Targeted disruption of the epidermal growth factor receptor impairs growth of squamous papillomas expressing the v-ras(Ha) oncogene but does not block in vitro keratinocyte responses to oncogenic ras.

摘要: Abstract We have assessed the role of epidermal growth factor receptor (EGFR) signaling in biological responses to v- ras Ha oncogene using primary keratinocytes from Egfr -/- mice and wild-type littermates. On basis several criteria, were unresponsive either acute or chronic exposure EGFR ligands but stimulated proliferate response other mitogens. Although conditioned medium transduced with retrovirus (v- keratinocytes) was a potent mitogen for not keratinocytes, transduction genotype resulted strong mitogenic response, arguing against an obligatory activation -mediated stimulation keratinocyte proliferation. Infection high-titer altered keratin expression pattern both genotypes, suppressing differentiation-specific keratins K1 K10 while activating aberrant K8 K18. In cultures, also suppressed following infection at lower retroviral titers, presumably as result paracrine on uninfected cells present these cultures. Squamous papillomas produced by grafting onto nude only 21% size tumors, striking redistribution S-phase detected immunostaining bromodeoxyuridine. papillomas, fraction total labeled nuclei suprabasal layers increased 19 39%. contrast, basal layer labeling index reduced 34%, compared 43% tumors. Our results indicate that, although autocrine is required oncogenic culture benign tumor formation mouse grafts, disruption this pathway impairs mechanism that may involve alterations cell cycle progression and/or migration vivo .