Temporary tumor cell reverse migration through EGFR stimulation: potential implications for HNSCC therapy

In squamous cell carcinomas of the upper aerodigestive tract (HNSCCs), metastasis plays a crucial role in determining prognosis. Current therapies primarily focus on slowing down tumor cell migration, while the direction of migration is scarcely investigated and insufficiently understood. The aim of this study was to investigate the influence of the epidermal growth factor (EGF) on the migration behavior of HNSCC cells. Three HNSCC cell lines (CAL-27, CLS-354, PE/CA-PJ15) were stimulated in vitro with EGF, and their movement into a gap was analyzed over 27 hours (migration). The influence on cell number (proliferation) and size over 7 days was separately examined, and EGFR expression was detected immunohistochemically. In two out of three cell lines, EGF treatment resulted in gap widening during the first 6 hours, although this gap later closed simultaneously with the negative control despite the increased distance. Initially, EGFR was expressed more strongly in the membrane between the cells than at the migration front toward the free gap. Addition of EGF led to EGFR internalization, increased tumor cell size, and reduced cell count. The growth factor accelerated migration and temporarily induced the reverse migration of tumor cells. The reduction in proliferation and cell enlargement further supported the increased motility caused by EGF. The direction of migration appears to depend on EGFR distribution in the membrane. Cellular receptor localization and the mechanisms of reverse migration should be further investigated. A deeper understanding of these processes could serve as the basis for new therapeutic approaches, particularly in controlling tumor growth and metastasis.