Tumor Innervation: History, Methodologies, and Significance

SIMPLE SUMMARY: This comprehensive review of tumor innervation summarizes the literature from the earliest publications on the topic to the most recent. It addresses the positive and negative evidence of tumor innervation and the historical developments in thought and methodology that have led to the consensus that tumors are innervated. The role of the immune response is described, as are some important biochemical and physiological mechanisms relevant to regulation of cancer development. 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.