Kinetics of v-src-induced epithelial-mesenchymal transition in developing glandular stomach

• Published in: Oncogene Vol. 22; no. 6; pp. 884 - 893
• Main Authors: SHIMIZU, Y, YAMAMICHI, N, YASUGI, S, ICHINOSE, M, IBA, H, SAITOH, K, WATANABE, A, ITO, T, YAMAMICHI-NISHINA, M, MIZUTANI, M, YAHAGI, N, SUZUKI, T, SASAKAWA, C
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 13.02.2003; Nature Publishing Group
• Subjects: Animals; Anoikis; Apoptosis; Avian Sarcoma Viruses - metabolism; Biological and medical sciences; Cell culture; Cell migration; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cell Transformation, Neoplastic - metabolism; Chick Embryo; Collagen (type I); Coturnix; Electroporation; Embryos; Epithelial cells; Epithelium; Epithelium - metabolism; Fibronectin; Fundamental and applied biological sciences. Psychology; Gene Expression Profiling; Gene transfer; Gene Transfer Techniques; Hedgehog protein; Immunology; Internal medicine; Kinases; Kinetics; MAP kinase; Mesenchyme; Mesoderm - metabolism; Molecular and cellular biology; Oncogene Protein pp60(v-src) - metabolism; Protein-Serine-Threonine Kinases - metabolism; Recombination; Sarcoma; Signal transduction; Signal Transduction - physiology; Stomach; Stomach - cytology; Stomach - metabolism; Transcription factors; Viruses; Japan; Stomach; Embryo; Enzyme; Mitogen-activated protein kinase; Mesenchyma; MAP kinase; apoptosis; Epithelium; Genetic transfer; Vertebrata; RSV; Development; v-src; Chicken; epithelial-mesenchymal transition; Kinetics; Aves; Differentiation
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1206174

The oncogene function in primary epithelial cells is largely unclear. Recombination organ cultures in combination with the stable and transient gene transfer techniques by retrovirus and electroporation, respectively, enable us to transfer oncogenes specifically into primary epithelial cells of the developing avian glandular stomach (proventriculus). In this system, the epithelium and mesenchyme are mutually dependent on each other for their growth and differentiation. We report here that either stable or transient expression of v-src in the epithelium causes budding and migration of epithelial cells into mesenchyme. In response to the transient expression of v-Src or a constitutive active mutant of MEK, we observed immediate downregulation of the Sonic hedgehog gene and subsequent elimination of E-cadherine expression in migrating cells, suggesting the involvement of MAP kinase signaling pathway in these processes. v-src-expressing cells that were retained in the epithelium underwent apoptosis (anoikis) and detached from the culture. Continuous expression of v-src by, for example, Rous sarcoma virus (RSV) was required for the epithelial cells to acquire the ability to express type I collagen and fibronectin genes (mesenchymal markers), and finally to establish the epithelial-mesenchymal transition. These observations would partly explain why RSV does not apparently cause carcinoma formation, but induces sarcomas exclusively.