Prostate carcinoma is one of the most important cancer-related causes of death in the adult male population in this country. This disease is not only significant because of its mortality, but also because of it high incidence in the later years of life and the effects related to therapy (i.e., incontinence and sexual dysfunction). Cure in prostate cancer is most likely in patients for whom treatment is not always necessary, and no treatments are available for those cases that require cure. As with most other cancers, prostate adenocarcinoma is a multistep process of which the last is acquisition of ability to spread to other parts of the body (metastatic ability). In the prostate, the ability to metastasize is related to perineural invasion (peri=around, neural=nerve). This refers to prostate cancer cells wrapping around nerves and traveling through them in the same manner cars travel on a highway. It seems natural that prostate cancer would select nerves as a mechanism of spread, for the prostate is a very richly innervated organ that has a substantial neuroendocrine component. Current theory states this form of metastasis occurs because traveling along nerves is the path of least resistance for the cancer cells, a purely physical process. In contradiction, our preliminary data indicates that perineural invasion is the result of an active, specific, and reciprocal interaction between nerves and prostate cancer cells. We co-cultured prostate cancer cells and ganglia/nerves of mice in a matrix. In the first stages, nerves were recruited by prostate cancer cells and grew directly toward them, establishing contact. Once contact was established, the cancer cells traveled along the nerve back to the point of origin. It is noteworthy that these cells wrap around the nerves in the same manner that human prostate cancer wraps around nerves in the prostate in vivo. In simpler words, the nerves go to the cells and open a pathway back to the original nerve, through which they can expand through the body. We also observed reciprocity, for nerves grew more in the presence of cancer cells, and cancer cells grew more in the presence of nerves. Such interactions most likely will have signaling and regulatory mechanisms that need to be determined. We will do so by using antibodies against growth factors and factors related to cell adhesion and matrix destruction, and observing their effect on each element of neuro-epithelial interactions. We will also investigate if neuro-epithelial interactions are exclusive to prostate cancer or if they can occur with other cancers such as pancreas and colon, benign cells such as benign prostate epithelium and foreskin cells, and benign prostate stromal cells. We propose to validate the in vitro data with an in vivo system. The same cell lines and permutations will be inserted into a small tube that will be attached to a large nerve inside mice. Nerve growth inside the tubes will be measured after a maximum of four weeks. We will also investigate the human prostate micro neuroanatomy and its variations in cancer in order to determine if neuroepithelial interactions are paramount in human prostate adenocarcinoma. Understanding the specific mechanisms of this carcinoma/nerve interaction is key to developing potential therapeutic targets. These new strategies would target the factor that defines mortality in prostate cancer, metastatic ability. If detention of metastatic ability is feasible, low-grade cancers would be treated with less morbidity and treatment for high-grade cancers would finally be attainable. This model not only sheds new concepts as to the nature of perineural invasion, but to our knowledge, is the only model that permits the study of perineural invasion and its regulation.