Tumor Neurobiology in the Pathogenesis and Therapy of Head and Neck Cancer

Abstract

The neurobiology of tumors has attracted considerable interest from clinicians and scientists and has become a multidisciplinary area of research. Neural components not only interact with tumor cells but also influence other elements within the TME, such as immune cells and vascular components, forming a polygonal relationship to synergistically facilitate tumor growth and progression. This review comprehensively summarizes the current state of the knowledge on nerve–tumor crosstalk in head and neck cancer and discusses the potential underlying mechanisms. Several mechanisms facilitating nerve–tumor crosstalk are covered, such as perineural invasion, axonogenesis, neurogenesis, neural reprogramming, and transdifferentiation, and the reciprocal interactions between the nervous and immune systems in the TME are also discussed in this review. Further understanding of the nerve–tumor crosstalk in the TME of head and neck cancer may provide new nerve-targeted treatment options and help improve clinical outcomes for patients.

The Neuroimmune Axis and Its Therapeutic Potential for Primary Liver Cancer

“…Attributes such as nerve diameter, nerve density, and their spatial relationship to cancer cells—including distant interactions to perineural invasion (PNI)—are critical factors in cancer metastasis and survival. Larger nerve diameters and higher nerve densities correlate with poorer clinical outcomes across various cancers [ 10 ]. Researchers found that a higher expression of tyrosine hydroxylase (TH) and vesicular acetylcholine transporter (VAChT) in cancerous tissues, indicative of sympathetic and parasympathetic nerve density, was associated with vascular invasion, clinical stage, and lower survival rates, with TH levels also linked to disease recurrence [ 11 ].…”

“…Furthermore, nerve fibers collaborate with other TME components to facilitate metabolic support and coordinate vascular growth, ensuring the supply of essential nutrients and oxygen for tumor survival and expansion. This intricate interplay highlights the necessity of understanding and targeting the neural components within the TME as potential therapeutic strategies in HCC treatment [ 10 ]. We highlight these advancements with a specific focus on the role of neuroimmune interaction in liver cancer.…”

Context-Dependent Regulation of Peripheral Nerve Abundance by the PI3K Pathway in the Tumor Microenvironment of Head and Neck Squamous Cell Carcinoma

“…Recently, peripheral nerves have emerged as a novel pathological structure within the TME. Several studies have demonstrated the critical role of tumor innervation and signaling via neurotrophic factors and neurotransmitters in various types of cancer, including head and neck cancer [ 2 , 3 , 4 ]. For example, perineural invasion (PNI) has been identified as a common interaction between tumor cells and peripheral nerves, describing tumor invasion of existing locoregional nerves.…”

“…However, the cancer–neuron interaction (CNI) appears to be much more complex. Tumor cells release multiple factors, such as axon guidance molecules and nerve growth factors, to promote neurogenesis, axonogenesis, and cellular transdifferentiation into neuron-like cells [ 4 , 6 , 7 ]. These processes increase local nerve density, facilitate tumor progression, and are associated with poor prognosis [ 8 , 9 ].…”

“…HNSCC is a remarkably heterogeneous disease, with tobacco, alcohol, and human papillomavirus (HPV) infection, especially HPV16, as major etiological risk factors [ 21 ]. Due to the abundant distribution of peripheral nerves in the head and neck region, HNSCC exhibits perineural invasion and intra-tumoral innervation to a greater extent than cancers originating from other anatomical sites [ 4 , 22 ]. Several recent landmark studies have provided compelling experimental and clinical evidence for a pivotal role of CNI in the pathogenesis of HNSCC and its potential as a promising drug target for anticancer therapy [ 6 ].…”