Cancer hallmarks intersect with neuroscience in the tumor microenvironment

Abstract

The mechanisms underlying the multistep process of tumorigenesis can be distilled into a logical framework involving the acquisition of functional capabilities, the so-called hallmarks of cancer, which are collectively envisaged to be necessary for malignancy. These capabilities, embodied both in transformed cancer cells as well as in the heterotypic accessory cells that together constitute the tumor microenvironment (TME), are conveyed by certain abnormal characteristics of the cancerous phenotype. This perspective discusses the link between the nervous system and the induction of hallmark capabilities, revealing neurons and neuronal projections (axons) as hallmark-inducing constituents of the TME. We also discuss the autocrine and paracrine neuronal regulatory circuits aberrantly activated in cancer cells that may constitute a distinctive "enabling" characteristic contributing to the manifestation of hallmark functions and consequent cancer pathogenesis.

Figure 1.. Neurons and their axonal projections are implicated as a common, functionally enabling constituent of the heterotypic cellular microenvironments of tumors

Peripheral innervation involves three principal subtypes: motor, sensory, and autonomic (including sympathetic and parasympathetic) nerves. Signaling between innervation (axonal projections of distant neurons, orange/yellow) and cancer cells enables multiple hallmarks of cancer, while reciprocal effects of cancer cells on the nervous system result in the remodeling of neural form and function that contributes to neurological complications of cancers and amplifies the consequences of neurons on cancer pathophysiology.

Figure 2.. Neuronal regulatory pathways co-opted in cancer cells are implicated in facilitating the acquisition of hallmark capabilities

While evidently activated by non-mutational epigenetic reprogramming and, in some cases, genome instability and mutation, the increasing breadth of co-opted neuronal regulatory circuits in cancer cells suggests that this concept warrants being highlighted as an important hallmark-enabling characteristic that is instrumental in multiple tumor phenotypes.

Figure 3.. Cancer hallmarks meet neuroscience

The examples presented herein demonstrate the functional involvement of innervation as a constituent of the TME, and/or of co-opted neuronal signaling in cancer cells, in modulating six (highlighted) of the ten parameters constituting the core hallmarks’ conceptualization. Future research may reveal connections to those that are currently unconnected, as well as to other provisional parameters on the horizon.