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Thromb Haemost 2002; 87(04): 674-683
DOI: 10.1055/s-0037-1613065
Review Article
Schattauer GmbH

Differential Effects of Fibroblast Growth Factors on Expression of Genes of the Plasminogen Activator and Insulin-like Growth Factor Systems by Human Breast Fibroblasts

Anieta M. Sieuwerts
1   Division of Endocrine Oncology (Department of Medical Oncology)
,
John W. M. Martens
1   Division of Endocrine Oncology (Department of Medical Oncology)
,
Lambert C. J. Dorssers
2   Division of Molecular Biology (Department of Pathology), Rotterdam Cancer Institute (Daniel den Hoed Kliniek) and University Hospital Rotterdam, Rotterdam, The Netherlands
,
Jan G. M. Klijn
1   Division of Endocrine Oncology (Department of Medical Oncology)
,
John A. Foekens
1   Division of Endocrine Oncology (Department of Medical Oncology)
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Publikationsverlauf

Received 15. Oktober 2001

Accepted after resubmission 15. Januar 2002

Publikationsdatum:
08. Dezember 2017 (online)

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Summary

In breast stroma urokinase plasminogen activator (uPA) is predominantly expressed by fibroblasts located in the near vicinity of tumor cells, and fibroblast-derived insulin-like growth factor-1 (IGF-1) may be involved in inhibiting the expression of uPA in these fibroblasts. To investigate a possible role for fibroblast growth factors (FGFs), we evaluated the expression of components of the PA system and the IGF system in normal and tumor-tissue-derived human breast fibroblasts exposed to various FGFs in vitro. mRNA analysis revealed that FGF-1, FGF-2 and FGF-4 induced the mRNA expression levels of uPA, tPA, uPAR, PAI-1 and PAI-2, and reduced those of IGF-1, IGF-1R, IGF-2R and IGFBP-4, without significantly affecting the levels of IGFBP-3, IGFBP-5 and IGFBP-6 mRNA. Concerning the expression of IGF-2 mRNA, the effects mediated by FGF-1, FGF-2 and FGF-4 were divergent. In general, the effects elicited by FGF-1 on the various mRNA levels studied were rapid and short-term. Those mediated by FGF-2 overall lagged behind but were longer-lasting. For FGF-4 an in between pattern was observed. Blocking transcription and translation demonstrated that a) both the FGF-1 and FGF-2 induced effects were the result of altered gene transcription or mRNA stability, b) the short-term effects mediated by FGF-1 and FGF-2 required de novo protein synthesis, and c) the long-term effects elicited by FGF-2 did not depend on de novo protein synthesis during the first 24 h, but were triggered by proteins produced or made available thereafter. The data presented propose that of the FGFs studied (FGF-1, -2, -4, -5, and -7), FGF-2 is the most attractive target for therapeutical strategies aimed at diminishing the contribution of stromal fibroblasts in the PA-directed breast tumor proteolysis.

Keywords

Fibroblast growth factors - plasminogen activator system - insulinlike growth factor system - fibroblasts - human breast cancer
 

