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. 1997 Feb;150(2):497–507.

Lysyl oxidase gene expression in the stromal reaction to in situ and invasive ductal breast carcinoma.

S Peyrol 1, M Raccurt 1, F Gerard 1, C Gleyzal 1, J A Grimaud 1, P Sommer 1
PMCID: PMC1858268  PMID: 9033266

Abstract

Lysyl oxidase is involved in the main pathway of collagen and elastin cross-linking: it has a role in the maturation of fibrillar matrix proteins in fibrosing processes and dictates their stability against metalloproteases. The stromal reaction patterns in ductal breast carcinoma are known to be morphologically varied. This has raised the hypothesis that there might be a differential expression of the lysyl oxidase gene as a function of stromal reaction pattern. The present study investigates this potential correlation and the role of matrix protein cross-linking in stromal differentiation. Lysyl oxidase was detected by immunohistochemistry and lysyl oxidase gene expression by in situ hybridization. Maximal expression was observed in myofibroblasts and myoepithelial cells around in situ tumors and in the reactive fibrosis facing the invasion front of infiltrating tumors. The lysyl oxidase substrates were observed in parallel, resulting in the stabilization of a scar-like peritumor barrier. In contrast, a lack of lysyl oxidase was associated with the loose or scirrhous stroma accompanying invading tumors; here, in situ hybridization revealed type I collagen synthesis, resulting in the deposition of non-cross-linked matrix proteins susceptible to degradation. The early development of a cross-linked matrix around ductal breast carcinoma suggests a possible bost defense mechanism, whereas the synchronous or late stromal reaction lacking lysyl oxidase favors tumor dispersion.

