LIV-1 Promotes Prostate Cancer Epithelial-to-Mesenchymal Transition and Metastasis through HB-EGF Shedding and EGFR-Mediated ERK Signaling

LIV-1, a zinc transporter, is an effector molecule downstream from soluble growth factors. This protein has been shown to promote epithelial-to-mesenchymal transition (EMT) in human pancreatic, breast, and prostate cancer cells. Despite the implication of LIV-1 in cancer growth and metastasis, there has been no study to determine the role of LIV-1 in prostate cancer progression. Moreover, there was no clear delineation of the molecular mechanism underlying LIV-1 function in cancer cells. In the present communication, we found increased LIV-1 expression in benign, PIN, primary and bone metastatic human prostate cancer. We characterized the mechanism by which LIV-1 drives human prostate cancer EMT in an androgen-refractory prostate cancer cells (ARCaP) prostate cancer bone metastasis model. LIV-1, when overexpressed in ARCaPE (derivative cells of ARCaP with epithelial phenotype) cells, promoted EMT irreversibly. LIV-1 overexpressed ARCaPE cells had elevated levels of HB-EGF and matrix metalloproteinase (MMP) 2 and MMP 9 proteolytic enzyme activities, without affecting intracellular zinc concentration. The activation of MMPs resulted in the shedding of heparin binding-epidermal growth factor (HB-EGF) from ARCaPE cells that elicited constitutive epidermal growth factor receptor (EGFR) phosphorylation and its downstream extracellular signal regulated kinase (ERK) signaling. These results suggest that LIV-1 is involved in prostate cancer progression as an intracellular target of growth factor receptor signaling which promoted EMT and cancer metastasis. LIV-1 could be an attractive therapeutic target for the eradication of pre-existing human prostate cancer and bone and soft tissue metastases

A novel spontaneous model of epithelial-mesenchymal transition (EMT) using a primary prostate cancer derived cell line demonstrating distinct stem-like characteristics

Cells acquire the invasive and migratory properties necessary for the invasion-metastasis cascade and the establishment of aggressive, metastatic disease by reactivating a latent embryonic programme: epithelial-to-mesenchymal transition (EMT). Herein, we report the development of a new, spontaneous model of EMT which involves four phenotypically distinct clones derived from a primary tumour-derived human prostate cancer cell line (OPCT-1), and its use to explore relationships between EMT and the generation of cancer stem cells (CSCs) in prostate cancer. Expression of epithelial (E-cadherin) and mesenchymal markers (vimentin, fibronectin) revealed that two of the four clones were incapable of spontaneously activating EMT, whereas the others contained large populations of EMT-derived, vimentin-positive cells having spindle-like morphology. One of the two EMT-positive clones exhibited aggressive and stem cell-like characteristics, whereas the other was non-aggressive and showed no stem cell phenotype. One of the two EMT-negative clones exhibited aggressive stem cell-like properties, whereas the other was the least aggressive of all clones. These findings demonstrate the existence of distinct, aggressive CSC-like populations in prostate cancer, but, importantly, that not all cells having a potential for EMT exhibit stem cell-like properties. This unique model can be used to further interrogate the biology of EMT in prostate cancer

Significance of tumor angiogenesis in clinically localized prostate carcinoma treated with external beam radiotherapy

To determine the prognostic significance of microvessel density (a measure of tumor angiogenesis) in comparison with other prognostic factors for patients with clinically localized prostatic carcinoma treated with external beam radiotherapy. Microvessel density was quantified within the initial invasive carcinoma from the diagnostic transurethral resection specimen of 25 patients with a mean follow-up of 44 months. Microvessels were identified by immunohistochemical staining of endothelial cells for factor VIII-related antigen in formalin-fixed, paraffin-embedded tissue. Microvessels were counted in a x200 field (0.754 mm2) in the area of maximal angiogenesis. Microvessel density correlated with several pretreatment prognostic factors, including prostate-specific antigen (PSA) (p < 0.0001), tumor grade (p = 0.006), and ploidy (p = 0.016). The degree of tumor angiogenesis also correlated with outcome following external beam radiotherapy. The mean microvessel count in the nine tumors from patients who failed radiotherapy (ie, had rising PSA and/or clinical relapse) was 97.0 +/- 33.6 (+/- SD) per x200 field compared with 46.1 +/- 17.1 for the 16 patients with no evidence of failure (p < 0.0001). Increased microvessel density was also associated with a significantly worse actuarial outcome at 4 years using either biochemical relapse (rising PSA) or a composite endpoint of rising PSA or clinical relapse (p = 0.0003). The intratumoral quantification of tumor angiogenesis may prove valuable as a prognostic indicator in patients with clinically localized prostate cancer treated with radiotherapy