Abstract
Malignant tumours often induce a fibroproliferative response in the adjacent stroma, characterized by increased expression of type I and type III procollagens. In normal tissues, fibrillar collagens normally undergo extensive intermolecular cross-linking that provides tensile strength to the tissue. Here we set out to characterize collagen cross-linking in human ovarian carcinoma tissue in vivo. Biochemical and immunochemical methods were used for cross-linked telopeptides of type I and III collagens in samples of benign and malignant serous tumours. The locations and staining patterns of these proteins were visualized immunohistochemically. The contents of both total collagen and the cross-linked type I and type III collagens in the malignant samples were only about 20% of those in the benign tumours. The cross-linked telopeptide antigens derived from the collagens were smaller and more heterogeneous in size in the malignant than in the benign tumours, indicating a defective cross-linking process scarcely leading to the formation of mature cross-links in the collagen fibres in malignancy. Immunostaining revealed disorganized type I and type III collagen bundles in carcinomas. These findings suggest that the collagen cross-linking process is aberrant in malignant tumours, possibly resulting in increased susceptibility of tumour collagens for the proteolysis often associated with tumour invasion.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Aznavoorian, S, Murphy, AN, Stetler-Stevenson, WG & Liotta, LA (1993) Molecular aspects of tumor cell invasion and metastasis. Cancer 71: 1368–1483
Birk, DE, Zycband, EI, Winkelmann, DA & Trelstad, RL (1990) Collagen fibrillogenesis in situ: discontinuous segmental assembly in extracellular compartments. Ann NY Acad Sci 580: 176–194
Bode, MK, Mosorin, M, Satta, J, Risteli, L, Juvonen, T & Risteli, J (1999) Complete processing of type III collagen in atherosclerotic plaques. Arterioscl Thromb Vasc Biol 19: 1506–1511
Contente, S, Kenyon, K, Rimoldi, D & Friedman, RM (1990) Expression of gene rrg is associated with reversion of NIH 3T3 transformed by LTR-c-H-ras. Science 249: 796–798
Cronlund, AL, Smith, BD & Kagan, HM (1985) Binding of lysyl oxidase to fibrils of type I collagen. Connect Tissue Res 14: 109–119
Desmouliere, A, Darby, I, Costa, AM, Raccurt, M, Tuchweber, B, Sommer, P & Gabbiani, G (1997) Extracellular matrix deposition, lysyl oxidase expression, and myofibroblastic differentation during the initial stages of cholestatic fibrosis in the rat. Lab Invest 76: 765–778
Dvorak, HF (1986) Tumors: wounds that do not heal: similarities between tumor stroma generation and wound healing. N Engl J Med 315: 1650–1659
Eyre, DR, Paz, MA & Gallop, PM (1984) Cross-linking in collagen and elastin. Ann Rev Biochem 53: 717–748
Feres-Filho, EJ, Menassa, GB & Trackman, PC (1996) Regulation of lysyl oxidase by basic fibroblast growth factor in osteoblastic MC3T3-E1 cells. J Biol Chem 271: 6411–6416
Fleischmajer, R, Perlish, JS & Timpl, R (1985) Collagen fibrillogenesis in human skin. Ann NY Acad Sci 460: 246–257
Furcht, LT, Skubitz, APN & Fields, GB (1994) Tumor cell invasion, matrix metalloproteinases, and the dogma. Lab Invest 70: 781–783
Fushida-Takemura, H, Fukuda, M, Maekawa, N, Chanoki, M, Kobayashi, H, Yashiro, N, Ishii, M, Hamada, T, Otani, S & Ooshima, A (1996) Detection of lysyl oxidase gene expression in rat skin during wound healing. Arch Dermatol Res 288: 7–10
Gui, GPH, Puddefoot, JR, Vinson, GP, Wells, CA & Carpenter, R (1995) In vitro regulation of human breast cancer cell adhesion and invasion via integrin receptors to the extracellular matrix. Br J Surg 82: 1192–1196
Hart, IR & Saini, A (1992) Biology of tumour metastasis. Lancet 339: 1453–1457
Hauptmann, S, Zardi, L, Siri, A, Carnemolla, B, Borsi, L, Castellucci, M, Klosterhalfen, B, Hartung, P, Weis, J, Stöcker, G, Haubeck, H-D & Kirkpatrick, CJ (1995) Extracellular matrix proteins in colorectal carcinomas. Expression of tenascin and fibronectin isoforms. Lab Invest 73: 172–182
Iozzo, RV (1995) Tumor stroma as a regulator of neoplastic behavior. Lab Invest 73: 157–160
Kauppila, S, Saarela, J, Stenbäck, F, Risteli, J, Kauppila, A & Risteli, L (1996) Expression of mRNAs for type I and type III procollagens in serous ovarian cystadenomas and cystadenocarcinomas. Am J Pathol 148: 539–548
Kelley, J, Chrin, L & Evans, JN (1984) Microquantitation of insoluble tissue collagen (Types I and III) by radiodilution assay. Anal Biochem 139: 115–125
Kenyon, K, Contente, S, Trackman, PC, Tang, J, Kagan, HM & Friedman, RM (1991) Lysyl oxidase and rrg messenger RNA? Science 253: 802
Kivirikko, KI, Laitinen, O & Prockop, DJ (1967) Modifications of a specific assay for hydroxyproline in urine. Anal Biochem 19: 249–255
Laiho, M & Keski-Oja, J (1989) Growth factors in the regulation of pericellular proteolysis: a review. Cancer Res 49: 2533–2553
Liotta, LA & Kohn, E (1990) Cancer invasion and metastases. JAMA 263: 1123–1126
Melkko, J, Kauppila, S, Niemi, S, Risteli, L, Haukipuro, K, Jukkola, A & Risteli, J (1996) Immunoassay for intact aminoterminal propeptide of human type I procollagen. Clin Chem 42: 947–954
Peyrol, S, Raccurt, M, Gerard, F, Gleyzal, C, Grimaud, JA & Sommer, P (1997) Lysyl oxidase gene expression in the stromal reactions to in situ and invasive ductal breast carcinoma. Am J Pathol 150: 497–507
Reiser, K, McCormic, RJ & Rucker, RB (1992) Enzymatic and nonenzymatic cross-linking of collagen and elastin. FASEB J 6: 2439–2449
Ricard-Blum, S, Bresson-Hadni, S, Guerret, S, Grenard, P, Volle, P-J, Risteli, L, Grimaud, J-A & Vuitton, DA (1996) Mechanism of collagen network stabilization in human irreversible granulomatous liver fibrosis. Gastroenterology 111: 172–182
Ricard-Blum, S, Esterre, P & Grimaud, JA (1993) Collagen cross-linking by pyridinoline occurs in non-reversible skin fibrosis. Cell Mol Biol 39: 723–727
Risteli, J, Niemi, S, Trivedi, P, Mäentausta, O, Mowat, AP & Risteli, L (1988) Rapid equilibrium radioimmunoassay for the aminoterminal propeptide of human type III procollagen. Clin Chem 34: 715–718
Risteli, J, Elomaa, I, Niemi, S, Novamo, A & Risteli, L (1993) Radioimmunoassay for the pyridinoline cross-linked carboxy-terminal telopeptide of type I collagen: a new serum marker of bone collagen degradation. Clin Chem 39: 635–640
Stetler-Stevenson, WG (1996) Dynamics of matrix turnover during pathologic remodeling of the extracellular matrix. Am J Pathol 148: 1345–1350
Stetler-Stevenson, WG, Aznavoorian, S & Liotta, LA (1993a) Tumor cell interactions with the extracellular matrix during invasion and metastasis. Annu Rev Cell Biol 9: 541–573
Stetler-Stevenson, WG, Liotta, LA & Kleiner, DE (1993b) Extracellular matrix 6: role of matrix metalloproteinases in tumor invasion and metastasis. FASEB J 7: 1434–1441
Van der Stappen, JWJ, Hendriks, T & Wobbes, T (1990) Correlation between collagenolytic activity and grade of histological differentiation in colorectal tumors. Int J Cancer 45: 1071–1078
Whalen, GF (1990) Solid tumours and wounds: transformed cells misunderstood as injured tissue? Lancet 336: 1489–1492
Yamauchi, M & Mechanic, GL (1988) Cross-linking of collagen. In:Collagen, Nimni ME (ed) CRC Press: Boca Raton pp. 157–172
Zhu, G-G, Risteli, J, Puistola, U, Kauppila, A & Risteli, L (1993a) Progressive ovarian carcinoma induces synthesis of type I and type III procollagens in the tumor tissue and peritoneal cavity. Cancer Res 53: 5028–5032
Zhu, G-G, Stenäck, F, Risteli, L, Risteli, J & Kauppila, A (1993b) Organization of type III collagen in benign and malignant ovarian tumors. Cancer 72: 1679–1684
Zhu, G-G, Risteli, L, Mäkinen, M, Risteli, J, Kauppila, A & Stenbäck, F (1995) Immunohistochemical study of type I collagen and type I pN-collagen in benign and malignant ovarian neoplasms. Cancer 75: 1010–1017
Author information
Authors and Affiliations
Additional information
Correspondence to:J Risteli
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Kauppila, S., Bode, M., Stenbäck, F. et al. Cross-linked telopeptides of type I and III collagens in malignant ovarian tumours in vivo. Br J Cancer 81, 654–661 (1999). https://doi.org/10.1038/sj.bjc.6690743
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/sj.bjc.6690743
