Why and How do Cancer Cells Interact with Neurons

Virtually all types of cancers have been observed to contract interactions with neuronal structures, at least at some generally advanced stages of the disease. Numerous types of cancers from epithelial (lung, breast, gut) or mesenchymal (bone) tissues give frequently rise to intracranial metastases, infiltrating the nervous tissues [13]. Another obvious example is the case of non-neuronal intracranial tumors, like gliomas. These astrocyte-derived tumors, diffusely infiltrate the normal brain. From a clinical point of view, the diffuse infiltration of these cancer cells into the healthy brain parenchyma makes complete surgical resection nearly impossible and focal radiation therapy difficult [14]. Neuro-neoplastic interactions have also been particularly well-described for a number of peripheral cancers that infiltrate the surrounding nerve arborescences, wrapping around these structures. This process called PNI, as cited above, has been described long ago by Ernst [3]. It has been particularly well-studied for prostate, bile duct, and pancreatic carcinomas as well as head and neck cancers [15-19]. For a long time, it was believed that in PNI, cancer cells where escaping the initial site of tumor, along lymphatic vessels following the perineural spaces, until Rodin et al. [4], demonstrated that these locations are frequently devoid of such vessels. The cellular and molecular events of PNI that lead cancer cells to interact and migrate along nerve trails remain however poorly documented.

One can speculate that the cooperation of cancer cells with nerve structures may be an indispensable adaptative process that ensures the survival and proliferation of selected cells. This could lead to the emergence of cancer cells presenting a particular phenotype that allow them to contract tight interactions with nerves, through the so-called neuro-neoplastic synapse (fig. 1). An attractive hypothesis should be that these cancer cells may have acquired several molecular components and mechanisms of peripheral neurons or more generally cells of neuroectodermal origin. An intriguing observation is the expression of synaptophysin, a marker of differentiated neurons involved in synaptogenesis, in non-neural cancers [5]. This could reflect the establishment of a novel cancerous phenotype in cells displaying a high-predilection for nerves and peri-neural spaces, a concept which is particularly well-illustrated by small cell lung carcinoma (SCLC) which display several features of neuronal cells [20]. Neuroendocrine tumoral cells that release neurotransmitter, neuropeptides as well as other growth and migratory-promoting factors, are frequently observed in the course of cancer progression. This process is particularly well-illustrated in SCLC, but also in some types of prostate cancers [20, 21]. Generally, this type of cells that display strong migratory properties and invasiveness, is considered of quite bad prognosis. Some compounds released by neuroendocrine cells are strong inducers of neoneurogenesis, but also of angiogenesis and lym-phangiogenesis. Conversely, cells in the perineural microenvironment may be influenced by the nerve to evolve a growth and survival advantage (fig. 1). This is the case for prostate cancer, for instance. The consequence is increased tumor volume around the nerve, a more aggressive phenotype and a poor survival score for patients [19]. Another dramatic consequence for cancer progression is that substances delivered by these cells, such as chemokines, excitatory neuro-transmitters, kininogen and tachykinin derivatives, may lead to an exacerbated development and activation of peripheral sensory nerves, leading to chronic and intractable neuroinflammation and pain.

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