Cancer neuroscience: State of the field, emerging directions

Abstract

The nervous system governs both ontogeny and oncology. Regulating organogenesis during development, maintaining homeostasis, and promoting plasticity throughout life, the nervous system plays parallel roles in the regulation of cancers. Foundational discoveries have elucidated direct paracrine and electrochemical communication between neurons and cancer cells, as well as indirect interactions through neural effects on the immune system and stromal cells in the tumor microenvironment in a wide range of malignancies. Nervous system-cancer interactions can regulate oncogenesis, growth, invasion and metastatic spread, treatment resistance, stimulation of tumor-promoting inflammation, and impairment of anti-cancer immunity. Progress in cancer neuroscience may create an important new pillar of cancer therapy.

Figure 1:. Mechanisms of nervous system-cancer interactions

The nervous system (grey) and cancer (red) interact in at least six ways. A) electrochemical interactions, including bona fide neuron-to-cancer synapses. B) Paracrine interactions from neurons/nerves to cancer cells, directly or through signaling with cells in the tumor microenvironment (green stromal cell and red blood vessel shown). In turn, cancer cells often secrete signaling molecules such as synaptogenic factors or axonogenic factors that locally remodel the nervous system to augment nervous system-cancer interactions. C) Systemic nervous system-cancer interactions, such as circulating neurotransmitters or neuropeptides that can influence cancer pathogenesis directly or indirectly such as through altered immune system (blue) function. Reciprocally, cancers can influence the nervous system at a distance through circulating factors or altered afferent neural signals. D) Three-way interactions between neurons or nerves, cancer cells, and immune cells can modulate anti-cancer immunity and pro-cancer inflammation. E) Cancer cells may leverage cell-intrinsic signaling and other processes classically associated with neural cells. For example, autocrine neurotrophin signaling is illustrated. F) Cancer therapies (chemotherapy, green) can profoundly alter nervous system function, including impaired function of various types of peripheral nerves and impaired cognitive function.

Figure 2.. Parallel mechanisms of glial plasticity and glial malignancy

Left) Neuron (grey) to oligodendroglial (blue) interactions involve neuron-to-oligodendrocyte precursor cell synapses and paracrine (red circles) signaling, e.g. BDNF-TrkB signaling, during development and throughout life. Neuronal activity can promote the proliferation of oligodendrocyte precursor cells, generation of new oligodendrocytes and adaptive changes to myelination that tune neural circuit function. Such plasticity of myelin contributes to healthy cognitive function throughout life. Right) Neuron to glioma (green) interactions involve neuron-to-glioma synapses and paracrine signaling, e.g. BDNF-TrkB signaling. Glioma hijacking of mechanisms that normally support myelin development, homeostasis and plasticity instead contribute to glial cancer initiation, growth and invasion.

Figure 3:. Therapeutic opportunities at the intersection of neuroscience and cancer biology

Increased understanding of nervous system-cancer crosstalk is beginning to elucidate therapeutic targets for a variety of cancer. While these targets vary in a tumor- specific manner, examples are shown here of the target structure or principle (dark green), a relevant molecular target (light green) and example of a drug or drug class that may prove useful for therapy (yellow). Please note that only examples are shown, and each target is not necessarily relevant for every tumor type; for instance, targeting AMPAR-mediated synapses using the anti-seizure medication parampanel has, to date, only been demonstrated as a potential strategy for gliomas. Each therapeutic strategy requires testing in prospective clinical trials, which has been initiated for several of those (see text).

Figure 4:. Techniques for studying nervous system-cancer interactions

Methodologies to study nervous system-cancer interactions can be broadly categorized into four dimensions that encompass the functional, structural and molecular characterization as well as the material or model system that is studied. Furthermore, techniques crossing these modalities are mentioned here at the intersections. Methods shown in light grey are methodologies that have not yet been applied to Cancer Neuroscience studies but are of potential future use.

Figure 5:. Cancer neuroscience from bench-to-bedside & bedside-to-bench

A framework for integrative cancer neuroscience at the intersection of preclinical and translational research. The figure provides an example for brain tumor studies, but can also serve as a blueprint for extracranial tumors.