Abstract
Loss of androgen receptor (AR) dependency in prostate cancer (PCa) cells is associated with progression to castration-resistant prostate cancer (CRPC). The tumor stroma is enriched in fibroblasts that secrete AR-activating factors. To investigate the roles of fibroblasts in AR activation under androgen deprivation, we used three sublines of androgen-sensitive LNCaP cells (E9 and F10 cells: low androgen sensitivity; and AIDL cells: androgen insensitivity) and original fibroblasts derived from patients with PCa. We performed in vivo experiments using three sublines of LNCaP cells and original fibroblasts to form homotypic tumors. The volume of tumors derived from E9 cells plus fibroblasts was reduced following androgen deprivation therapy (ADT), whereas that of F10 or AIDL cells plus fibroblasts was increased even after ADT. In tumors derived from E9 cells plus fibroblasts, serum prostate-specific antigen (PSA) decreased rapidly after ADT, but was still detectable. In contrast, serum PSA was increased even in F10 cells inoculated alone. In indirect cocultures with fibroblasts, PSA production was increased in E9 cells. Epidermal growth factor treatment stimulated Akt and p44/42 mitogen-activated protein kinase phosphorylation in E9 cells. Notably, AR splice variant 7 was detected in F10 cells. Overall, we found that fibroblast-secreted AR-activating factors modulated AR signaling in E9 cells after ADT and loss of fibroblast-dependent AR activation in F10 cells may be responsible for CRPC progression.
Highlights
The number of men diagnosed with prostate cancer (PCa) is increasing worldwide [1]
In androgen-sensitive PCa cells, we have recently reported that fibroblast-derived epidermal growth factor (EGF), insulin-like growth factor (IGF)-1, and IL-6 can activate androgen receptor (AR) signaling, leading to preservation of AR signaling after androgen deprivation therapy (ADT) [17]
We found that fibroblast-secreted AR-activating factors preserved AR signaling in E9 cells after ADT, indicating that these PCa cells could be controlled by ADT
Summary
The number of men diagnosed with prostate cancer (PCa) is increasing worldwide [1]. Most patients with early-stage PCa can be treated with therapies such as radical prostatectomy or irradiation. Patients with advanced PCa are treated with androgen deprivation therapy (ADT), the standard systemic therapy. ADT induces temporary remission, the majority of patients (approximately 60%) eventually develop and progress to castration-resistant prostate cancer (CRPC), which is associated with a high mortality rate [2,3]. In the development and progression of CRPC, a decrease or loss of androgen sensitivity in PCa cells often occurs. Low androgen sensitivity of PCa cells is associated with a more malignant phenotype and is difficult to cure. Changes in the androgen sensitivity of PCa cells are often caused artificially as negative effects of ADT and by spontaneously arising variants of androgen receptor (AR) even before ADT is started [4,5]
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