doi.org/10.1054/bjoc.2001.1929
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DOI: https://doi.org/10.1054/bjoc.2001.1929
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