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  1. Aznavoorian S., Murphy A. N., Stetler-Stevenson W. G., Liotta L. A. Molecular aspects of tumor cell invasion and metastasis. Cancer. 1993 Feb 15;71(4):1368–1383. doi: 10.1002/1097-0142(19930215)71:4<1368::aid-cncr2820710432>3.0.co;2-l. [DOI] [PubMed] [Google Scholar]
  2. Barsky S. H., Gopalakrishna R. Increased invasion and spontaneous metastasis of BL6 melanoma with inhibition of the desmoplastic response in C57 BL/6 mice. Cancer Res. 1987 Mar 15;47(6):1663–1667. [PubMed] [Google Scholar]
  3. Boak A. M., Roy R., Berk J., Taylor L., Polgar P., Goldstein R. H., Kagan H. M. Regulation of lysyl oxidase expression in lung fibroblasts by transforming growth factor-beta 1 and prostaglandin E2. Am J Respir Cell Mol Biol. 1994 Dec;11(6):751–755. doi: 10.1165/ajrcmb.11.6.7946403. [DOI] [PubMed] [Google Scholar]
  4. Chu M. L., Myers J. C., Bernard M. P., Ding J. F., Ramirez F. Cloning and characterization of five overlapping cDNAs specific for the human pro alpha 1(I) collagen chain. Nucleic Acids Res. 1982 Oct 11;10(19):5925–5934. doi: 10.1093/nar/10.19.5925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cleary E. G., Gibson M. A. Elastin-associated microfibrils and microfibrillar proteins. Int Rev Connect Tissue Res. 1983;10:97–209. doi: 10.1016/b978-0-12-363710-9.50009-5. [DOI] [PubMed] [Google Scholar]
  6. Contente S., Kenyon K., Rimoldi D., Friedman R. M. Expression of gene rrg is associated with reversion of NIH 3T3 transformed by LTR-c-H-ras. Science. 1990 Aug 17;249(4970):796–798. doi: 10.1126/science.1697103. [DOI] [PubMed] [Google Scholar]
  7. Deak S. B., Glaug M. R., Pierce R. A., Bancila E., Amenta P., Mackenzie J. W., Greco R. S., Boyd C. D. Desmoplasia in benign and malignant breast disease is characterized by alterations in level of mRNAs coding for types I and III procollagen. Matrix. 1991 Aug;11(4):252–258. doi: 10.1016/s0934-8832(11)80232-5. [DOI] [PubMed] [Google Scholar]
  8. Desmoulière A., Geinoz A., Gabbiani F., Gabbiani G. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993 Jul;122(1):103–111. doi: 10.1083/jcb.122.1.103. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Emonard H., Peyrol S., Grimaud J. A. Tissue hyperfibrils are degraded forms of collagen fibrils. An ultrastructural study employing enzymatic treatments. J Submicrosc Cytol Pathol. 1991 Jul;23(3):427–430. [PubMed] [Google Scholar]
  10. Furcht L. T., Skubitz A. P., Fields G. B. Tumor cell invasion, matrix metalloproteinases, and the dogma. Lab Invest. 1994 Jun;70(6):781–783. [PubMed] [Google Scholar]
  11. Gindre D., Peyrol S., Raccurt M., Sommer P., Loire R., Grimaud J. A., Cordier J. F. Fibrosing vasculitis in Wegener's granulomatosis: ultrastructural and immunohistochemical analysis of the vascular lesions. Virchows Arch. 1995;427(4):385–393. doi: 10.1007/BF00199387. [DOI] [PubMed] [Google Scholar]
  12. Gorsch S. M., Memoli V. A., Stukel T. A., Gold L. I., Arrick B. A. Immunohistochemical staining for transforming growth factor beta 1 associates with disease progression in human breast cancer. Cancer Res. 1992 Dec 15;52(24):6949–6952. [PubMed] [Google Scholar]
  13. Gusterson B. A., Warburton M. J., Mitchell D., Ellison M., Neville A. M., Rudland P. S. Distribution of myoepithelial cells and basement membrane proteins in the normal breast and in benign and malignant breast diseases. Cancer Res. 1982 Nov;42(11):4763–4770. [PubMed] [Google Scholar]
  14. Hajnal A., Klemenz R., Schäfer R. Up-regulation of lysyl oxidase in spontaneous revertants of H-ras-transformed rat fibroblasts. Cancer Res. 1993 Oct 1;53(19):4670–4675. [PubMed] [Google Scholar]
  15. Jourdan-Le Saux C., Gleyzal C., Garnier J. M., Peraldi M., Sommer P., Grimaud J. A. Lysyl oxidase cDNA of myofibroblast from mouse fibrotic liver. Biochem Biophys Res Commun. 1994 Mar 15;199(2):587–592. doi: 10.1006/bbrc.1994.1269. [DOI] [PubMed] [Google Scholar]
  16. Kagan H. M., Trackman P. C. Properties and function of lysyl oxidase. Am J Respir Cell Mol Biol. 1991 Sep;5(3):206–210. doi: 10.1165/ajrcmb/5.3.206. [DOI] [PubMed] [Google Scholar]
  17. Kenyon K., Contente S., Trackman P. C., Tang J., Kagan H. M., Friedman R. M. Lysyl oxidase and rrg messenger RNA. Science. 1991 Aug 16;253(5021):802–802. doi: 10.1126/science.1678898. [DOI] [PubMed] [Google Scholar]
  18. Kenyon K., Modi W. S., Contente S., Friedman R. M. A novel human cDNA with a predicted protein similar to lysyl oxidase maps to chromosome 15q24-q25. J Biol Chem. 1993 Sep 5;268(25):18435–18437. [PubMed] [Google Scholar]
  19. Krzyzosiak W. J., Shindo-Okada N., Teshima H., Nakajima K., Nishimura S. Isolation of genes specifically expressed in flat revertant cells derived from activated ras-transformed NIH 3T3 cells by treatment with azatyrosine. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4879–4883. doi: 10.1073/pnas.89.11.4879. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kuivaniemi H., Korhonen R. M., Vaheri A., Kivirikko K. I. Deficient production of lysyl oxidase in cultures of malignantly transformed human cells. FEBS Lett. 1986 Jan 20;195(1-2):261–264. doi: 10.1016/0014-5793(86)80172-7. [DOI] [PubMed] [Google Scholar]
