Basal prostate epithelial cells stimulate the migration of prostate cancer cells

Abstract

Carcinoma cells in PIN are situated above a layer of basal epithelial cells, which shield the tumor cells from stimulation by factors from the prostate stroma. During progression to invasive carcinoma, the basal cell layer becomes disrupted and tumor cells adhere to the basement membrane. The close proximity of basal epithelial cells to tumor cells in the early stages of prostate oncogenesis raises the possibility that basal epithelial cells participate in tumor cell invasion. Here, we investigated the migration-promoting activity of secreted factors from basal epithelial cells on BPH-1 cells, which we used as an in vitro model of preinvasive prostate cancer cells. We showed that the conditioned medium of basal epithelial cells (PEC-CM) contains adhesion proteins and chemotactic factors that stimulate adhesion, planar polarization, migration, and phosphorylation of Akt and that LY294002 and Wortmannin partially inhibit PEC-CM-triggered migration. We identified laminin-5 as a major migration-stimulating protein for BPH-1 cells in PEC-CM. Laminin-5 induced migration is completely inhibited by LY294002 or Wortmannin. In addition, antibody-depletion of laminin-5 from PEC-CM significantly diminishes the migration of BPH-1 cells. These results demonstrated, that laminin-5 is secreted by basal prostate epithelial cells in vivo and in vitro and stimulates migration of BPH-1 cells through a PI3-kinase dependent mechanism. Altogether, the possibility that basal epithelial cells assist in the invasion of in situ carcinoma cells is supported by the results from our in vitro system.

Wounding activates p38 map kinase and activation transcription factor 3 in leading keratinocytes

“…These abnormalities are detectable even in non-blistered regions in the basement membrane zone as discontinuities in hemidesmosome components including integrin α6β4 (Ryan et al, 1999). Similar discontinuities are also apparent in the basement membrane zone of LKs in epidermal wounds (Nguyen et al, 2000a) and prostate cancer (Klezovitch et al, 2004;Yu et al, 2004). This suggests that LKs in wounds that display elevated ATF3 (Fig.…”

“…Journal of Cell Science 3473 Laminin 5 regulates p38 MAPK and ATF3 in wounds BSA adhesion assay The BSA adhesion assay couples deposition of laminin 5 to subsequent adhesion to the deposits and was performed as previously described (Frank, 2004;Gil et al, 2002). MKs from laminin 5 null mice (α3 -/-MKs) and from a wild-type mouse (α3 +/+ MKs) were grown to confluence, suspended and re-plated onto petri dishes coated with HD-BSA, a non-adhesive surface, or onto laminin 5 surfaces.…”

“…Many studies have reported that P-p38 is required for cell migration (see Discussion). Furthermore, we have previously shown that deposition of laminin 5 at the rear of migrating LKs is necessary for polarized migration of LKs (Frank, 2004). First, we determined if null defects in laminin 5 would elevate levels of P-p38 in vitro (Fig.…”

“…1B). Prior studies have shown that re-adhesion to laminin 5 is mediated by integrin α6β4 and α3β1 whereas spreading and motility are mediated by α3β1 (Frank, 2004;Xia et al, 1996). The predictive capability of the wound model and DNA microarray were validated by examining transcripts known to be elevated in wounds in vivo (Fig.…”

“…Consistently, active Rho and P-p38 contribute to degradation of substrate collagen (Berdeaux et al, 2004;Turchi et al, 2003). Therefore, deposition of laminin 5 that reduces P-p38 and Rho-dependent adhesion on collagen may also reduce collagen degradation (Frank, 2004) or cell invasion.We would like to thank Diane Frank, Randy Sigle, Clarence Dunn, Beatrice Knudsen and Paul Lampe for critical review of the manuscript. We would also like to thank Tim King for help and advice with the cDNA microarrays.…”