Reciprocal interactions between prostate cancer cells (PCa) and prostate or bone stromal cells demonstrated to alter the genotypes and behaviors of human PCa. The purposes of this investigation are: 1) to determine cellular interactions could result in reciprocal genotypic and behavioral changes of the stromal cells; 2) to validate such changes may occur in clinical specimens; 3) to determine the “reciprocal interaction” between tumor and stroma may explain these changes; and 4) to determine the model may mimicked by stromal cells isolated from clinical specimens. Human PCa, LNCaP, or its lineage-derived androgen-independent C4-2 cells co-cultured with bone stromal cells, MG63, HS-27A or HS-5, under 3-D rotary wall vessel (RWV) system. Cytogenetic, microarray and qRT-PCR analyses were performed to validated gene expression profiles of stromal cells exposed to PCa. Five paired human prostate stromal cells from benign or prostate cancer area of cancer specimens were harvested to confirm these studies. Protein expression levels of potential candidate genes were confirmed by tissue array or ELISA analyses. To determine the tumorigenecity, in vivo study was performed using a luciferase-tagged and PSA-producing human PCa. Cytogenetic analysis showed non-random permanent genetic changes in reactive stromal cells. Gross morphology differences were observed in reactive stromal after 3-D RWV. Microarray study showed gene profile changes that can be confirmed by qRT-PCR. Tissue array and ELISA analyses confirmed these protein expressions in clinical specimens. The co-inoculated reactive stromal cells as a chimera with C4-2 cells in vivo induce marked tumor growth, increased angiogenesis and host serum PSA in comparison to control in athymic mice. This tumorigenesis by reactive stromal cells mimicked the behaviors of the prostate stromal cells harvested and cultured from cancer-associated. The plasticity of bone stromal cells and their interactions with human PCa were demonstrated. Permanent genetic, gene expression and behavioral changes were observed in bone stromal cells subsequent to cellular interaction with human prostate cancer cells. The resulting bone stromal cells expressed higher level of ECMs, chemokines and cytokines that induced prostate cancer growth in nude mice. Gene expression profile changes induced in bone stromal cells through co-culture with PCa in the 3-D RWV mimic changes seen in stromal cells associated with prostate cancer, but not in benign tissues. These data demonstrated the tumor-stroma interaction generates a reciprocal interaction leads to increased malignant potential of human prostate cancer. Therapeutic targeting of this interaction could prove to be beneficial to patients with prostate cancer bone metastasis.

98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA