Enhancement of Antiproliferative Effects of Interleukin‐1β and Tumor Necrosis Factor‐α on Human Prostate Cancer LNCaP Cells by Coculture with Normal Fibroblasts through Secreted Interleukin‐6

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Abstract
The cell‐cell interactions between tumor cells and stromal cells are considered to be important in the regulation of tumor development at primary and metastatic secondary sites. We studied the effects of various cytokines on the cell‐cell interactions between androgen‐dependent LNCaP or androgen‐independent PC‐3 human prostate cancer cell lines and normal fibroblasts using a coculture system. Among the tested combinations of cytokines and fibroblasts, strong modulations of cytokine actions were seen in coculture with human normal fibroblasts WI‐38. While interleukin (IL)‐1β or tumor necrosis factor‐α (TNF‐α)) partially suppressed LNCaP cell growth in monoculture, each cytokine completely inhibited it in the case of coculture with WI‐38 cells. On the other hand, they did not inhibit PC‐3 cell growth significantly, regardless of monoculture or coculture. Conditioned medium prepared from WI‐38 cells pretreated with IL‐1β or TNF‐α also strongly inhibited LNCaP cell growth. In the conditioned medium, marked IL‐6 secretion was induced from WI‐38 cells by IL‐1β or TNF‐α. Furthermore, neutralizing antibodies to IL‐6 or IL‐6 receptor abrogated the antiproliferative effects of IL‐1β‐ and TNF‐α‐pretreated WI‐38 conditioned medium. These results demonstrate that the antiproliferative effects of IL‐1β and TNF‐α on prostate cancer cells are enhanced by coculture with normal fibroblasts through some diffusible factor(s), such as IL‐6, from the stimulated fibroblasts.