Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 2001 Jun;84(12):1656–1663. doi: 10.1054/bjoc.2001.1813

FGF-1 and FGF-2 modulate the E-cadherin/catenin system in pancreatic adenocarcinoma cell lines

I EI-Hariry 1, M Pignatelli 2, N R Lemoine 1
PMCID: PMC2363682  PMID: 11401320

Abstract

Fibroblast growth factors (FGFs) and fibroblast growth factor receptors (FGFRs) have been increasingly recognized to play an important role in the pathobiology of pancreatic malignancy. We have investigated the effects of FGF-1 and FGF-2 on the behaviour and adhesion properties of human pancreatic adenocarcinoma cell lines (BxPc3, T3M4 and HPAF) that were previously characterised for the expression of FGFRs. Here we show that exposure to FGF-1 and FGF-2 leads to significant and dose-dependent increase in E-cadherin-dependent cell-cell adhesion, tubular differentiation, and a reduced capacity to invade collagen gels. FGF stimulation produces phosphorylation of E-cadherin and β-catenin on tyrosine residues, as well as increased E-cadherin localisation to the cytoplasmic membrane and association with FGFR1 demonstrable by coimmunoprecipitation. These results demonstrate that FGF-1 and FGF-2 may be involved in the regulation of cell adhesion, differentiation and invasion of pancreatic cancer. © Cancer Research Campaign http://www.bjcancer.com

