Stromal inhibition of prostatic epithelial cell proliferation not mediated by transforming growth factor beta

Abstract

Summary The paracrine influence of prostatic stroma on the proliferation of prostatic epithelial cells was investigated. Stromal cells from the human prostate have previously been shown to inhibit anchoragedependent as well as anchorage-independent growth of the prostatic tumour epithelial cell lines PC-3 and LNCaP. Antiproliferative activity, mediated by a diffusible factor in the stromal cell conditioned medium, was found to be produced specifically by prostatic stromal cells. In the present study the characteristics of this factor were examined. It is demonstrated that prostate stroma-derived inhibiting factor is an acid-and heat-labile, dithiothreitol-sensitive protein. Although some similarities with type beta transforming growth factor (TGF-P)-like inhibitors are apparent, evidence is presented that the factor is not identical to TGF-J3 or to the TGF-p-like factors activin and inhibin. Absence of TGF-P activity was shown by the lack of inhibitory response of the TGF-p-sensitive mink lung cell line CCL-64 to prostate stromal cell conditioned medium and to concentrated, partially purified preparations of the inhibitor. Furthermore, neutralising antibodies against TGF-PI or TGF-P2 did not cause a decline in the level of PC-3 growth inhibition caused by partially purified inhibitor. Using Northern blot analyses, we excluded the involvement of inhibin or activin. It is concluded that the prostate stroma-derived factor may be a novel growth inhibitor different from any of the currently described inhibiting factors.

In vitro modelling of epithelial and stromal interactions in non-malignant and malignant prostates

“…However, the results presented here and those found previously (Lang et al, 1998) do not support this hypothesis. Our results, using a mixed population of stromal cells, would agree with both the theories that fibroblasts can stimulate (Kabalin et al, 1989;Gleave et al, 1991) or inhibit (Kooistra et al, 1995a;Degeorges et al, 1996) epithelial cell growth when compared to growth on tissue culture plastic. However, the majority of stromal cultures had no effect on, or inhibited epithelial cell growth.…”

“…A range of established epithelial cell lines and primary stromal tissue cultures have been used with the aim of reproducing the heterogeneity of disease presentation seen in the population. Ultimately it is hoped this approach will allow us to identify the most relevant findings and further understand the conflicting findings of other groups (Kabalin et al, 1989;Gleave et al, 1991;Kooistra et al, 1995a). Overall, we found that prostate stromal cells had no significant effects on epithelial cell growth but significantly stimulated epithelial cell motility and invasion, and altered cell morphology in direct co-culture.…”

“…Earlier work has indicated that the proportion of smooth muscle decreases in the stroma of tumour samples (Hayward et al, 1997) but we did not find significant differences in the cell composition of primary stromal cultures, even of stromal cultures from poorly differentiated tissue. Stromal cultures were used which were unpassaged, therefore giving rise to a mixed population of cells, and while this may be considered ill-defined, we wished to use this as a model to mimic the cell populations present in the patient and also to avoid using later passaged cultures whose characteristics and growth stimulating effects become altered (Kooistra et al, 1995a(Kooistra et al, , 1995bPasternack et al, 1997). Further investigation is required to isolate primary cultures of smooth muscle cells or fibroblasts alone and analyse their effects on epithelial cell growth.…”

“…In vitro models have shown that primary cultures of prostatic stromal cells can stimulate epithelial growth derived from normal and malignant tissue (Kabalin et al, 1989) but also that prostate fibroblasts derived from normal and malignant tissue inhibit or have mixed effects on epithelial growth (Konig et al, 1987;Kooistra et al, 1995a;Degeorges et al, 1996). In vivo models indicate that whilst rat prostate tumour fibroblasts can stimulate LNCaP tumour cell growth, embryonic mouse fibroblasts had no effect (Camps et al, 1990;Gleave et al, 1991).…”

Expression of transforming growth factors beta-1, beta 2 and beta 3 in human bladder carcinomas

“…It is well established that the TGF-fs are secreted proteins; thus, certain cells may synthesize and release TGF-P into the extracellular matrix of adjacent cells that have the potential to respond. Both autocrine and paracrine factors, which are produced by epithelial and stromal cells, may play an important role in the local growth control, since it is known that epithelium loses its growth capacity when separated from the stroma (Kooistra et al, 1995). Some malignant tumours may use TGF-f released from their environment for enhancing their invasiveness and metastatic behaviour, while at the same time being resistant to the growth-suppressive effect of TGF-0.…”