  • References

  • 1 Wolf C, Rouyer N, Lutz Y, Adida C, Loriot M, Bellocq JP, Chambon P, Basset P. Stromelysin 3 belongs to a subgroup of proteinases expressed in breast carcinoma fibroblasts cells and possibly implicated in tumor progression. Proc Natl Acad Sci USA 1993; 90: 1843-7.
    CrossrefPubMedSuche in Google Scholar
  • 2 Basset P, Bellocq JP, Wolf C, Stoll I, Hutin P, Limacher JM, Podhajcer OL, Chenard MP, Rio MC, Chambon P. A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature 1990; 348: 699-704.
    CrossrefPubMedSuche in Google Scholar
  • 3 Uría JA, Stahle-Bäckdahl M, Seiki M, Fueyo A, López-Otin C. Regulation of collagenase-3 expression in human breast carcinomas is mediated by stromal-epithelial cell interactions. Cancer Res 1997; 57: 4882-8.
    PubMedSuche in Google Scholar
  • 4 Okada A, Bellocq JP, Rouyer N, Chenard MP, Rio MC, Chambon P, Basset P. Membrane-type matrix metalloproteinase (MT-MMP) gene is expressed in stromal cells of human colon, breast, and head and neck carcinomas. Proc Natl Acad Sci USA 1995; 92: 2730-4.
    CrossrefPubMedSuche in Google Scholar
  • 5 Rømer J, Pyke C, Lund LR, Eriksen J, Kristensen P, Rønne E, Høyer-Hansen G, Danø K, Brünner N. Expression of uPA and its receptor by both neoplastic and stromal cells during xenograft invasion. Int J Cancer 1994; 57: 553-60.
    CrossrefPubMedSuche in Google Scholar
  • 6 Nielsen BS, Sehested M, Tiomshel S, Pyke C, Danø K. Messenger RNA for urokinase plasminogen activator is expressed in myofibroblasts adjacent to cancer cells in human breast cancer. Lab Invest 1996; 74: 168-77.
    PubMedSuche in Google Scholar
  • 7 Andreasen PA, Egelund R, Petersen HH. The plasminogen activation system in tumor growth, invasion, and metastasis. Cell Mol Life Sci 2000; 57: 25-40.
    CrossrefPubMedSuche in Google Scholar
  • 8 Duffy MJ, Duggan C, Maguire T, Mulcahy K, Elvin P, McDermott E, Fennelly JJ, O’Higgins N. Urokinase plasminogen activator as a predictor of aggressive disease in breast cancer. Enzyme Protein 1996; 49: 85-93.
    CrossrefPubMedSuche in Google Scholar
  • 9 Schmitt M, Harbeck N, Thomssen C, Wilhelm O, Magdolen V, Reuning U, Ulm K, Höfler H, Jänicke F, Graeff H. Clinical impact of the plasminogen activation system in tumor invasion and metastasis: prognostic relevance and target for therapy. Thromb Haemost 1997; 78: 285-96.
    Thieme ConnectPubMedSuche in Google Scholar
  • 10 Look MP, Foekens JA. Clinical relevance of the urokinase plasminogen activator system in breast cancer. Apmis 1999; 107: 150-9.
    CrossrefPubMedSuche in Google Scholar
  • 11 Sieuwerts AM, Klijn JG, Henzen-Logmans SC, Foekens JA. Cytokineregulated urokinase-type-plasminogen-activator (uPA) production by human breast fibroblasts in vitro. Breast Cancer Res Treat 1999; 55: 9-20.
    CrossrefPubMedSuche in Google Scholar
  • 12 Coope RC, Browne PJ, Yiangou C, Bansal GS, Walters J, Groome N, Shousha S, Johnston CL, Coombes RC, Gomm JJ. The location of acidic fibroblast growth factor in the breast is dependent on the activity of proteases present in breast cancer tissue. Br J Cancer 1997; 75: 1621-30.
    CrossrefPubMedSuche in Google Scholar
  • 13 Visscher DW, DeMattia F, Ottosen S, Sarkar FH, Crissman JD. Biologic and clinical significance of basic fibroblast growth factor immunostaining in breast carcinoma. Mod Pathol 1995; 08: 665-70.
    PubMedSuche in Google Scholar
