P-selectin activates integrin-mediated colon carcinoma cell adhesion to fibronectin

• Published in: Experimental cell research Vol. 312; no. 20; pp. 4056 - 4069
• Main Authors: Reyes-Reyes, Merit E., George, Margaret D., Roberts, John D., Akiyama, Steven K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10-12-2006; Elsevier BV
• Subjects: Adenocarcinoma - metabolism; Cell Adhesion; Cell adhesion & migration; Cell Line, Tumor; Cellular biology; Colonic Neoplasms - metabolism; Colorectal cancer; Enzyme Activation; Fibronectins - metabolism; Humans; Inhibitor drugs; Integrin alpha5beta1 - metabolism; Integrin alpha5beta1 - physiology; Integrins; Leukocytes; MAP Kinase Signaling System; Molecular biology; P-selectin; P-Selectin - pharmacology; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphatidylinositol 3-Kinases - metabolism; Protein Binding; P-selectin; Cell adhesion; Integrins
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2006.09.008

During hematogenous cancer metastasis, tumor cells separate from a primary mass, enter the bloodstream, disperse throughout the body, migrate across vessel walls, and generate distant colonies. The later steps of metastasis superficially resemble leukocyte extravasation, a process initiated by selectin-mediated cell tethering to the blood vessel wall followed by integrin-mediated arrest and transendothelial migration. Some cancer cells express P-selectin ligands and attach to immobilized P-selectin, suggesting that these cells can arrest in blood vessels using sequential selectin- and integrin-mediated adhesion, as do leukocytes. We hypothesize that selectin binding may regulate subsequent integrin-mediated steps in metastasis. Using a model system of cultured Colo 320 human colon adenocarcinoma cells incubated with soluble P-selectin-IgG chimeric protein, we have found that P-selectin can stimulate activation of the α
5β
1 integrin resulting in a specific increase of adhesion and spreading of these cells on fibronectin substrates. P-selectin binding also induced activation of p38 mitogen-activated protein kinase (p38 MAPK) and phosphatidylinositol 3-kinase (PI3-K). PI3-K inhibitors blocked P-selectin-mediated integrin activation, cell attachment, and cell spreading. Inhibition of p38 MAPK activation blocked cell spreading, but not cell attachment. P-selectin binding also resulted in formation of a signaling complex containing PI3-K and p38 MAPK. These results suggest that P-selectin binding to tumor cells can activate α
5β
1 integrin via PI3-K and p38 MAPK signaling pathways leading to increased cell adhesion. We propose that P-selectin ligands are important tumor cell signaling molecules that modulate integrin-mediated cell adhesion in the metastatic process.