RESUMO
BACKGROUND: A specific type of prostate cancer (PC) that exhibits neuroendocrine (NE) differentiation is known as NEPC. NEPC has little to no response to androgen deprivation therapy and is associated with the development of metastatic castration-resistant PC (CRPC), which has an extremely poor prognosis. Our understanding of genetic drivers and activated pathways in NEPC is limited, which hinders precision medicine approaches. L1 cell adhesion molecule (L1CAM) is known to play an oncogenic role in metastatic cancers, including CRPC. However, the impact of L1CAM on NEPC progression remains elusive. METHODS: L1CAM expression level was investigated using public gene expression databases of PC cohorts and patient-derived xenograft models. L1CAM knockdown was performed in different PC cells to study in vitro cell functions. A subline of CRPC cell line CWR22Rv1 was established after long-term exposure to abiraterone to induce NE differentiation. The androgen receptor-negative cell line PC3 was cultured under the tumor sphere-forming condition to enrich cancer stemness features. Several oxidative stress inducers were tested on PC cells to observe L1CAM-mediated gene expression and cell death. RESULTS: L1CAM expression was remarkably high in NEPC compared to CRPC or adenocarcinoma tumors. L1CAM was also correlated with NE marker expressions and associated with the adenocarcinoma-to-NEPC progression in gene expression databases and CRPC cells with NE differentiation. L1CAM also promoted cancer stemness and NE phenotypes in PC3 cells under cancer stemness enrichment. L1CAM was also identified as a reactive oxygen species-induced gene, by which L1CAM counteracted CRPC cell death triggered by ionizing radiation. CONCLUSIONS: Our results unveiled a new role of L1CAM in the acquisition of the NE phenotype in PC, contributing to the NE differentiation-related therapeutic resistance of CRPC.
RESUMO
Stromal-epithelial interaction has been shown to promote local tumor growth and distant metastasis. We sought to create a promising gene therapy approach that co-targets cancer and its supporting stromal cells for combating castration-resistant prostate tumors. Herein, we demonstrated that human osteonectin is overexpressed in the prostate cancer epithelium and tumor stroma in comparison with their normal counterpart. We designed a novel human osteonectin promoter (hON-522E) containing positive transcriptional regulatory elements identified in both the promoter and exon 1 region of the human osteonectin gene. In vitro reporter assays revealed that the hON-522E promoter is highly active in androgen receptor negative and metastatic prostate cancer and bone stromal cells compared to androgen receptor-positive prostate cancer cells. Moreover, in vivo prostate-tumor-promoting activity of the hON-522E promoter was confirmed by intravenous administration of an adenoviral vector containing the hON-522E promoter-driven luciferase gene (Ad-522E-Luc) into mice bearing orthotopic human prostate tumor xenografts. In addition, an adenoviral vector with the hON-522E-promoter-driven herpes simplex virus thymidine kinase gene (Ad-522E-TK) was highly effective against the growth of androgen-independent human prostate cancer PC3M and bone stromal cell line in vitro and in pre-established PC3M tumors in vivo upon addition of the prodrug ganciclovir. Because of the heterogeneity of human prostate tumors, hON-522E promoter-mediated gene therapy has the potential for the treatment of hormone refractory and bone metastatic prostate cancers.