Stromal-epithelial interaction contributes to local prostate
tumor growth,
androgen-independent progression and distant
metastasis. We have established in vitro coculture and in vivo chimeric
tumor models to evaluate the roles of stromal cells isolated from either
osteosarcoma or normal bone, a site where
prostate cancer cells frequently metastasize, in contributing to the growth and survival of human
prostate cancer cells. We have evaluated extensively the effects of toxic gene therapy using
luciferase-tagged chimeric human
prostate cancer models both in vitro and in vivo. In the in vitro cocultured cell model, we assessed
cancer cell growth and residual cellular
proteins after targeting either
prostate cancer epithelial cells alone or both
prostate cancer and bone stromal cells. In the in vivo animal model, we measured
tumor volume and serum
prostate-specific antigen (PSA) in mice bearing chimeric prostate
tumors comprised of human prostate
tumor cells and normal bone stromal cells. Our results demonstrated that: (1) The rate of human
prostate cancer cell growth in vitro is accelerated by coculturing with human and rat
osteosarcoma or normal mouse bone marrow stromal cell lines. No growth stimulation was noted when cocultured with a human prostate epithelial cell line. (2) Disabling the growth of normal bone stromal cells using transgenic targeting with a bystander gene, herpes simplex virus
thymidine kinase (hsv-TK), plus the
pro-drug ganciclovir (GCV) or
acyclovir markedly depressed the growth of cocultured human
prostate cancer cells in vitro and human
prostate cancer-mouse normal bone stroma chimeric
tumors in vivo. (3) By cotargeting both human
prostate cancer and normal mouse bone stromal cells in vitro with an adenoviral construct, Ad-hOC-TK (a replication-defective Ad5 vector with the bystander transgene hsv-TK under the control of a human
osteocalcin (hOC) promoter) plus GCV4, we observed greater inhibition of
tumor cell growth than by targeting a single cell compartment with Ad-PSA-TK (a vector construct similar to Ad-hOC-TK except that the transgene expression is under regulation by a full-length human PSA promoter). These results, taken together, established a basic principle that cotargeting both
tumor and its supporting stroma is more efficacious than targeting a single cell compartment in the treatment of human
prostate cancer bone
metastasis. This principle can be applied to other clinical conditions of
cancer growth where stroma contribute to the overall growth and survival potential of the
cancer.