Cancer-Associated Neurogenesis and Nerve-Cancer Cross-talk

Abstract

In this review, we highlight recent discoveries regarding mechanisms contributing to nerve-cancer cross-talk and the effects of nerve-cancer cross-talk on tumor progression and dissemination. High intratumoral nerve density correlates with poor prognosis and high recurrence across multiple solid tumor types. Recent research has shown that cancer cells express neurotrophic markers such as nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor and release axon-guidance molecules such as ephrin B1 to promote axonogenesis. Tumor cells recruit new neural progenitors to the tumor milieu and facilitate their maturation into adrenergic infiltrating nerves. Tumors also rewire established nerves to adrenergic phenotypes via exosome-induced neural reprogramming by p53-deficient tumors. In turn, infiltrating sympathetic nerves facilitate cancer progression. Intratumoral adrenergic nerves release noradrenaline to stimulate angiogenesis via VEGF signaling and enhance the rate of tumor growth. Intratumoral parasympathetic nerves may have a dichotomous role in cancer progression and may induce Wnt-β-catenin signals that expand cancer stem cells. Importantly, infiltrating nerves not only influence the tumor cells themselves but also impact other cells of the tumor stroma. This leads to enhanced sympathetic signaling and glucocorticoid production, which influences neutrophil and macrophage differentiation, lymphocyte phenotype, and potentially lymphocyte function. Although much remains unexplored within this field, fundamental discoveries underscore the importance of nerve-cancer cross-talk to tumor progression and may provide the foundation for developing effective targets for the inhibition of tumor-induced neurogenesis and tumor progression.

Figure 1.

A) Cancer cells drive nerve alteration. Cancer signals to induce nerve growth and innervation through multiple mechanisms. Cancer-induced axonogenesis includes the secretion of numerous neurogenic factors, axon-guidance molecules, and extracellular vesicles containing increased levels of axonal guidance molecules. Neural reprogramming occurs through extracellular vesicles containing orchestrated levels of miR-34a and miR-121, transforming a sensory nerve into an adrenergic nerve. Finally, cancer communicate with distant organs to recruit neural progenitor cells to initiate neurogenesis, while cancer stem cells drive de novo neurogenesis. B) Sympathetic innervation promotes the tumor microenvironment and tumor growth. Sympathetic signaling induces an angiogenic switch through increased vascular endothelial growth factor (VEGF) levels and the induction of aerobic glycolysis. It also promotes the infiltration of CD11b+F4/80+, FoxP3+ Tregs, and myeloid-derived suppressor cells (MDSCs). It stimulates the secretion of interleukin (IL)-6 and decreases the numbers of CD8+ cells and natural killers (NK) cells. It participates in a tumor-type dependent M2-type/M1-type macrophage shift and N2-type/N1-type neutrophil shift. Sympathetic nerves also express protein programmed cell death-1 (PD-1) in some cancer types, potentially contributing to immune suppression. In addition, sympathetic signaling drive chemoresistance via p53-dependent Sirt1 signaling among other mechanisms, and expression of neurogenic ligands and receptors on tumor cells promote stemness and self-renewal within the tumor.