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.

Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery—namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex—correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events.

We recently reported a novel role for nerve-cancer crosstalk, demonstrating that tumor protein p53 (TP53) deficiency in head and neck squamous cell carcinoma leads to a decrease in miR-34a in tumor-shed vesicles. This directed sensory nerve reprogramming in the tumor microenvironment which enhanced tumor growth.