Role of the nervous system in cancers: a review

Abstract

Nerves are important pathological elements of the microenvironment of tumors, including those in pancreatic, colon and rectal, prostate, head and neck, and breast cancers. Recent studies have associated perineural invasion with tumor progression and poor outcomes. In turn, tumors drive the reprogramming of neurons to recruit new nerve fibers. Therefore, the crosstalk between nerves and tumors is the hot topic and trend in current cancer investigations. Herein, we reviewed recent studies presenting direct supporting evidences for a better understanding of nerve-tumor interactions.

Fig. 1. The nerve–tumor crosstalk.

Nerves can secrete the neuroactive molecules that act on tumor cells, lymphocytes, and macrophages to promote tumor proliferation, invasion, angiogenesis, and inflammation. In turn, tumor cells migrate to nerves and damage them to induce the cancer-associated pain. Moreover, tumor cells secrete cytokines, which drive nerve reprogramming and regeneration. PNI perineural invasion.

Fig. 2. Two direct ways of communication between tumor cells and nerves.

Tumors release molecules also secreted by nerves, including neurotropic factors, axon guidance molecules, and neurotransmitters. These factors act on receptors of nerves to drive the nerve reprogramming, while they can also act on tumor receptors to activate downstream signaling. In addition to the paracrine model, tumors and nerves can form the synapses for depolarization to promote tumor progression. TrkA tyrosine kinase receptor A, TrkB tyrosine kinase receptor B, NGFR nerve growth factor receptor, AchR acetylcholine receptor, ADRβ adrenoceptor β receptor, CX3CR1 C-X3-C motif chemokine receptor 1, GFR glial cell-derived neurotrophic factor family receptor.

Fig. 3. Nerves affect tumor cell behaviors through indirect pathways.

Nerves induce angiogenesis through secreting transmitters and neurotrophic factors. On the other hand, they regulate tumor-associated macrophages via cholinergic and adrenergic signaling. In addition, nerves mediate the expression of immune checkpoint molecules (PD-1, PD-L1 FOXP3) by lymphocytes; all the above processes influence tumor behaviors.

Fig. 4. Crosstalk between nerves and immune cells.

ACh is synthesized in the T cells by enzyme choline acetyltransferase. Adrenergic innervation stimulates production of the T-cell-derived ACh, which is involved in regulating the tumor immunity and tumor biology behavior. Endoneural macrophages also regulate tumor metastasis through CXCL10. CXCL10 recruits the myeloid cells and suppresses T cells via VISTA and PD-L1.