NGF and its receptor TrkA in the neurobiology of human cancers

Peripheral nerves reach almost all organs and tissues of the body where they control normal physiological function and homeostasis. Recent discoveries have revealed that nerves are also present within the microenvironment of many types of tumours where they actively engage in a crosstalk with cancer cells, driving disease progression. This phenomenon is termed nerve dependence. The nervous system dictates tumour initiation and metastasis through direct neurotransmitter signalling within the tumour microenvironment while reciprocally, cancer cells may induce the outgrowth of nerves through release of neurotrophic growth factors such as nerve growth factor (NGF). NGF regulates development of the nervous system and is also known to expressed by many human cancers, however the role of NGF, its precursor proNGF as well as its receptors TrkA, p75NTR and sortilin in the context of the nerve cancer crosstalk is unclear. The primary aim of this thesis was to clarify both the presence of nerves and the expression of neurotrophin receptors in malignancies for which neurobiology is understudied. The results encompassed herein reveal the presence of nerves within the microenvironment of oesophageal, cervical and lung tumours and their association with NGF and its receptors TrkA and p75NTR. Furthermore, the clinicopathological significance of the protein expression of NGF and its receptors was analysed via immunohistochemistry in three independent studies of oesophageal, cervical and lung cancer. Across all cancer types it was shown that TrkA was markedly overexpressed in squamous cell carcinomas compared to both normal adjacent tissues and other histological cancer subtypes. This body of work in its entirety suggests that the upregulation of this family of growth factors and their receptors is a common phenotypical feature across a variety of human tumour types and proposes the potential therapeutic value of specifically targeting the NGF-TrkA signalling axis in histological subtypes of cancer.