Keywords: E-cadherin, catenins, FGF, FGFR, pancreatic adenocarcinoma

Full Text

The Full Text of this article is available as a PDF (301.0 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Behrens J., Vakaet L., Friis R., Winterhager E., Van Roy F., Mareel M. M., Birchmeier W. Loss of epithelial differentiation and gain of invasiveness correlates with tyrosine phosphorylation of the E-cadherin/beta-catenin complex in cells transformed with a temperature-sensitive v-SRC gene. J Cell Biol. 1993 Feb;120(3):757–766. doi: 10.1083/jcb.120.3.757. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Birchmeier W., Weidner K. M., Behrens J. Molecular mechanisms leading to loss of differentiation and gain of invasiveness in epithelial cells. J Cell Sci Suppl. 1993;17:159–164. doi: 10.1242/jcs.1993.supplement_17.23. [DOI] [PubMed] [Google Scholar]
  3. Blanckaert V. D., Hebbar M., Louchez M. M., Vilain M. O., Schelling M. E., Peyrat J. P. Basic fibroblast growth factor receptors and their prognostic value in human breast cancer. Clin Cancer Res. 1998 Dec;4(12):2939–2947. [PubMed] [Google Scholar]
  4. Boyer B., Dufour S., Thiery J. P. E-cadherin expression during the acidic FGF-induced dispersion of a rat bladder carcinoma cell line. Exp Cell Res. 1992 Aug;201(2):347–357. doi: 10.1016/0014-4827(92)90283-e. [DOI] [PubMed] [Google Scholar]
  5. Bracke M. E., Charlier C., Bruyneel E. A., Labit C., Mareel M. M., Castronovo V. Tamoxifen restores the E-cadherin function in human breast cancer MCF-7/6 cells and suppresses their invasive phenotype. Cancer Res. 1994 Sep 1;54(17):4607–4609. [PubMed] [Google Scholar]
  6. Bracke M. E., Van Larebeke N. A., Vyncke B. M., Mareel M. M. Retinoic acid modulates both invasion and plasma membrane ruffling of MCF-7 human mammary carcinoma cells in vitro. Br J Cancer. 1991 Jun;63(6):867–872. doi: 10.1038/bjc.1991.191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bracke M. E., Vyncke B. M., Bruyneel E. A., Vermeulen S. J., De Bruyne G. K., Van Larebeke N. A., Vleminckx K., Van Roy F. M., Mareel M. M. Insulin-like growth factor I activates the invasion suppressor function of E-cadherin in MCF-7 human mammary carcinoma cells in vitro. Br J Cancer. 1993 Aug;68(2):282–289. doi: 10.1038/bjc.1993.329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Calautti E., Cabodi S., Stein P. L., Hatzfeld M., Kedersha N., Paolo Dotto G. Tyrosine phosphorylation and src family kinases control keratinocyte cell-cell adhesion. J Cell Biol. 1998 Jun 15;141(6):1449–1465. doi: 10.1083/jcb.141.6.1449. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Day R. M., Hao X., Ilyas M., Daszak P., Talbot I. C., Forbes A. Changes in the expression of syndecan-1 in the colorectal adenoma-carcinoma sequence. Virchows Arch. 1999 Feb;434(2):121–125. doi: 10.1007/s004280050315. [DOI] [PubMed] [Google Scholar]
  10. Doherty P., Williams E., Walsh F. S. A soluble chimeric form of the L1 glycoprotein stimulates neurite outgrowth. Neuron. 1995 Jan;14(1):57–66. doi: 10.1016/0896-6273(95)90240-6. [DOI] [PubMed] [Google Scholar]
  11. El-Hariry I., Jordinson M., Lemoine N., Pignatelli M. Characterization of the E-cadherin-catenin complexes in pancreatic carcinoma cell lines. J Pathol. 1999 Jun;188(2):155–162. doi: 10.1002/(SICI)1096-9896(199906)188:2<155::AID-PATH356>3.0.CO;2-Y. [DOI] [PubMed] [Google Scholar]
  12. Hazan R. B., Norton L. The epidermal growth factor receptor modulates the interaction of E-cadherin with the actin cytoskeleton. J Biol Chem. 1998 Apr 10;273(15):9078–9084. doi: 10.1074/jbc.273.15.9078. [DOI] [PubMed] [Google Scholar]
  13. Hoschuetzky H., Aberle H., Kemler R. Beta-catenin mediates the interaction of the cadherin-catenin complex with epidermal growth factor receptor. J Cell Biol. 1994 Dec;127(5):1375–1380. doi: 10.1083/jcb.127.5.1375. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Kanai Y., Ochiai A., Shibata T., Oyama T., Ushijima S., Akimoto S., Hirohashi S. c-erbB-2 gene product directly associates with beta-catenin and plakoglobin. Biochem Biophys Res Commun. 1995 Mar 28;208(3):1067–1072. doi: 10.1006/bbrc.1995.1443. [DOI] [PubMed] [Google Scholar]
  15. Kato M., Saunders S., Nguyen H., Bernfield M. Loss of cell surface syndecan-1 causes epithelia to transform into anchorage-independent mesenchyme-like cells. Mol Biol Cell. 1995 May;6(5):559–576. doi: 10.1091/mbc.6.5.559. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Kinoshita Y., Kinoshita C., Heuer J. G., Bothwell M. Basic fibroblast growth factor promotes adhesive interactions of neuroepithelial cells from chick neural tube with extracellular matrix proteins in culture. Development. 1993 Nov;119(3):943–956. doi: 10.1242/dev.119.3.943. [DOI] [PubMed] [Google Scholar]
  17. Leppä S., Vleminckx K., Van Roy F., Jalkanen M. Syndecan-1 expression in mammary epithelial tumor cells is E-cadherin-dependent. J Cell Sci. 1996 Jun;109(Pt 6):1393–1403. doi: 10.1242/jcs.109.6.1393. [DOI] [PubMed] [Google Scholar]
