Concomitant Cell Growth and Differentiation are Dependent on ErbB1 and Integrin Activation in an Autonomously Surviving Colon Adenocarcinoma: Involvement of Autocrine Amphiregulin Secretion

• Published in: Anticancer research 2006-07, Vol.26 (4B), p.2769-2783
• Main Authors: PICHARD, Véronique, BERTHOIS, Yolande, ROCCABIANCA, Monique, PREVOT, Charles, SARRAZIN, Marcel, PORTUGAL, Henri, KUMAR, Shant, KUMAR, Pat, ROGNONI, Jean-Baptiste
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - enzymology; Adenocarcinoma - metabolism; Adenocarcinoma - pathology; Adenocarcinoma - secretion; Alkaline Phosphatase - biosynthesis; Amphiregulin; Antigens, Neoplasm - metabolism; Biological and medical sciences; Cell Adhesion - physiology; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cell Growth Processes - drug effects; Cell Growth Processes - physiology; Cell Line, Tumor; Cell Membrane - metabolism; Colonic Neoplasms - enzymology; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colonic Neoplasms - secretion; Cyclins - biosynthesis; EGF Family of Proteins; Enzyme Activation; Focal Adhesion Kinase 1 - antagonists & inhibitors; Focal Adhesion Kinase 1 - metabolism; Glycoproteins - metabolism; Glycoproteins - secretion; HT29 Cells; Humans; Integrin alpha2beta1 - metabolism; Integrins - metabolism; Intercellular Signaling Peptides and Proteins - metabolism; Intercellular Signaling Peptides and Proteins - secretion; Medical sciences; Microfilament Proteins - biosynthesis; Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors; Mitogen-Activated Protein Kinase 3 - metabolism; Quinazolines; Receptor, Epidermal Growth Factor - metabolism; Retinoblastoma Protein - biosynthesis; Sucrase-Isomaltase Complex - biosynthesis; Tumors; Tyrphostins - pharmacology
• ISSN: 0250-7005; 1791-7530

In normal colon epithelium, cell proliferation is followed by cell differentiation. The purpose of this work was to investigate, in the HT29-D4 colon adenocarcinoma cell line, the occurrence of a temporal sequence of changes in cell proliferation and differentiation, the role of autocrine EGF family ligands and to determine which transduction pathway(s) are involved in these processes. In a medium lacking both growth factor and serum, HT29-D4 cells secreted amphiregulin (AR), which was shown to be strongly involved in cell adhesion, growth and differentiation. In the main, integrins α2β1 and αvβ6 intervened in these processes. Using tyrphostins, it was demonstrated that AR involvement was mediated through the ErbB1/ERK1,2 and ErbB1/ FAK pathways. These signalling molecules were directly involved in pRb inhibition and, thus, in cyclin A expression. Concomitantly, colon differentiation markers were also expressed. Furthermore, terminal cell maturation resulted in a colon absorptive cell with strong polarisation, the growth of which was inhibited by tyrphostin and an ERK1,2 inhibitor. It was concluded that in a colon adenocarcinoma, cell proliferation and differentiation can occur concomitantly and that these deregulated processes are controlled by autocrine secretion through the ErbB1/ERK1,2 and FAK pathways.