GPI-anchored CEA family glycoproteins CEA and CEACAM6 mediate their biological effects through enhanced integrin alpha5beta1-fibronectin interaction.
Carcinoembryonic antigen (CEA) and CEA family member CEACAM6 are glycophosphatidyl inositol (GPI)-anchored, intercellular adhesion molecules that are up-regulated in a wide variety of human cancers, including colon, breast, and lung. When over-expressed in a number of cellular systems, these molecules are capable of inhibiting cellular differentiation and anoikis, as well as disrupting cell polarization and tissue architecture, thus increasing tumorigenicity. The present study shows that perturbation of the major fibronectin receptor, integrin alpha5beta1, underlies some of these biological effects. Using confocal microscopy and specific antibodies, CEA and CEACAM6 were demonstrated to co-cluster with integrin alpha5beta1 on the cell surface. The presence of CEA and CEACAM6 was shown to lead to an increase in the binding of the integrin alpha5beta1 receptor to its ligand fibronectin, without changing its cell surface levels, resulting in increased adhesion of CEA/CEACAM6-expressing cells to fibronectin. More tenacious binding of free fibronectin to cells led to enhanced fibronectin matrix assembly and the formation of a polymerized fibronectin "cocoon" around the cells. Disruption of this process with specific monoclonal antibodies against either fibronectin or integrin alpha5beta1 led to the restoration of cellular differentiation and anoikis in CEA/CEACAM6 producing cells.
Ordonez
Cosme
C
Department of Biochemistry and McGill Cancer Centre, McGill University, Montreal, Quebec, Canada.
Zhai
Alexander B
AB
Camacho-Leal
Pilar
P
Demarte
Luisa
L
Fan
Mannie M Y
MM
Stanners
Clifford P
CP
D000818:Animals; D023102:Anoikis / Q000502:physiology; D015703:Antigens, CD / Q000502:physiology*; D002272:Carcinoembryonic Antigen / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D004285:Dogs; D005109:Extracellular Matrix / Q000378:metabolism; D005353:Fibronectins / Q000378:metabolism*; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D018613:Microscopy, Confocal; D032446:Myoblasts / Q000166:cytology; D011485:Protein Binding / Q000502:physiology; D051381:Rats
D015703:Antigens, CD; C504117:CEACAM6 protein, human; D002272:Carcinoembryonic Antigen; D015815:Cell Adhesion Molecules; D005353:Fibronectins; D058851:GPI-Linked Proteins; D039081:Integrin alpha5beta1