Purpose: Perineural invasion is the only interaction between cancer cells and nerves studied to date. It is a symbiotic relationship between cancer and nerves that results in growth advantage for both. In this article, we present data on a novel biological phenomenon, cancer-related axonogenesis and neurogenesis. Experimental Design: We identify spatial and temporal associations between increased nerve density and preneoplastic and neoplastic lesions of the human prostate. Results: Nerve density was increasedin cancer areas as well as in preneoplastic lesions compared with controls. Two-and three-dimensional reconstructions of entire prostates confirmed axonogenesis in human tumors. Furthermore, patients with prostate cancer had increased numbers of neurons in their prostatic ganglia compared with controls, corroborating neurogenesis. Finally, two in vitro models confirmed that cancer cells, particularly when interacting with nerves in perineural invasion, induce neurite outgrowth in prostate cancer. Neurogenesis is correlated with features of aggressive prostate cancer and with recurrence in prostate cancer.We also present a putative regulatory mechanism based on semaphorin 4F (S4F). S4F is overexpressed in cancers cells in the perineural in vitro model. Overexpression of S4F in prostate cancer cells induces neurogenesis in the N1E-115 neurogenesis assay and S4F inhibition by small interfering RNA blocks this effect. Conclusions: This is the first description of cancer-related neurogenesis and its putative regulatory mechanism.Nerves play a fundamental role not only in the biology of prostate cancer but also in the normal prostate epithelium. The prostate is thoroughly innervated and receives autonomic innervation through the hypogastric and pelvic nerves (1). Our studies of prostate nerve density in a group of cancer-free patients have shown that nerve density of the peripheral zone, where prostate cancer is more frequent, is significantly greater than that of the transition zone. Both overall nerve density and peripheral zone nerve density decrease with increasing age.Nerves have numerous interactions with the epithelial and stromal components of the prostate. Nerves are involved in prostate development and maintenance of the adult phenotype. Several reports have shown that mechanical and/or chemical denervation of the pelvic plexus of Sprague-Dawley and Wistar rats and dogs causes morphologic and functional changes in the prostate (2 -6). Denervated prostates have an overall decrease in cell height and secretory reduction (3). In humans and rats, the embryologic formation of the prostate requires intact innervation. Maturation of the prostate during adolescence also requires the presence of nerves. These findings strongly suggest that prostate function not only is regulated by androgens but also is subject to the trophic influences of nerves (5,7,8).The best-known interaction between nerves and cancer in prostate cancer is perineural invasion (PNI), the process by which cancer cells invade around ne...

Perineural invasion (PNI) is the major mechanism of prostate cancer spread outside the prostate. Apoptotic and proliferation indices were determined in PNI cells using the PNI in vitro model and human PNI in tissue microarrays. RNA was extracted from the PNI model and controls and evaluated by cDNA microarray analysis. Differential expression of candidate genes was confirmed by real-time quantitative PCR, fluorescence, and immunohistochemistry using tissue microarrays. Genistein and BAY 11-7085 were added to the supernatant of cocultures and controls in microchamber cultures. The significance of nuclear factor B (NFB) nuclear translocation in human PNI was analyzed using Kaplan-Meier analysis. An increase in proliferation and a decrease in apoptosis were observed in human PNI cells and the PNI model as compared with controls. Three of 15 genes up-regulated in the cDNA microarray were involved in the apoptosis signaling pathway (NFB), and its downstream targets defender against cell death 1 and PIM-2. The increase was corroborated by real-time quantitative PCR and immunofluorescence. NFB nuclear translocation was seen in the in vitro model and human tissues, where strong nuclear expression was associated with a decrease in recurrence-free survival. Addition of genistein and BAY 11-7085 resulted in a decrease in NFB, PIM-2 and defender against cell death 1 as well as a reversal of the inhibition of apoptosis. This is the first description of a biological mechanism and functional significance of PNI. Cancer cells in a perineural location acquire a survival and growth advantage using a NFB survival pathway. Targeting PNI might help detain local spread of the tumor and influence survival.

These results are quantitative in nature, performed in cancer-free patients ranging over four different decades of age. We plan to soon compare this profile with our developing profile of cancerous prostates, hoping to learn more about interactions between nerves and prostate cancer.

We probe shock-induced chemistry in two organic liquids by measuring broadband, midinfrared absorption in the 800–1400 cm−1 frequency range. To test this new method and understand the signatures of chemical reactions in time resolved vibrational spectra, we compared liquid benzene shocked to unreactive conditions (shocked to a pressure of 18 GPa for a duration of 300 ps) to nitromethane under reactive conditions (25 GPa). We see clear signatures of shock-induced chemistry that are distinguishable from the pressure- and temperature-induced changes in vibrational mode shapes. While shocked benzene shows primarily a broadening and shifting of the vibrational modes, the nitromethane vibrational modes vanish once the shock wave enters the liquid and simultaneously, a spectrally broad feature appears that we interpret as the infrared spectrum of the complex mixture of product and intermediate species. To further interpret these measurements, we compare them to reactive quantum molecular dynamics simulations, which gives qualitatively consistent results. This work demonstrates a promising method for time resolving shock-induced chemistry, illustrating that chemical reactions produce distinct changes in the vibrational spectra.