  18. Leung H. Y., Gullick W. J., Lemoine N. R. Expression and functional activity of fibroblast growth factors and their receptors in human pancreatic cancer. Int J Cancer. 1994 Dec 1;59(5):667–675. doi: 10.1002/ijc.2910590515. [DOI] [PubMed] [Google Scholar]
  19. McLeskey S. W., Ding I. Y., Lippman M. E., Kern F. G. MDA-MB-134 breast carcinoma cells overexpress fibroblast growth factor (FGF) receptors and are growth-inhibited by FGF ligands. Cancer Res. 1994 Jan 15;54(2):523–530. [PubMed] [Google Scholar]
  20. Metzgar R. S., Gaillard M. T., Levine S. J., Tuck F. L., Bossen E. H., Borowitz M. J. Antigens of human pancreatic adenocarcinoma cells defined by murine monoclonal antibodies. Cancer Res. 1982 Feb;42(2):601–608. [PubMed] [Google Scholar]
  21. Miyamoto S., Teramoto H., Gutkind J. S., Yamada K. M. Integrins can collaborate with growth factors for phosphorylation of receptor tyrosine kinases and MAP kinase activation: roles of integrin aggregation and occupancy of receptors. J Cell Biol. 1996 Dec;135(6 Pt 1):1633–1642. doi: 10.1083/jcb.135.6.1633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ohta T., Yamamoto M., Numata M., Iseki S., Tsukioka Y., Miyashita T., Kayahara M., Nagakawa T., Miyazaki I., Nishikawa K. Expression of basic fibroblast growth factor and its receptor in human pancreatic carcinomas. Br J Cancer. 1995 Oct;72(4):824–831. doi: 10.1038/bjc.1995.420. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Okabe T., Yamaguchi N., Ohsawa N. Establishment and characterization of a carcinoembryonic antigen (CEA)-producing cell line from a human carcinoma of the exocrine pancreas. Cancer. 1983 Feb 15;51(4):662–668. doi: 10.1002/1097-0142(19830215)51:4<662::aid-cncr2820510419>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  24. Pignatelli M., Ansari T. W., Gunter P., Liu D., Hirano S., Takeichi M., Klöppel G., Lemoine N. R. Loss of membranous E-cadherin expression in pancreatic cancer: correlation with lymph node metastasis, high grade, and advanced stage. J Pathol. 1994 Dec;174(4):243–248. doi: 10.1002/path.1711740403. [DOI] [PubMed] [Google Scholar]
  25. Pignatelli M., Liu D., Nasim M. M., Stamp G. W., Hirano S., Takeichi M. Morphoregulatory activities of E-cadherin and beta-1 integrins in colorectal tumour cells. Br J Cancer. 1992 Oct;66(4):629–634. doi: 10.1038/bjc.1992.328. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Roghani M., Moscatelli D. Basic fibroblast growth factor is internalized through both receptor-mediated and heparan sulfate-mediated mechanisms. J Biol Chem. 1992 Nov 5;267(31):22156–22162. [PubMed] [Google Scholar]
  27. Saffell J. L., Williams E. J., Mason I. J., Walsh F. S., Doherty P. Expression of a dominant negative FGF receptor inhibits axonal growth and FGF receptor phosphorylation stimulated by CAMs. Neuron. 1997 Feb;18(2):231–242. doi: 10.1016/s0896-6273(00)80264-0. [DOI] [PubMed] [Google Scholar]
  28. Smith K., Fox S. B., Whitehouse R., Taylor M., Greenall M., Clarke J., Harris A. L. Upregulation of basic fibroblast growth factor in breast carcinoma and its relationship to vascular density, oestrogen receptor, epidermal growth factor receptor and survival. Ann Oncol. 1999 Jun;10(6):707–713. doi: 10.1023/a:1008303614441. [DOI] [PubMed] [Google Scholar]
  29. Takeichi M. Cadherin cell adhesion receptors as a morphogenetic regulator. Science. 1991 Mar 22;251(5000):1451–1455. doi: 10.1126/science.2006419. [DOI] [PubMed] [Google Scholar]
  30. Tan M. H., Nowak N. J., Loor R., Ochi H., Sandberg A. A., Lopez C., Pickren J. W., Berjian R., Douglass H. O., Jr, Chu T. M. Characterization of a new primary human pancreatic tumor line. Cancer Invest. 1986;4(1):15–23. doi: 10.3109/07357908609039823. [DOI] [PubMed] [Google Scholar]
  31. Wang H., Rubin M., Fenig E., DeBlasio A., Mendelsohn J., Yahalom J., Wieder R. Basic fibroblast growth factor causes growth arrest in MCF-7 human breast cancer cells while inducing both mitogenic and inhibitory G1 events. Cancer Res. 1997 May 1;57(9):1750–1757. [PubMed] [Google Scholar]
  32. Williams E. J., Furness J., Walsh F. S., Doherty P. Activation of the FGF receptor underlies neurite outgrowth stimulated by L1, N-CAM, and N-cadherin. Neuron. 1994 Sep;13(3):583–594. doi: 10.1016/0896-6273(94)90027-2. [DOI] [PubMed] [Google Scholar]
  33. Yamanaka Y., Friess H., Buchler M., Beger H. G., Uchida E., Onda M., Kobrin M. S., Korc M. Overexpression of acidic and basic fibroblast growth factors in human pancreatic cancer correlates with advanced tumor stage. Cancer Res. 1993 Nov 1;53(21):5289–5296. [PubMed] [Google Scholar]
  34. van Puijenbroek A. A., van Weering D. H., van den Brink C. E., Bos J. L., van der Saag P. T., de Laat S. W., den Hertog J. Cell scattering of SK-N-MC neuroepithelioma cells in response to Ret and FGF receptor tyrosine kinase activation is correlated with sustained ERK2 activation. Oncogene. 1997 Mar 13;14(10):1147–1157. doi: 10.1038/sj.onc.1200911. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES