Heparin-Binding Epidermal Growth Factor-Like Growth Factor Stimulates Androgen-Independent Prostate Tumor Growth and Antagonizes Androgen Receptor Function
| Autor: | Dana C. Rice, Liyan Zhuang, Michael R. Freeman, Jayoung Kim, Anna Orsola, Rosalyn M. Adam, Jianqing Lin |
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| Rok vydání: | 2002 |
| Předmět: |
Male
medicine.medical_specialty medicine.medical_treatment Immunoblotting Gene Expression Mice SCID Biology Transfection urologic and male genital diseases Neuroendocrine differentiation Mice Prostate cancer Endocrinology Prostate Internal medicine LNCaP Androgen Receptor Antagonists Tumor Cells Cultured medicine Animals Growth factor receptor inhibitor Epidermal Growth Factor Growth factor Prostatic Neoplasms Dihydrotestosterone medicine.disease In vitro Androgen receptor medicine.anatomical_structure Solubility Receptors Androgen Culture Media Conditioned Phosphopyruvate Hydratase Androgens Cancer research Intercellular Signaling Peptides and Proteins Cell Division Neoplasm Transplantation Heparin-binding EGF-like Growth Factor |
| Zdroj: | Endocrinology. 143:4599-4608 |
| ISSN: | 1945-7170 0013-7227 |
| DOI: | 10.1210/en.2002-220561 |
| Popis: | Peptide growth factors have been implicated in progression of prostate cancer (PCa) to the androgen-independent state; however, much of the evidence linking diffusible mitogens and survival factors to this process remains circumstantial. Heparin-binding epidermal growth factor-like growth factor (HB-EGF), a prostate stroma-derived factor, promotes survival, proliferation, and neuroendocrine differentiation of androgen-dependent LNCaP PCa cells in vitro. To test whether sustained exposure to HB-EGF can confer an androgen-independent phenotype, we generated stable populations of LNCaP cells that express constitutively a secreted form of HB-EGF (LNCaP/sHB). LNCaP/sHB cells proliferated more rapidly under androgen-depleted conditions in vitro and formed larger tumors with higher frequency in intact and castrated severe combined immunodeficient mice, in comparison to control cells. LNCaP/sHB tumors also expressed higher levels of the neuroendocrine marker, neuron-specific enolase, compared with control tumors. In castrates, increased neuron-specific enolase expression in LNCaP/sHB tumors was associated with reduced androgen receptor (AR) levels. In vitro, AR protein levels were reduced in LNCaP/sHB cells, and in transient transfection assays using an androgen-responsive promoter (mouse mammary tumor virus-long terminal repeat), LNCaP/sHB cells showed reduced sensitivity to dihydrotestosterone compared with controls. This is the first demonstration that continuous exposure of AR-positive PCa cells to a single growth factor can promote an androgen-independent phenotype in vivo. These findings also emphasize the potential role of pathways other than the AR axis in acquisition of androgen independence. |
| Databáze: | OpenAIRE |
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