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.