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The p53 tumour suppressor is activated by numerous stressors to induce apoptosis, cell cycle arrest, or senescence. To study the biological effects of altered p53 function, we generated mice with a deletion mutation in the first six exons of the p53 gene that express a truncated RNA capable of encoding a carboxy-terminal p53 fragment. This mutation confers phenotypes consistent with activated p53 rather than inactivated p53. Mutant (p53+/m) mice exhibit enhanced resistance to spontaneous tumours compared with wild-type (p53+/+) littermates. As p53+/m mice age, they display an early onset of phenotypes associated with ageing. These include reduced longevity, osteoporosis, generalized organ atrophy and a diminished stress tolerance. A second line of transgenic mice containing a temperature-sensitive mutant allele of p53 also exhibits early ageing phenotypes. These data suggest that p53 has a role in regulating organismal ageing.

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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...

Mice with disrupted germline p53 alleles have been engineered by us and others and have been shown to have enhanced susceptibility to spontaneous tumors of various types. We monitored a large number of p53-deficient mice (p53+/- and p53-/-) and their wild-type littermates (p53+/+) of two different genetic backgrounds (129/Sv and mixed C57BL/6 x 129/Sv) up to 2 yr of age. p53+/- and p53-/- 129/Sv mice show accelerated tumorigenesis rates compared with their p53-deficient counterparts of mixed C57BL/6 x 129/Sv genetic background. The tumor spectra of the two strains of mice are similar except that almost half of 129/Sv p53-/- males develop malignant teratomas, whereas these tumors are rarely observed in C57BL/6 x 129/Sv mice and never in 129/Sv p53+/- males. In the study reported here, we further characterized the lymphomas that arose in the p53-nullizygous mice and found that over three-quarters of the lymphomas were of thymic origin and contained primarily immature (CD4+/CD8+) T-cells, whereas the remainder originated in the spleen and peripheral lymph nodes and were of B-cell type. The high incidence of early-onset lymphomas in the nullizygous mice makes these animals a good lymphoma model, whereas the heterozygous mice may be a useful model for Li-Fraumeni syndrome, a human inherited cancer predisposition.