Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination

SIMPLE SUMMARY: Significant progress has recently been made in understanding the role of the neuronal system in cancer biology, in many solid tumors such as prostate, breast, pancreatic, gastric and brain cancers. Solid tumors and the nervous system appear to influence each other’s development both directly and indirectly. A recurring element in such interactions is constituted by nerve-related substances such as neurotransmitters and neurotrophins, to which the first part of the current review is devoted. The second part of the review focuses on the potential role played by alternative splicing in cancer progression associated with neural signaling. Alternative splicing is the process where pre-mRNA is cut and re-ligated in different ways to give rise to multiple protein isoforms whose expression profile is often cancer specific. Alternative splicing is known to take place in the mRNA of genes that code for proteins involved in neuronal development and the creation of new nerve fibers. The change in alternative splicing patterns that occur as tumors develop and progress may make these splice variants potential targets for the development of drug treatments. They may also serve as diagnostic or prognostic biomarkers. ABSTRACT: During development, as tissues expand and grow, they require circulatory, lymphatic, and nervous system expansion for proper function and support. Similarly, as tumors arise and develop, they also require the expansion of these systems to support them. While the contribution of blood and lymphatic systems to the development and progression of cancer is well known and is targeted with anticancer drugs, the contribution of the nervous system is less well studied and understood. Recent studies have shown that the interaction between neurons and a tumor are bilateral and promote metastasis on one hand, and the formation of new nerve structures (neoneurogenesis) on the other. Substances such as neurotransmitters and neurotrophins being the main actors in such interplay, it seems reasonable to expect that alternative splicing and the different populations of protein isoforms can affect tumor-derived neurogenesis. Here, we report the different, documented ways in which neurons contribute to the development and progression of cancer and investigate what is currently known regarding cancer-neuronal interaction in several specific cancer types. Furthermore, we discuss the incidence of alternative splicing that have been identified as playing a role in tumor-induced neoneurogenesis, cancer development and progression. Several examples of changes in alternative splicing that give rise to different isoforms in nerve tissue that support cancer progression, growth and development have also been investigated. Finally, we discuss the potential of our knowledge in alternative splicing to improve tumor diagnosis and treatment.