Gene Therapy for Prostate Cancer Bone Metastasis

Cancer is not a single cell disease but involves complex interaction between cancer cells and their microenvironment (Ingber, 2002; Liotta and Kohn, 2001; Quaranta, 2002; Shekhar et al., 2003; Sung and Chung, 2002). It has been widely recognized that the growth, survival and invasion of cancer cells require the participation of vascular endothelial component of the host (Folkman, 2001; Monsky et al., 2002), the inflammatory and neuroendocrine cells and their cytokine repertoire (Aprikian et al., 1994; Coussens and Werb, 2002; Murakami et al., 2002), and the inductive fibromuscular stromal cells (Aumuller, 1989; Franks et al., 1970; Tuxhorn et al., 2002). Experimental model systems to determine the molecular and cellular basis of prostate cancer progression to androgen independence and metastasis to bone revealed that intimate interaction between cancer cells and prostate or bone stromal cells is required (Chung et al., 1989; Gleave et al., 1991; Gleave et al., 1992; Olumi et al., 1998; Olumi et al., 1999). Under the inductive influence of prostate or bone stromal cells, the human LNCaP prostate cancer cell line can be driven to express both androgen-independent (AI) and bone metastatic potential when co-cultured in vitro as 3- dimensional (3-D) prostate organoids or allowed to form chimeric tumors when co-inoculated in vivo in castrated hosts (Rhee et al., 2001; Thalmann et al., 1994; Wu et al., 1994). These experiments demonstrated a fundamental principle that governs prostate cancer progression, the reciprocal interaction between genetically modified prostate cancer cells and the relevant fibromuscular stromal environment under androgen-deprived and 3-dimensional (3-D) growth conditions. Only in the presence of such interactions can the AI and bone metastatic progression of human prostate cancer cells be achieved. Apparently, permanent phenotypic and genotypic changes are induced in both prostate cancer and interactive stromal compartments (Hyytinen et al., 1997; Pathak et al, 1997). The consequences of cellular interaction include changes observed in the stroma, which becomes “reactive” and drives further progression of human prostate cancer cells to the AI and metastatic state (Sung and Chung, 2002). To tackle the molecular mechanisms underlying the progression of prostate cancer cells to androgen independence and bone metastasis under the influence of fibromuscular stromal cells, we and others have proposed that both soluble factors and insoluble extracellular matrices (ECMs) are likely to be involved through cellular communication or “cross-talk” between these mosaic factors, their receptors and downstream signaling pathways (Sung and Chung, 2002; Tuxhorn et al., 2001; Varani et al., 1999; Wong and Wang, 2000). In this review, we will focus our discussion on three areas: first, the development of the gene therapy concept and strategies to co-target prostate cancer growth in bone; second, the application of local-regional and systemic gene therapy in human clinical trials; and third, a discussion of the future development of effective gene therapy approaches for the treatment of prostate cancer bone metastasis.