  • 14 Quarto N, Amalric F. Heparan sulfate proteoglycans as transducers of FGF-2 signalling. J Cell Sci 1994; 107: 3201-12.
    PubMedSuche in Google Scholar
  • 15 Fernig DG, Chen HL, Rahmoune H, Descamps S, Boilly B, Hondermarck H. Differential regulation of FGF-1 and -2 mitogenic activity is related to their kinetics of binding to heparan sulfate in MDA-MB-231 human breast cancer cells. Biochem Biophys Res Commun 2000; 267: 770-6.
    CrossrefPubMedSuche in Google Scholar
  • 16 Sperinde GV, Nugent MA. Mechanisms of fibroblast growth factor 2 intracellular processing: a kinetic analysis of the role of heparan sulfate proteoglycans. Biochemistry 2000; 39: 3788-96.
    CrossrefPubMedSuche in Google Scholar
  • 17 Johnson DE, Williams LT. Structural and functional diversity in the FGF receptor multigene family. Adv Cancer Res 1993; 60: 1-41.
    PubMedSuche in Google Scholar
  • 18 Wernert N, Gilles F, Fafeur V, Bouali F, Raes MB, Pyke C, Dupressoir T, Seitz G, Vandenbunder B, Stehelin D. Stromal expression of c-Etsl transcription factor correlates with tumor invasion. Cancer Res 29994; 54: 5683-8.
    PubMed
  • 19 D’Orazio D, Besser D, Marksitzer R, Kunz C, Hume DA, Kiefer B, Nagamine Y. Cooperation of two PEA3/AP1 sites in uPA gene induction by TPA and FGF-2. Gene 1997; 201: 179-87.
    CrossrefPubMedSuche in Google Scholar
  • 20 Kitange G, Shibata S, Tokunaga Y, Yagi N, Yasunaga A, Kishikawa M, Naito S. Ets-1 transcription factor-mediated urokinase-type plasminogen activator expression and invasion in glioma cells stimulated by serum and basic fibroblast growth factors. Lab Invest 1999; 79: 407-16.
    PubMedSuche in Google Scholar
  • 21 Pepper MS, Sappino AP, Stocklin R, Montesano R, Orci L, Vassalli JD. Upregulation of urokinase receptor expression on migrating endothelial cells. J Cell Biol 1993; 122: 673-84.
    CrossrefPubMedSuche in Google Scholar
  • 22 Sandberg T, Eriksson P, Gustavsson B, Casslen B. Differential regulation of the plasminogen activator inhibitor-1 (PAI-1) gene expression by growth factors and progesterone in human endometrial stromal cells. Mol Hum Reprod 1997; 03: 781-7.
    CrossrefPubMedSuche in Google Scholar
  • 23 Mandriota SJ, Pepper MS. Vascular endothelial growth factor-induced in vitro angiogenesis and plasminogen activator expression are dependent on endogenous basic fibroblast growth factor. J Cell Sci 1997; 110: 2293-302.
    PubMedSuche in Google Scholar
  • 24 Sieuwerts AM, Klijn JG, Foekens JA. Insulin-like growth factor 1 (IGF-1) and urokinase-type plasminogen activator (uPA) are inversely related in human breast fibroblasts. Mol Cell Endocrinol 1999; 154: 179-85.
    CrossrefPubMedSuche in Google Scholar
  • 25 O’Connor R. Survival factors and apoptosis. Adv Biochem Eng Biotechnol 1998; 62: 137-66.
    PubMedSuche in Google Scholar
  • 26 Baxter RC. Insulin-like growth factor (IGF)-binding proteins: interactions with IGFs and intrinsic bioactivities. Am J Physiol Endocrinol Metab 2000; 278: E967-76.
    CrossrefPubMedSuche in Google Scholar
  • 27 Butt AJ, Firth SM, Baxter RC. The IGF axis and programmed cell death. Immunol Cell Biol 1999; 77: 256-62.
    CrossrefPubMedSuche in Google Scholar
  • 28 Lee AV, Hilsenbeck SG, Yee D. IGF system components as prognostic markers in breast cancer. Breast Cancer Res Treat 1998; 47: 295-302.
    CrossrefPubMedSuche in Google Scholar
  • 29 Smith J, Yelland A, Baillie R, Coombes RC. Acidic and basic fibroblast growth factors in human breat tissue. Eur J Cancer 1994; 04: 496-503.
    PubMedSuche in Google Scholar
  • 30 Anandappa SY, Winstanley JH, Leinster S, Green B, Rudland PS, Barraclough R. Comparative expression of fibroblast growth factor mRNAs in benign and malignant breast disease. Br J Cancer 1994; 69: 772-6.
    CrossrefPubMedSuche in Google Scholar
  • 31 Penault-Llorca F, Bertucci F, Adelaide J, Parc P, Coulier F, Jacquemier J, Birnbaum D, de Lapeyriere O. Expression of FGF and FGF receptor genes in human breast cancer. Int J Cancer 1995; 61: 170-6.
    CrossrefPubMedSuche in Google Scholar
  • 32 van Roozendaal CEP, van Ooijen B, Klijn JGM, Claassen C, Eggermont AMM, Henzen-Logmans SC, Foekens JA. Stromal influences on breast cancer cell growth. Br J Cancer 1992; 65: 77-81.
    CrossrefPubMedSuche in Google Scholar
  • 33 van Roozendaal CEP, Klijn JGM, van Ooijen B, Claassen C, Eggermont AMM, Henzen-Logmans SC, Foekens JA. Transforming growth factor beta secretion from primary breast cancer fibroblasts. Mol Cell Endocrinol 1995; 111: 1-6.
    CrossrefPubMedSuche in Google Scholar
  • 34 Grebenschikov N, Geurts-Moespot A, De Witte H, Heuvel J, Leake R, Sweep F, Benraad T. A sensitive and robust assay for urokinase and tissuetype plasminogen activators (uPA and tPA) and their inhibitor type I (PAI-1) in breast tumor cytosols. Int J Biol Markers 1997; 12: 6-14.
    CrossrefPubMedSuche in Google Scholar
  • 35 Jänicke F, Prechtl A, Thomssen C, Harbeck N, Meisner C, Untch M, Sweep CG, Selbmann HK, Graeff H, Schmitt M. Randomized adjuvant chemotherapy trial in high-risk, lymph node-negative breast cancer patients identified by urokinase-type plasminogen activator and plasminogen activator inhibitor type 1. J Natl Cancer Inst 2001; 93: 913-20.
    CrossrefPubMedSuche in Google Scholar
  • 36 Hayes DF, Bast RC, Desch CE, Fritsche Jr H, Kemeny NE, Jessup JM, Locker GY, Macdonald JS, Mennel RG, Norton L, Ravdin P, Taube S, Winn RJ. Tumor marker utility grading system: a framework to evaluate clinical utility of tumor markers. J Natl Cancer Inst 1996; 88: 1456-66.
    CrossrefPubMedSuche in Google Scholar
  • 37 Rasmussen AA, Cullen KJ. Paracrine/autocrine regulation of breast cancer by the insulin-like growth factors. Breast Cancer Res Treat 1998; 47: 219-33.
    CrossrefPubMedSuche in Google Scholar
  • 38 Speirs V, Atkin SL. Production of VEGF and expression of the VEGF receptors Flt-1 and KDR in primary cultures of epithelial and stromal cells derived from breast tumours. Br J Cancer 1999; 80: 898-903.
    CrossrefPubMedSuche in Google Scholar
  • 39 Zhou FY, Owens RT, Hermonen J, Jalkanen M, Hook M. Is the sensitivity of cells for FGF-1 and FGF-2 regulat ed by cell surface heparan sulfate proteoglycans?. Eur J Cell Biol 1997; 73: 166-74.
    PubMedSuche in Google Scholar
  • 40 Saksela O, Rifkin DB. Release of basic fibroblast growth factor-heparan sulfate complexes from endothelial cells by plasminogen activator-mediated proteolytic activity. J Cell Biol 1990; 110: 767-75.
    CrossrefPubMedSuche in Google Scholar
  • 41 Ribatti D, Leali D, Vacca A, Giuliani R, Gualandris A, Roncali L, Nolli ML, Presta M. In vivo angiogenic activity of urokinase: role of endogenous fibroblast growth factor-2. J Cell Sci 1999; 112: 4213-21.
    PubMedSuche in Google Scholar
