Abstract
As in the development of many human cancers, in a transgenic mouse model of β-cell carcinogenesis (Rip1Tag2), expression of neural cell adhesion molecule (NCAM) changes from the 120-kDa isoform in normal tissue to the 140/180-kDa isoforms in tumors. NCAM-deficient Rip1Tag2 mice, generated by crossing Rip1Tag2 mice with NCAM knockout mice, develop metastases, a tumor stage that is not seen in normal Rip1Tag2 mice. In contrast, overexpression of NCAM 120 in NCAM-deficient Rip1Tag2 mice prevents tumor metastasis. The results indicate that the loss of NCAM-mediated cell adhesion is one rate-limiting step in the actual metastatic dissemination of β tumor cells.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Cunningham, B.A. Cell adhesion molecules as morphoregulators. Curr. Opin. Cell Biol. 7, 628–633 ( 1995).
Goridis, C. and Brunet, J.F. N-CAM: structural diversity, function and regulation of expression. Semin. Cell Biol. 3, 189–197 (1992).
Rutishauser, U. Cell adhesion molecules of the nervous system. Curr. Opin. Neurobiol. 3, 709–715 ( 1993).
Walsh, F.S. & Doherty, P. Neural cell adhesion molecules of the immunoglobulin superfamily: role in axon growth and guidance. Annu. Rev. Cell Dev. Biol. 13, 425– 456 (1997).
Rutishauser, U. Polysialic acid and the regulation of cell interactions. Curr. Opin. Cell Biol. 8, 679–684 (1996).
Dickson, G., Peck, D., Moore, S.E., Barton, C.H. & Walsh, F.S. Enhanced myogenesis in N-CAM transfected mouse myoblasts. Nature 344, 348–351 (1990).
Goridis, C. & Brunet, J.F. N-CAM: structural diversity, function and regulation of expression. Semin. Cell Biol. 3, 189–197 (1992).
Crossin, K.L., Chuong, C.M. & Edelman, G.M. Expression sequences of cell adhesion molecules. Proc. Natl. Acad. Sci. USA 82, 6942– 6946 (1985).
Gower, H.J. et al. Alternative splicing generates a secreted form of N-cam in muscle and Brain. Cell 55, 955– 964 (1988).
Dickson, G. et al. Human muscle neural cell adhesion molecule (N-cam): identification of a muscle specific sequence in the extracellular domain. Cell 50, 1119–1130 ( 1987).
Rouiller, D.G., Cirulli, V. & Halban, P.A. Differences in aggregation properties and levels of the neural cell adhesion molecule (NCAM) between islet cell types. Exp. Cell Res. 191, 305–312 (1990).
Cirulli, V. et al. Expression of neural cell adhesion molecule (N-CAM) in rat islets and its role in islet cell type segregation. J. Cell Sci. 107, 1429–1436 ( 1994).
Langley, O.K., Aletsee-Ufrecht, M.C., Grant, N.J. & Gratzl, M. Expression of the neural cell adhesion molecule NCAM in endocrine cells. J. Histochem. Cytochem. 37, 781–791 (1989).
Tomasiewicz, H. et al. Genetic deletion of a neural cell adhesion molecule variant (N-CAM-180) produces distinct defects in the central nervous system. Neuron 11, 1163–1174 ( 1993).
Cremer, H. et al. Inactivation of the N-CAM gene in mice results in size reduction of the olfactory bulb and deficits in spatial learning. Nature 367, 455–459 ( 1994).
Johnson, J.P. Cell adhesion molecules of the immunoglobulin supergene family and their role in malignant transformation and progression to metastatic disease. Cancer Metastasis Rev. 10, 11–22 (1991).
Kaiser, U., Auerbach, B. & Oldenburg, M. The neural cell adhesion molecule NCAM in multiple myeloma. Leuk. Lymphoma 20, 389– 395 (1996).
Lipinski, M. et al. Characterization of neural cell adhesion molecules (NCAM) expressed by Ewing and neuroblastoma cell lines. Int. J.Cancer 40, 81–86 ( 1987).
Moolenaar, C.E., Pieneman, C., Walsh, F.S., Mooi, W.J. & Michalides, R.J. Alternative splicing of neural-cell-adhesion molecule mRNA in human small-cell lung-cancer cell line H69. Int. J. Cancer 51, 238–243 ( 1992).
Roth, J. et al. Reexpression of poly(sialic acid) units of the neural cell adhesion molecule in Wilms' tumor. Proc. Natl. Acad. Sci. USA 85, 2999–3003 (1988).
Fogar, P. et al. Neural cell adhesion molecule (N-CAM) in gastrointestinal neoplasias. Anticancer Res. 17, 1227– 1230 (1997).
Hanahan, D. Heritable formation of pancreatic β-cell tumors in transgenic mice expressing recombinant insulin/simian virus 40 oncogenes. Nature 315, 115–21 (1985).
