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

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.

Keywords: alternative splicing; cancer growth and development; neoneurogenesis; nerves; therapeutic targets.

Figure 1

Neurosignaling in sympathetic (A) and parasympathetic (B) innervation respectively. Neurotransmitters are in blue, nerves are in yellow and receptors in red.

Figure 2

Schematic representations of the role played by nervous system in tumor development. (A) Tumor-nerve bi-directional interaction. (B) The role of nerve growth factors and axon guidance molecules in tumor-nerve relationship. (C) The mechanism of neurotransmitter signaling in a synapse.

Figure 3

Splice variants of Doublecortin and Doublecortin-like. (A) Doublecortin (DCX) is alternately spliced to give rise to two isoforms. It interacts with microtubules in neuronal precursor cells and promotes cell division. It is expressed in the CNS and primary tumors. (B) Doublecortin-such as (DCLK) is alternately spliced to give rise to three isoforms. The short isoform of DCLK lacks both doublecortin domains and is generally only expressed in adults while the full-length form is expressed in developing embryos. However, the embryonic form is also expressed in tumors. The different numbered colored boxes represent exons. The size of the boxes represents the relative length of them. The frames represent functional domains within the different isoforms.

Figure 4

Isoforms of fibroblast growth factor receptor. These isoforms include the FGFR-1 isoform Alpha A3 which arises due to skipping of the alpha exon. This isoform has increased affinity for fibroblast growth factors and overexpression of this isoform results in increased malignancy. The different numbered colored boxes represent exons. The size of the boxes represents the relative length of them. The frames represent functional domains within the different isoforms.

Figure 5

Alternative splicing of Tyrosine kinases in neurogenesis related to cancer: Tyrosinase is responsible for the synthesis of neuromelanin, dopamine and has been implicated in the spread of melanomas. Tyrosinase is spliced into two isoforms. One isoform lacks one of the coppers binding domain, resulting in decreased enzymatic abilities. The different numbered colored boxes represent exons. The size of the boxes represents the relative length of them. The frames represent functional domains within the different isoforms.

Figure 6

Alternative splicing of Tropomyosin receptor kinase B (TrkB): TrkB plays a role in synaptic survival and plasticity and is alternately spliced to give rise to an isoform that lacks the tyrosine kinase domain. It therefore lacks the ability to initiate intracellular signaling.

Figure 7

Isoforms of Amphiphysin II. The Amphiphysin II mRNA is alternately spliced to give rise to 11 isoforms. Different tissues express different ratios of these isoforms. The BIN1 isoform acts as a tumor suppressor and lacks exons 12A, 12B, 12C, and 12D. The inclusion of these exons results in an isoform that promotes cancer. The different numbered colored boxes represent exons. The size of the boxes represents the relative length of them. The frames represent functional domains within the different isoforms.

Figure 8

Alternative splicing in neuroendocrine prostate cancer progression: BHC80 and GIT1. (A) The histone demethylase BHC80 is alternately spliced to give rise to multiple isoforms. Only three are represented here. Two isoforms BHC80-1 and BHC80-2. Levels of BHC80-2 are expressed at higher levels in neuroendocrine prostate cancer (B) alternative splicing of G protein-coupled receptor kinase-interacting protein 1 (GIT1) gives rise to 3 isoforms. In the development of neuroendocrine carcinoma, the A isoform is upregulated, while the C isoform is downregulated. These isoforms control the splicing and expression of different populations of mRNA. The different numbered colored boxes represent exons. The size of the boxes represents the relative length of them. The frames represent functional domains within the different isoforms.

Figure 9

Alternative splicing of TDP-43. The RNA binding protein TDP-43 is alternately spliced to give rise to two isoforms. It controls the splicing of multiple mRNAs. Many of the RNA targets of TDP-43 play a role in neurodegenerative disease. It also controls its own splicing and gives rise to an isoform that either cannot be translated and is degraded or only contains a single RNA recognition domain, changing the population of RNA molecules it is able to interact with. The different numbered colored boxes represent exons. The size of the boxes represents the relative length of them. The frames represent functional domains within the different isoforms.

Figure 10

Methods to target alternative splicing: (A) altering splicing using specific antisense oligonucleotides (ASOs) using small oligonucleotides that are complementary to the target mRNA; (B) small molecular inhibitors can be used to interfere with the activity of splicing factors such as hnRNPs and SR proteins; Other small molecule inhibitors can block access to splice sites.