This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Kang, H.-G. Articles by Sorensen, P. H.B. Search for Related Content PubMed PubMed Citation Articles by Kang, H.-G. Articles by Sorensen, P. H.B.

E-Cadherin Cell-Cell Adhesion in Ewing Tumor Cells Mediates Suppression of Anoikis through Activation of the ErbB4 Tyrosine Kinase

¹ Department of Pathology and Laboratory Medicine; ² Developmental Therapeutics Program, USC-CHLA Institute for Pediatric Clinical Research; and ³ Division of Hematology-Oncology, Children's Hospital Los Angeles, Los Angeles, California; and ⁴ Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, British Columbia, Canada

Requests for reprints: Poul H.B. Sorensen, Department of Molecular Oncology, British Columbia Cancer Research Centre, Room 4-112, Vancouver, British Columbia, Canada V5Z 1L4. Phone: 604-675-8202; Fax: 604-675-8218; E-mail: psor{at}interchange.ubc.ca.

Ability to grow under anchorage-independent conditions is one of the major hallmarks of transformed cells. Key to this is the capacity of cells to suppress anoikis, or programmed cell death induced by detachment from the extracellular matrix. To model this phenomenon in vitro, we plated Ewing tumor cells under anchorage-independent conditions by transferring them to dishes coated with agar to prevent attachment to underlying plastic. This resulted in marked up-regulation of E-cadherin and rapid formation of multicellular spheroids in suspension. Addition of calcium chelators, antibodies to E-cadherin (but not to other cadherins or ß₁-integrin), or expression of dominant negative E-cadherin led to massive apoptosis of spheroid cultures whereas adherent cultures were unaffected. This correlated with reduced activation of the phosphatidylinositol 3-kinase-Akt pathway but not the Ras-extracellular signal–regulated kinase 1/2 cascade. Furthermore, spheroid cultures showed profound chemoresistance to multiple cytotoxic agents compared with adherent cultures, which could be reversed by -E-cadherin antibodies or dominant negative E-cadherin. In a screen for potential downstream effectors of spheroid cell survival, we detected E-cadherin–dependent activation of the ErbB4 receptor tyrosine kinase but not of other ErbB family members. Reduction of ErbB4 levels by RNA interference blocked Akt activation and spheroid cell survival and restored chemosensitivity to Ewing sarcoma spheroids. Our results indicate that anchorage-independent Ewing sarcoma cells suppress anoikis through a pathway involving E-cadherin cell-cell adhesion, which leads to ErbB4 activation of the phosphatidylinositol 3-kinase-Akt pathway, and that this is associated with increased resistance of cells to cytotoxic agents. [Cancer Res 2007;67(7):3094–105]

This article has been cited by other articles:

				M. Haraguchi, T. Okubo, Y. Miyashita, Y. Miyamoto, M. Hayashi, T. N. Crotti, K. P. McHugh, and M. Ozawa Snail Regulates Cell-Matrix Adhesion by Regulation of the Expression of Integrins and Basement Membrane Proteins J. Biol. Chem., August 29, 2008; 283(35): 23514 - 23523. [Abstract] [Full Text] [PDF]

				M. J. Wheelock, Y. Shintani, M. Maeda, Y. Fukumoto, and K. R. Johnson Cadherin switching J. Cell Sci., March 15, 2008; 121(6): 727 - 735. [Abstract] [Full Text] [PDF]

				Z. Ma, D. P. Myers, R. F. Wu, F. E. Nwariaku, and L. S. Terada p66Shc mediates anoikis through RhoA J. Cell Biol., October 8, 2007; 179(1): 23 - 31. [Abstract] [Full Text] [PDF]