  21. Lieubeau B., Garrigue L., Barbieux I., Meflah K., Gregoire M. The role of transforming growth factor beta 1 in the fibroblastic reaction associated with rat colorectal tumor development. Cancer Res. 1994 Dec 15;54(24):6526–6532. [PubMed] [Google Scholar]
  22. Nakanishi H., Oguri K., Takenaga K., Hosoda S., Okayama M. Differential fibrotic stromal responses of host tissue to low- and high-metastatic cloned Lewis lung carcinoma cells. Lab Invest. 1994 Mar;70(3):324–332. [PubMed] [Google Scholar]
  23. Paweletz N., Boxberger H. J. Defined tumor cell-host interactions are necessary for malignant growth. Crit Rev Oncog. 1994;5(1):69–105. doi: 10.1615/critrevoncog.v5.i1.40. [DOI] [PubMed] [Google Scholar]
  24. Peyrol S., Cordier J. F., Grimaud J. A. Intra-alveolar fibrosis of idiopathic bronchiolitis obliterans-organizing pneumonia. Cell-matrix patterns. Am J Pathol. 1990 Jul;137(1):155–170. [PMC free article] [PubMed] [Google Scholar]
  25. Ricard-Blum S., Bresson-Hadni S., Vuitton D. A., Ville G., Grimaud J. A. Hydroxypyridinium collagen cross-links in human liver fibrosis: study of alveolar echinococcosis. Hepatology. 1992 Apr;15(4):599–602. doi: 10.1002/hep.1840150408. [DOI] [PubMed] [Google Scholar]
  26. Ricard-Blum S., Ville G., Grimaud J. A. Pyridinoline, a mature collagen cross-link, in fibrotic livers from Schistosoma mansoni-infected mice. Am J Trop Med Hyg. 1992 Dec;47(6):816–820. doi: 10.4269/ajtmh.1992.47.816. [DOI] [PubMed] [Google Scholar]
  27. Roch A. M., Noel P., el Alaoui S., Charlot C., Quash G. Differential expression of isopeptide bonds N epsilon (gamma-glutamyl) lysine in benign and malignant human breast lesions: an immunohistochemical study. Int J Cancer. 1991 May 10;48(2):215–220. doi: 10.1002/ijc.2910480211. [DOI] [PubMed] [Google Scholar]
  28. Roskelley C. D., Srebrow A., Bissell M. J. A hierarchy of ECM-mediated signalling regulates tissue-specific gene expression. Curr Opin Cell Biol. 1995 Oct;7(5):736–747. doi: 10.1016/0955-0674(95)80117-0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Ross R., Bornstein P. The elastic fiber. I. The separation and partial characterization of its macromolecular components. J Cell Biol. 1969 Feb;40(2):366–381. doi: 10.1083/jcb.40.2.366. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Rossi P., Karsenty G., Roberts A. B., Roche N. S., Sporn M. B., de Crombrugghe B. A nuclear factor 1 binding site mediates the transcriptional activation of a type I collagen promoter by transforming growth factor-beta. Cell. 1988 Feb 12;52(3):405–414. doi: 10.1016/s0092-8674(88)80033-3. [DOI] [PubMed] [Google Scholar]
  31. Rønnov-Jessen L., Petersen O. W. Induction of alpha-smooth muscle actin by transforming growth factor-beta 1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia. Lab Invest. 1993 Jun;68(6):696–707. [PubMed] [Google Scholar]
  32. Rønnov-Jessen L., Petersen O. W., Koteliansky V. E., Bissell M. J. The origin of the myofibroblasts in breast cancer. Recapitulation of tumor environment in culture unravels diversity and implicates converted fibroblasts and recruited smooth muscle cells. J Clin Invest. 1995 Feb;95(2):859–873. doi: 10.1172/JCI117736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Sappino A. P., Schürch W., Gabbiani G. Differentiation repertoire of fibroblastic cells: expression of cytoskeletal proteins as marker of phenotypic modulations. Lab Invest. 1990 Aug;63(2):144–161. [PubMed] [Google Scholar]
  34. Schillaci R., Luparello C., Minafra S. Type I and I-trimer collagens as substrates for breast carcinoma cells in culture. Effect on growth rate, morphological appearance and actin organization. Eur J Cell Biol. 1989 Feb;48(1):135–141. [PubMed] [Google Scholar]
  35. Schmitt-Gräff A., Gabbiani G. Phenotypic features of stromal cells in normal, premalignant and malignant conditions. Eur J Cancer. 1992;28A(11):1916–1920. doi: 10.1016/0959-8049(92)90035-z. [DOI] [PubMed] [Google Scholar]
  36. Schürch W., Lagacé R., Seemayer T. A. Myofibroblastic stromal reaction in retracted scirrhous carcinoma of the breast. Surg Gynecol Obstet. 1982 Mar;154(3):351–358. [PubMed] [Google Scholar]
  37. Sommer P., Gleyzal C., Raccurt M., Delbourg M., Serrar M., Joazeiro P., Peyrol S., Kagan H., Trackman P. C., Grimaud J. A. Transient expression of lysyl oxidase by liver myofibroblasts in murine schistosomiasis. Lab Invest. 1993 Oct;69(4):460–470. [PubMed] [Google Scholar]
  38. Takiya C., Peyrol S., Cordier J. F., Grimaud J. A. Connective matrix organization in human pulmonary fibrosis. Collagen polymorphism analysis in fibrotic deposits by immunohistological methods. Virchows Arch B Cell Pathol Incl Mol Pathol. 1983;44(2):223–240. doi: 10.1007/BF02890172. [DOI] [PubMed] [Google Scholar]
  39. Vater C. A., Harris E. D., Jr, Siegel R. C. Native cross-links in collagen fibrils induce resistance to human synovial collagenase. Biochem J. 1979 Sep 1;181(3):639–645. doi: 10.1042/bj1810639. [DOI] [PMC free article] [PubMed] [Google Scholar]

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