Tumor Innervation: History, Methodologies, and Significance

Abstract

The role of the nervous system in cancer development and progression has been under experimental and clinical investigation since nineteenth-century observations in solid tumor anatomy and histology. For the first half of the twentieth century, methodological limitations and opaque mechanistic concepts resulted in ambiguous evidence of tumor innervation. Differential spatial distribution of viable or disintegrated nerve tissue colocalized with neoplastic tissue led investigators to conclude that solid tumors either are or are not innervated. Subsequent work in electrophysiology, immunohistochemistry, pathway enrichment analysis, neuroimmunology, and neuroimmunooncology have bolstered the conclusion that solid tumors are innervated. Regulatory mechanisms for cancer-related neurogenesis, as well as specific operational definitions of perineural invasion and axonogenesis, have helped to explain the consensus observation of nerves at the periphery of the tumor signifying a functional role of nerves, neurons, neurites, and glia in tumor development.

Expression Profile and Diagnostic Significance of MicroRNAs in Papillary Thyroid Cancer

“…Using the GO approach, biological processes were significantly enriched for nervous system development and several metabolism-related terms. Neurogenesis, similar to angiogenesis, is also an important modulator of cancer cells progression [ 87 ]. Literature data demonstrate the presence of nerves in the tumor microenvironment and their promotion of tumorigenesis and disease progression [ 88 ].…”

Integrative Approaches to the Treatment of Cancer

“…The nervous system is also involved in cancer aetiology and pathogenesis [ 22 , 23 ]. Research indicates that tumour growth occurs in relation to the nervous system, indicating a functional role of nerves, neurons, neurites and neuroglia in tumorigenesis, discussed in depth by Baraldi and colleagues [ 22 ].…”

“…The nervous system is also involved in cancer aetiology and pathogenesis [ 22 , 23 ]. Research indicates that tumour growth occurs in relation to the nervous system, indicating a functional role of nerves, neurons, neurites and neuroglia in tumorigenesis, discussed in depth by Baraldi and colleagues [ 22 ]. For example, tumour cells can release neurotrophins which stimulate adjacent neurites to grow into the tumour, and neurons can release neurotransmitters that initiate tumour cell migration [ 22 ].…”

“…Research indicates that tumour growth occurs in relation to the nervous system, indicating a functional role of nerves, neurons, neurites and neuroglia in tumorigenesis, discussed in depth by Baraldi and colleagues [ 22 ]. For example, tumour cells can release neurotrophins which stimulate adjacent neurites to grow into the tumour, and neurons can release neurotransmitters that initiate tumour cell migration [ 22 ]. Research also suggests sensory nerves may be able to regulate growth of tumours and metastasis by promoting or inhibiting immunosuppression [ 24 ].…”

Emerging Roles of the Nervous System in Gastrointestinal Cancer Development

“…The role of nervous system in tumorigenesis involves a wide range of aspects, at both systemic (neuroendocrine system) and tissue-specific (via tumor-associated nerve fibers) levels [ 10 ]. While the role of the neuroendocrine pathway in tumorigenesis has been well-recognized, it is only very recently that tumor-associated neurogenesis has been established as an important driver of GI tumorigenesis [ 3 ].…”