Understanding and modeling nerve-cancer interactions

Abstract

The peripheral nervous system plays an important role in cancer progression. Studies in multiple cancer types have shown that higher intratumoral nerve density is associated with poor outcomes. Peripheral nerves have been shown to directly regulate tumor cell properties, such as growth and metastasis, as well as affect the local environment by modulating angiogenesis and the immune system. In this Review, we discuss the identity of nerves in organs in the periphery where solid tumors grow, the known mechanisms by which nerve density increases in tumors, and the effects these nerves have on cancer progression. We also discuss the strengths and weaknesses of current in vitro and in vivo models used to study nerve-cancer interactions. Increased understanding of the mechanisms by which nerves impact tumor progression and the development of new approaches to study nerve-cancer interactions will facilitate the discovery of novel treatment strategies to treat cancer by targeting nerves.

Keywords: Cancer; Innervation; Models.

Fig. 1.

Peripheral nerve supply to organs affected by solid tumors. (A,B) Human (A) and mouse (B) nerve supply. The images depict sections of the peripheral nervous system, from top to bottom: cranial, cervical, thoracic, lumbar, sacral and coccygeal. Ganglia of the peripheral nervous system are organized symmetrically, and organs often receive innervation from the same ganglia from both sides of the body. Solid tumors can also be innervated by the enteric nervous system, but this is not shown in the figure as this system is regarded as separate from the peripheral nervous system. Sensory, sympathetic and parasympathetic nerve fibers are marked in green, blue and orange, respectively. DRG, dorsal root ganglion; GI, gastrointestinal; IMG, inferior mesenteric ganglion; NG, nodose ganglion; SCG, superior cervical ganglion; SMG, superior mesenteric ganglion; TG, trigeminal ganglion.

Fig. 2.

In vivo models to study nerve–cancer interaction. (A) Autochthonous and allograft/xenograft mouse models are used to study nerve–cancer interaction. (B) In vivo nerve perturbation strategies include pharmacology, denervation surgery and genetic engineering. (C) Outputs of in vivo models include studying how nerves affect cancer progression, how innervation happens in cancer, and the effects nerves have on stromal cells. 6-OHDA, 6-hydroxy-dopamine.

Fig. 3.

In vitro models to study nerve–cancer interaction. (A) Neuron sources: immortalized cell lines, induced pluripotent stem cell (iPSC) differentiation and primary neurons from rodent dissection. (B) Current in vitro models of nerve–cancer interaction include two-dimensional (2D) cultures and exchanging conditioned media between the two cell types, which can be achieved either via media transfer between separate culture vessels or in Boyden chamber-based assays. Alternatively, direct co-culture of the two cell types is possible within the same vessel and in microfluidic devices. In three-dimensional (3D) co-culture models, the cells are individually suspended in Matrigel, an extracellular matrix mimetic. (C) In vitro models allow thorough investigation into the mechanism of nerve–cancer crosstalk by studying the individual effects of cancer cells and neurons, as well as their gene expression and signaling pathways in response to reciprocal stimuli, multi-omics and electrical communication between the two cell types.