Suppression of EGF-R signaling reduces the incidence of prostate cancer metastasis in nude mice

Abstract

The activation of epidermal growth factor receptor (EGF-R) plays a key role in the promotion of proliferation and invasion in prostatic carcinoma (PCa). Gefitinib (Iressa; ZD1839), an orally active EGF-R tyrosine kinase inhibitor, has shown an important anti-proliferative activity in tumors expressing EGF-R both in vitro and in vivo. Our aim was to elucidate the role of gefitinib in the modulation of the metastatic spread of PCa cells. The therapeutic role of gefitinib was investigated by evaluating the proliferative and invasive ability of the PCa cell line PC3 and of its high metastatic sub-line, PCb2, by in vitro assays and intracardiac injection in nude mice. The inhibitory effect of gefitinib was tested in vivo by injecting PCa cells subcutaneously or in the left ventricle of nude mice and by administrating daily 150 mg/kg of gefitinib. While xenograft growth was equally reduced in all PCa lines (about 50%), the bone metastasis formation was inhibited especially for the high metastatic PCb2 sub-line (81%) in comparison to PC3 cells (47%). The comparative in vitro analysis among PCa cell lines showed that PCb2 cells were more sensitive to the inhibitory effect of gefitinib in their invasive ability compared to parental PC3 cells but not in their proliferation rate. Moreover, PCb2 cells demonstrated an increased invasive ability in vitro in response to bone stromal cell conditioned medium (BCM). The simultaneous presence of 0.1 ng/ml gefitinib was sufficient to reduce the number of invaded cells in the presence of both EGF and BCM. The molecular characterization of the highly aggressive PCa sub-lines demonstrated that this phenomenon was associated with an increment in uPA/uPAR axis but not in EGF-R expression. In conclusion, our data suggest that the use of gefitinib as a therapeutic agent may be indicated in the control of PCa spreading to bone.

Epidermal Growth Factor Promotes Protein Degradation of Epithelial Protein Lost in Neoplasm (EPLIN), a Putative Metastasis Suppressor, during Epithelial-mesenchymal Transition

“…On the other hand, the blockade of EGFR signaling could be more effective in preventing and retarding PCa progression toward metastasis. Supporting this notion, gefitinib treatment significantly reduced bone metastatic incidence in an experimental model of PCa (14).…”

Co-culturing human prostate carcinoma cells with hepatocytes leads to increased expression of E-cadherin

“…Thus, targeting EGFR kinase may have effects other than promoting the metastatic engraftment proposed herein by the upregulation of E-cadherin. For instance, the recent report of EGFR kinase inhibitors limiting prostate tumour dissemination in experimental models (Angelucci et al, 2006) is likely due to inhibiting pathways and cell behaviors before the proposed upregulation of E-cadherin at the metastatic site, though re-expression of E-cadherin at the primary tumour site would also limit spread by preventing initial detachment (Jawhari et al, 1999;Lowy et al, 2002;Wong and Gumbiner, 2003). (C) PC-3 cells were exposed to PD153035 for 48 h with a resultant upregulation of E-cadherin as shown by immunoblotting.…”

Osteoblast-induced EGFR/ERBB2 signaling in androgen-sensitive prostate carcinoma cells characterized by multiplex kinase activity profiling

“…Additionally, given that EGFR and ERBB2 are phosphorylated in androgen-sensitive LNCaP cells upon influence of osteoblasts, a functional androgen signalling axis [16,17] may appear to be permissive for activity of these particular pathways in prostate cancer. Not the less, EGFR phosphorylation resulting from short-term incubation with bone stromal conditioned medium (containing 6% FBS) and suppression of in vivo bone metastasis formation following targeted inhibition of EGFR-dependent signalling have been demonstrated in androgen-independent prostate carcinoma PC3 cells [34]. Separately, EGFR and ERBB2 may facilitate androgen receptor-driven activity in prostate cancer at the level of target gene transcription in the absence or at low concentrations of androgens [35,36].…”