Christofori, G., Naik, P. & Hanahan, D. Vascular endothelial growth factor and its receptors, flt-1 and flk-1, are expressed in normal pancreatic islets and throughout islet cell tumorigenesis. Mol. Endocrinol. 9, 1760–1770 (1995).
Folkman, J., Watson, K., Ingber, D. & Hanahan, D. Induction of angiogenesis during the transition from hyperplasia to neoplasia. Nature 339, 58–61 (1989).
Christofori, G., Naik, P. & Hanahan, D. A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature 369, 414–418 (1994).
Teitelman, G., Alpert, S. & Hanahan, D. Proliferation, senescence, and neoplastic progression of β cells in hyperplastic pancreatic islets. Cell 52, 97–105 (1988).
Perl, A.-K., Wilgenbus, P., Dahl, U., Semb, H. & Christofori, G. A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature 392, 190– 193 (1998).
Efrat, S. et al. Beta-cell lines derived from transgenic mice expressing a hybrid insulin gene-oncogene. Proc. Natl. Acad. Sci. USA 85, 9037–9041 (1988).
Esni, F. et al. Neural cell adhesion molecule (N-CAM) is required for cell type segregation and normal ultrastructure in pancreatic islets. J. Cell Biol. 144, 325–337 (1999).
Lackie, P.M., Zuber, C. & Roth, J. Polysialic acid of the neural cell adhesion molecule (N-CAM) is widely expressed during organogenesis in mesodermal and endodermal derivatives. Differentiation 57, 119-131 ( 1994).
Moller, C.J. et al. Differential expression of neural cell adhesion molecule and cadherins in pancreatic islets, glucagonomas, and insulinomas. Mol. Endocrinol. 6, 1332–1342 (1992).
Hutton, J.C. et al. Molecular cloning of mouse pancreatic islet R-cadherin: differential expression in endocrine and exocrine tissue. Mol. Endocrinol. 7, 1151–1160 (1993).
Dahl, U., Sjodin, A. & Semb, H. Cadherins regulate aggregation of pancreatic beta-cells in vivo. Development 122, 2895– 2902 (1996).
Doherty, P. et al. A threshold effect of the major isoforms of NCAM on neurite outgrowth. Nature 343, 464– 466 (1990).
Thiery, J.P., Duband, J.L., Rutishauser, U. & Edelman, G.M. Cell adhesion molecules in early chicken embryogenesis. Proc. Natl. Acad. Sci. USA 79, 6737–6741 (1982).
Doherty, P. & Walsh, F.S. CAM-FGF receptor interactions: a model for axonal growth. Mol. Cell Neurosci. 8, 99–111 (1996).
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 13, 583– 594 (1994).
Beggs, H.E., Baragona, S.C., Hemperly, J.J. & Maness, P.F. NCAM140 interacts with the focal adhesion kinase p125(fak) and the SRC-related tyrosine kinase p59(fyn). J. Biol. Chem. 272, 8310–8319 (1997).
Hogan, B., Beddington, R., Constantini, F. & Lacy, E. in Manipulating the Mouse Embryo (Cold Spring Harbor Laboratory Press, New York, 1994).
Acknowledgements
We thank A. Compagni and M. Herzig for discussions and technical support, W. Jochum for expertise in histopathology, and M. Takeichi, E. Bock, T. Jessell and D. Bitter-Suermann for antibodies. We are grateful to E. Wagner, K. Wilgenbus, M. Busslinger, and M. Cotten for critical comments on the manuscript, and H. Tkadletz for artwork. Animal care was in accordance with institutional guidelines. This work was supported in part by the Austrian Industrial Research Promotion Fund (A.-K.P., P.W. and G.C.) and by the Swedish Cancer Society, Lion's Cancer Research Foundation, Umeå University, and M. Bergvalls Stiftelse (U.D. and H.S.)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Perl, AK., Dahl, U., Wilgenbus, P. et al. Reduced expression of neural cell adhesion molecule induces metastatic dissemination of pancreatic β tumor cells. Nat Med 5, 286–291 (1999). https://doi.org/10.1038/6502
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/6502
This article is cited by
-
Transcription Factors Contribute to Differential Expression in Cellular Pathways in Lung Adenocarcinoma and Lung Squamous Cell Carcinoma
Interdisciplinary Sciences: Computational Life Sciences (2018)
-
Intrabodies against the Polysialyltransferases ST8SiaII and ST8SiaIV inhibit Polysialylation of NCAM in rhabdomyosarcoma tumor cells
BMC Biotechnology (2017)
-
Hypoxia inducible factor-1α is necessary for invasive phenotype in Vegf-deleted islet cell tumors
Scientific Reports (2012)
-
CADM1 is a strong neuroblastoma candidate gene that maps within a 3.72 Mb critical region of loss on 11q23
BMC Cancer (2008)
-
B-Raf is required for ERK activation and tumor progression in a mouse model of pancreatic β-cell carcinogenesis
Oncogene (2008)