Nerve input to tumours: Pathophysiological consequences of a dynamic relationship.

It is well known that tumours arising in different organs are innervated and that 'perineural invasion' (cancer cells escaping from the tumour by following the nerve trunk) is a negative prognostic factor. More surprisingly, increasing evidence suggests that the nerves can provide active inputs to tumours and there is two-way communication between nerves and cancer cells within the tumour microenvironment. Cells of the immune system also interact with the nerves and cancer cells. Thus, the nerve connections can exert significant control over cancer progression and modulating these (physically or chemically) can affect significantly the cancer process. Nerve inputs to tumours are derived mainly from the sympathetic (adrenergic) and the parasympathetic (cholinergic) systems, which are interactive. An important component of the latter is the vagus nerve, the largest of the cranial nerves. Here, we present a two-part review of the nerve inputs to tumours and their effects on tumorigenesis. First, we review briefly some relevant general issues including ultrastructural aspects, stemness, interactions between neurones and primary tumours, and communication between neurones and metastasizing tumour cells. Ultrastructural characteristics include synaptic vesicles, tumour microtubes and gap junctions enabling formation of cellular networks. Second, we evaluate the pathophysiology of the nerve input to five major carcinomas: cancers of prostate, stomach, colon, lung and pancreas. For each cancer, we present (i) the nerve inputs normally present in the cancer organ and (ii) how these interact and influence the cancer process. The best clinical evidence for the role of nerves in promoting tumorigenesis comes from prostate cancer patients where metastatic progression has been shown to be suppressed significantly in cases of spinal cord injury. The balance of the sympathetic and parasympathetic contributions to early versus late tumorigenesis varies amongst the different cancers. Different branches of the vagus provide functional inputs to several of the carcinomas and, in two-way interaction with the sympathetic nervous system, affect different stages of the cancer process. Overall, the impact of the vagus nerve can be 'direct' or 'indirect'. Directly, the effect of the vagus is primarily to promote tumorigenesis and this is mediated through cholinergic receptor mechanisms. Indirectly, pro- and anti-tumour effects can occur by stimulation or inhibition of the sympathetic nervous system, respectively. Less well understood are the 'indirect' anti-tumour effect of the vagus nerve via immunomodulation/inflammation, and the role of sensory innervation. A frequent occurrence in the nerve-tumour interactions is the presence of positive feedback driven by agents like nerve growth factor. We conclude that the nerve inputs to tumours can actively and dynamically impact upon cancer progression and are open to clinical exploitation.