  • 42 Guimond S, Maccarana M, Olwin BB, Lindahl U, Rapraeger AC. Activating and inhibitory heparin sequences for FGF-2 (basic FGF). Distinct requirements for FGF-1, FGF-2, and FGF-4. J Biol Chem 1993; 268: 23906-14.
    PubMedSuche in Google Scholar
  • 43 Lalou C, Silve C, Rosato R, Segovia B, Binoux M. Interactions between insulin-like growth factor-I (IGF-I) and the system of plasminogen activators and their inhibitors in the control of IGF-binding protein-3 production and proteolysis in human osteosarcoma cells. Endocrinology 1994; 135: 2318-26.
    CrossrefPubMedSuche in Google Scholar
  • 44 Dunn SE, Torres JV, Oh JS, Cykert DM, Barrett JC. Up-regulation of urokinase-type plasminogen activator by insulin-growth factor-I depends upon phosphatidylinositol-3 kinase and mitogen-activated protein kinase kinase. Cancer Res 2001; 61: 1367-74.
    PubMedSuche in Google Scholar
  • 45 Campbell PG, Novak JF, Yanosick TB, McMaster JH. Involvement of the plasmin system in dissociation of the insulin-like growth factor-binding protein complex. Endocrinology 1992; 130: 1401-12.
    PubMedSuche in Google Scholar
  • 46 Hasnain M, Khndwala HM, McCutcheon IE, Flyvbjerg A, Friendl KE. The effects of insulin-like growth factors on tumorigenesis and neoplastic growth. Endocr Rev 2000; 21: 215-44.
    CrossrefPubMedSuche in Google Scholar
  • 47 Colomer R, Aparicio J, Montero S, Guzman C, Larrodera L, Cortes-Funes H. Low levels of basic fibroblast growth factor (bFGF) are associated with a poor prognosis in human breast carcinoma. Br J Cancer 1997; 76: 1215-20.
    CrossrefPubMedSuche in Google Scholar
  • 48 Yiangou C, Gomm JJ, Coope RC, Law M, Luqmani YA, Shousha S, Coombes RC, Johnston CL. Fibroblast growth factor 2 in breast cancer: occurrence and prognostic significance. Br J Cancer 1997; 75: 28-33.
    CrossrefPubMedSuche in Google Scholar
  • 49 Rosen N, Yee D, Lippman ME, Paik S, Cullen KJ. Insulin-like growth factors in human breast cancer. Breast Cancer Res Treat 1991; 18 (Suppl. 01) S55-62.
    CrossrefPubMedSuche in Google Scholar
  • 50 Pyke C, Eriksen J, Solberg H, Nielsen BS, Kristensen P, Lund LR, Danø K. An alternatively spliced variant of mRNA for the human receptor for urokinase plasminogen activator. FEBS Lett 1993; 326: 69-74.
    CrossrefPubMedSuche in Google Scholar
  • 51 Prats H, Kaghad M, Prats AC, Klagsbrun M, Lelias JM, Liauzun P, Chalon P, Tauber JP, Amalric F, Smith JA. et al. High molecular mass forms of basic fibroblast growth factor are initiated by alternative CUG codons. Proc Natl Acad Sci USA 1989; 86: 1836-40.
    CrossrefPubMedSuche in Google Scholar
  • 52 Neufeld G, Cohen T, Gitay-Goren H, Poltorak Z, Tessler S, Sharon R, Gengrinovitch S, Levi BZ. Similarities and differences between the vascular endothelial growth factor (VEGF) splice variants. Cancer Metastasis Rev 1996; 15: 153-8.
    CrossrefPubMedSuche in Google Scholar
  • 53 Jorcyk CL, Watson DK, Mavrothalassitis GJ, Papas TS. The human ETS1 gene: genomic structure, promoter characterization and alternative splicing. Oncogene 1991; 06: 523-32.
    PubMedSuche in Google Scholar
  • 54 Jansen M, van Schaik FM, Ricker AT, Bullock B, Woods DE, Gabbay KH, Nussbaum AL, Sussenbach JS, Van den Brande JL. Sequence of cDNA encoding human insulin-like growth factor I precursor. Nature 1983; 306: 609-11.
    CrossrefPubMedSuche in Google Scholar