Regulation of prostatic carcinoma cell proliferation and secretory activity by extracellular matrix and stromal secretions

Abstract

Previous studies from our laboratory have shown that reconstituted basement membrane and stromal secretory products are important regulators of benign prostatic epithelial cell growth and differentiation. In the present study we evaluated the impact of extracellular matrix (ECM) and soluble stromal secretory products on the proliferation and secretory activity of the androgen-responsive prostatic carcinoma cell line LNCaP. In these studies, dihydrotestosterone (DHT) was a potent mitogen for LNCaP cells cultured on plastic or on type I collagen. The growth response to DHT was greatly attenuated when LNCaP cells were grown on prostatic stromal ECM. Cells grown on stromal ECM also exhibited clustered morphology compared to the monolayer growth observed on plastic and secreted elevated levels of prostate specific antigen (PSA) and prostatic acid phosphatase (PAP). These findings indicate that cultivation of LNCaP on stromal ECM will promote the expression of differentiated functions. In additional studies, stromal cell conditioned medium (SCM) significantly increased PSA/PAP secretion by LNCaP cells in the presence of 10 nM DHT. The enhancement of DHT-induced PSA/PAP secretion by SCM was most pronounced when LNCaP cells were grown on stromal ECM. SCM did not significantly alter LNCaP proliferation. These studies indicate that prostatic stromal ECM and soluble secretory products will promote differentiated function in cultured LNCaP cells. In addition, we show that DHT can act as either a growth or differentiation-promoting stimulus depending on the presence of stromal factors.

Estradiol Activates the Prostate Androgen Receptor and Prostate-specific Antigen Secretion through the Intermediacy of Sex Hormone-binding Globulin

“…That the stromal cell products, keratinocyte growth factor, epidermal growth factor, and insulin-like growth factor I all have been shown to activate the AR (34), is consistent with such a mechanism. Furthermore, stromal cell conditioned medium enhanced DHT-induced PSA secretion by LNCaP cells (39). Taken together, these observations raise the possibility of stromal cell participation in the E 2 -induced increase in PSA secretion.…”

Relationship between Prostatic Specific Antigen (PSA) and volume of the prostate in the Benign Prostatic Hyperplasia in the elderly

“…Moreover, the absence of a correlation between age and PSAD (which is a volume-corrected PSA) strongly reinforces this conclusion. Therefore, as suggested in previous papers [3,4,13,16], it is likely the increased amount of secreting tissue, as it occurs in BPH, is the main responsible for these slight to moderate increases in PSA values.…”

COUP-TF Upregulates NGFI-A Gene Expression through an Sp1 Binding Site

“…As shown VOL. 19,1999 COUP-TF UPREGULATES NGFI-A GENE EXPRESSIONin Fig. 1B, the COUP-TFI-overexpressing cell lines (IS6, IS18, and IS21) contain three to five times more NGFI-A transcription factor than control untransfected cells.…”

“…Since COUP-TFII is highly expressed in the mesenchyme but is undetectable in the epithelium of most organs, it is likely that COUP-TFII plays an important role in mesenchymal cell-epithelial cell interactions during organogenesis. This process has been well studied for the prostate, where several growth factors and the extracellular matrix are involved in this communication between the mesenchyme and the epithelium (11,19).COUP-TFs are able to bind to a variety of dispositions of the basic AGGTCA motif, including those recognized by the receptors of retinoic acid (RAR), thyroid hormone, and vitamin D (13). This ability makes COUP-TFs capable of competing for the response elements of these receptors, thus acting as passive repressors of the transcriptional activation induced by them (12,13,56).…”

“…Since COUP-TFII is highly expressed in the mesenchyme but is undetectable in the epithelium of most organs, it is likely that COUP-TFII plays an important role in mesenchymal cell-epithelial cell interactions during organogenesis. This process has been well studied for the prostate, where several growth factors and the extracellular matrix are involved in this communication between the mesenchyme and the epithelium (11,19).…”