Gastrin-releasing peptide mediates its morphogenic properties in human colon cancer by upregulating intracellular adhesion protein-1 (ICAM-1) via focal adhesion kinase.
Gastrin-releasing peptide (GRP) and its receptor (GRPR) act as morphogens when expressed in colorectal cancer (CRC), promoting the assumption of a better differentiated phenotype by regulating cell motility in the context of remodeling and retarding tumor cell metastasis by enhancing cell-matrix attachment. Although we have shown that these processes are mediated by focal adhesion kinase (FAK), the downstream target(s) of GRP-induced FAK activation are not known. Since osteoblast differentiation is mediated by FAK-initiated upregulation of ICAM-1 (Nakayamada S, Okada Y, Saito K, Tamura M, Tanaka Y. J Biol Chem 278: 45368-45374, 2003), we determined whether GRP-induced activation of FAK alters ICAM-1 expression in CRC and, if so, determined the contribution of ICAM-1 to mediating GRP's morphogenic properties. Caco-2 and HT-29 cells variably express GRP/GRPR. These cells only express ICAM-1 when GRPR are present. In human CRC, GRPR and ICAM-1 are only expressed by better differentiated tumor cells, with ICAM-1 located at the basolateral membrane. ICAM-1 expression was only observed subsequent to GRPR signaling via FAK. To study the effect of ICAM-1 expression on tumor cell motility, CRC cells expressing GRP, GRPR, and ICAM-1 were cultured in the presence and absence of GRPR antagonist or monoclonal antibody to ICAM-1. CRC cells engaged in directed motility in the context of remodeling and were highly adherent to the extracellular matrix, only in the absence of antagonist or ICAM-1 antibody. These data indicate that GRP upregulation of ICAM-1 via FAK promotes tumor cell motility and attachment to the extracellular matrix.
Taglia
Lauren
L
Department of Medicine, University of Illinois at Chicago, 840 South Wood St., Chicago, IL 60612, USA.
Matusiak
Damien
D
Matkowskyj
Kristina A
KA
Benya
Richard V
RV
D000595:Amino Acid Sequence; D002460:Cell Line; D002465:Cell Movement; D003110:Colonic Neoplasms; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D005109:Extracellular Matrix / Q000378:metabolism; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D019886:Gastrin-Releasing Peptide; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics*; D008969:Molecular Sequence Data; D009024:Morphogenesis / Q000502:physiology*; D010446:Peptide Fragments; D018004:Receptors, Bombesin / Q000737:chemistry / Q000502:physiology
D010446:Peptide Fragments; D018004:Receptors, Bombesin; D018799:Intercellular Adhesion Molecule-1; D019886:Gastrin-Releasing Peptide; D051416:Focal Adhesion Protein-Tyrosine Kinases