Carcinomas of the prostate and other lineages often present an autocrine stimulatory loop acting via the
EGF receptor (EGFR). We have recently shown that EGFR-mediated signals enhance DU-145 prostate
carcinoma cell transmigration of an extracellular matrix in vitro, and that this increased invasiveness was independent of proteolytic degradation of the matrix (Xie et al., 1995, Clin Exp
Metastasis, 13, 407). To determine whether up-regulated EGFR signaling promotes
tumor progression in vivo and to define the EGFR-induced cell property responsible, we inoculated athymic mice with genetically-engineered DU-145 cells. Parental DU-145 cells and those transduced to overexpress a full-length wild type (WT) EGFR formed
tumors and metastasized to the lung when inoculated in the prostate and peritoneal cavity. The WT DU-145
tumors were more invasive. DU-145 cells expressing a mitogenically-active, but motility-deficient (c'973) EGFR formed small, non-invasive
tumors without evidence of
metastasis. All three sublines demonstrated identical, EGFR-dependent rates of cell growth in vitro, suggesting that the differential invasiveness was not due to altered growth rates. To determine whether cell motility may be, in part, responsible for
tumor invasiveness, we treated WT DU-145 intraperitoneal
tumors with a pharmacologic agent (
U73122) which blocks EGFR-mediated cell motility but not mitogenesis. Under this treatment regimen, the WT DU-145 cells formed
tumors of similar numbers and size to those formed without treatment; however, these
tumors were much less invasive. These data suggest that EGFR-mediated cell motility is an important mechanism involved in
tumor progression, and that this cell property may represent a novel target to limit the spread of
tumors.