Retinal regeneration mechanisms linked to multiple cancer molecules: A therapeutic conundrum

Abstract

Over the last decade, a large number of research articles have been published demonstrating regeneration and/or neuroprotection of retinal ganglion cells following manipulation of specific genetic and molecular targets. Interestingly, of the targets that have been identified to promote repair following visual system damage, many are genes known to be mutated in different types of cancer. This review explores recent literature on the potential for modulating cancer genes as a therapeutic strategy for visual system repair and looks at the potential clinical challenges associated with implementing this type of therapy. We also discuss signalling mechanisms that have been implicated in cancer and consider how similar mechanisms may improve axonal regeneration in the optic nerve.

Introduction

In recent years there has been an exponential increase in the number of publications reporting cell survival and/or axon regeneration in models of optic nerve injury, for example where intraocular pressure is elevated to induce retinal ganglion cell (RGC) loss or following localised optic nerve crush. Numerous factors with diverse physiological functions, including mammalian target of rapamycin (mTOR), kruppel-like family (KLF) transcription factors, suppressor of cytokine signalling 3 (SOCS3) and cytokines (ciliary neurotrophic factor (CNTF)/leukemia inhibitory factor (LIF)), have been suggested to play a key role in RGC survival and/or axon regeneration. Proposed mechanisms include effects on the availability of neurotrophic factors, activation of intrinsic survival/growth mechanisms, modulation of axonal transport and glia-dependent support as well as inhibition of apoptotic mechanisms in RGCs. Interestingly, many of the mechanisms that have been suggested to promote either survival and/or axon regeneration in the damaged visual system are directly or indirectly associated with cancer, including malignancies that affect the eye and visual pathways.

Cancer can be defined as the loss of normal cellular growth control where unregulated proliferation of cells result in malignant pathologies (De Potter et al., 2002). In contrast, failure of neuronal regeneration can be considered as an intrinsic inability to re-activate the normal growth mechanisms that occur during development. In this sense, cancer and regenerative failure could be viewed as different sides of the same coin. The central nervous system (CNS) can be stimulated to regenerate by manipulation of a variety of cancer-associated molecular signalling pathways and excellent reviews have been published on this subject recently (Benowitz et al., 2015, He and Jin, 2016, Kaplan et al., 2015, Smith et al., 2015). Of the identified regeneration-associated genes, many are tumour suppressors, including phosphatase and tensin homolog (PTEN (Park et al., 2008)) or oncogenes such as MYC (Buchser et al., 2010, Pomerantz and Blau, 2013). In this review, we will focus on cancer genes and signalling mechanisms that have been proposed to underlie both malignancy and regeneration in the mature nervous system. We will review several signalling pathways, including PTEN/mTOR pathway, phosphatidylinositol-3-kinase (PI3K), cytokine and inflammatory factors including SOCS-3, trophic factors (such as CNTF), anti-apoptotic factors (including Bcl-2), KLF, transcription factors (including signal transducer and activator of transcription-3 (STAT-3)) as well as additional proposed mechanisms that are known to be involved in cancer pathology but that have also been implicated in axon regeneration. The optic nerve crush model has been extensively utilized to evaluate the impact of modulating different signalling factors on axon regeneration in a physiological setting and has been important in defining signalling mechanisms involved in promoting axon regeneration in the adult mammalian CNS. A major question is whether manipulation of genes involved in cancer can be considered as a feasible mechanism to promote axon regeneration in a clinical setting, where the potential for oncogenesis is a concern. However, it is conceivable that the post-mitotic nature of neurons in the mature visual system may limit this risk of malignancy. In this review we will also consider how oncogenic risk might be mitigated through careful selection and application of the pharmacological or molecular tools used to manipulate cancer-associated pathways.