The voltage-gated ionic currents of two rodent prostatic cancer cell lines were investigated using the whole-cell patch clamp technique. The highly metastatic Mat-Ly-Lu cells expressed a transient, inward Na ÷ current (blocked by 600 nM tetrodotoxin), which was not found in any of the weakly metastatic AT-2 cells. Although both cell lines expressed a sustained, outward K ÷ current, this occurred at a significantly higher density in the AT-2 than in the Mat-Ly-Lu cells. Incubation of the MatLy-Lu cell line with 600 nM tetrodotoxin significantly reduced the invasive capacity of the cells in vitro. Under identical conditions, tetrodotoxin had no effect on the invasiveness of the AT-2 cells.

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Interest in the interactions between nervous and immune systems involved in both pathological and homeostatic mechanisms of host defence has prompted studies of neuroendocrine immune modulation and cytokine involvement in neuropathologies. In this review we concentrate on a distinct area of homeostatic control of both normal and abnormal host defence activity involving the network of peripheral c-fibre nerve fibres. These nerve fibres have long been recognized by dermatologists and gastroenterologists as key players in abnormal inflammatory processes, such as dermatitis and eczema. However, the involvement of nerves can all too easily be regarded as that of isolated elements in a local phenomenon. On the contrary, it is becoming increasingly clear that neural monitoring of host defence activities takes place, and that involvement of central/spinal mechanisms are crucial in the co-ordination of the adaptive response to host challenge. We describe studies demonstrating neural control of host defence and use the specific examples of bone marrow haemopoiesis and contact sensitivity to highlight the role of direct nerve fibre connections in these activities. We propose a host monitoring system that requires interaction between specialized immune cells and nerve fibres distributed throughout the body and that gives rise to both neural and immune memories of prior challenge. While immunological mechanisms alone may be sufficient for local responsiveness to subsequent challenge, data are discussed that implicate the neural memory in co-ordination of host defence across the body, at distinct sites not served by the same nerve fibres, consistent with central nervous mediation.

Biochemical properties of Ras oncoproteins and their transforming ability strongly support a dominant mechanism of action in tumorigenesis. However, genetic studies unexpectedly suggested that wild-type (WT) Ras exerts tumor suppressor activity. Expressing oncogenic NrasG12D in the hematopoietic compartment of mice induces an aggressive myeloproliferative neoplasm (MPN) that is exacerbated in homozygous mutant animals. Here we show that increased NrasG12D gene dosage, but not inactivation of WT Nras, underlies the aggressive in vivo behavior of NrasG12D/G12D hematopoietic cells. Modulating N-RasG12D dosage had discrete effects on myeloid progenitor growth, signal transduction, and sensitivity to MEK inhibition. Furthermore, enforced WT N-Ras expression neither suppressed the growth of Nras mutant cells nor inhibited myeloid transformation by exogenous NrasG12D. Importantly NRAS expression in increased in human cancer cell lines with NRAS mutations. These data have therapeutic implications and support reconsidering the proposed tumor suppressor activity of WT Ras in other cancers. Significance Understanding mechanisms of Ras-induced transformation and adaptive cellular responses are fundamental questions. The observation that oncogenic Nras lacks tumor suppressor activity while increased dosage strongly modulates cell growth and alters sensitivity to MEK inhibition suggests new therapeutic opportunities in cancer.