- Title
- ProNGF, NGF and their receptors in tumour innervation and progression: a study in breast and thyroid cancers
- Creator
- Faulkner, Sam
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2018
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Infiltration of the tumour microenvironment by nerve fibres, termed cancer neurogenesis, is a relatively understudied feature of human carcinogenesis. Until only recently, perineural invasion (PNI), a process by which cancer cells surround and invade nerves, was thought to be the sole interaction between both tumoural and neuronal populations. PNI has traditionally been associated with clinically advanced tumours, in which it is thought to provide an alternate route for metastasis, generally resulting in a relatively poor prognosis for the patients. Recent studies however have demonstrated that denervation can supress tumour growth and metastasis, suggesting that there is separate interplay between both cancer and neuronal cells, extending far beyond that of PNI. However, what is yet to be fully elucidated in the literature is the molecular mechanism or mediators at play, responsible for facilitating this nerve-cancer cell crosstalk. What has been hypothesised, and since proven in a handful of human cancers, is that trophic factors are released by nerves and are capable of acting on cancer or other cells encompassing the tumour microenvironment. Conversely, cancer cells release neurotrophic factors that are capable of stimulating nerve infiltration or neurogenesis of the tumour. Neurotrophins and their receptors are one such family of neurotrophic factors that are emerging targets in oncology. More specifically, NGF and its precursor protein proNGF, along with their receptors, TrkA, p75NTR and sortilin, have already been implicated in several human cancers, including but not limited to that of the breast, skin (melanoma) and prostate. The overarching aim of this thesis was to develop a greater understanding of the emerging importance of both nerves and neurotrophic growth factors in influencing the growth and dissemination of human cancers. More specifically, this body of work aims to elucidate the extent and role of nerve infiltration within the tumour microenvironment of breast and thyroid cancers, as well as to determine any associations with the expression and function of NGF, proNGF and their receptors, TrkA, p75NTR and sortilin. In a large cohort of primary breast tumours, we detected neural infiltration using the broad neuronal marker, PGP9.5. Invasive ductal carcinomas had a higher proportion of nerves as compared with that of invasive lobular carcinomas as well as ductal carcinomas in situ. Additionally, the secretion of NGF was detected from a series of breast cancer cell lines, within their conditioned culture media. Co-culturing breast cancer cells with that of neuronal-like cells resulted in neurite outgrowth, which was ablated with the use of an NGF blocking-antibody, highlighting its potential role in stimulating breast cancer neurogenesis. Following this, we looked to further clarify the expression and function of both nerves and neurotrophic growth factors in thyroid cancer. ProNGF expression was analysed by immunohistochemistry in two cohorts of cancer versus benign and normal thyroid tissues. Although innervation of thyroid cancers has not been previously reported, using the neuronal marker PGP9.5 we detected nerves in primary thyroid tumours. In both cohorts, proNGF was found to be overexpressed in thyroid cancer cells, as compared with both thyroid adenomas and normal thyroid tissue. We also demonstrated that proNGF is secreted by anaplastic thyroid cancer cell lines, highlighting its potential as a diagnostic biomarker, both histologically and within that of the blood. Next we looked to define the expression of TrkA, p75NTR and sortilin in thyroid cancer, as well as to determine if targeting these receptors reduced features of aggressiveness. TrkA was found to be more commonly expressed in tumours, where it was found to be associated with lymph node metastasis. In addition, nerves in the tumour microenvironment were positive for TrkA. P75NTR was overexpressed in anaplastic thyroid cancers compared to papillary and follicular subtypes whereas sortilin was overexpressed in all histological subtypes, as compared with adenomas and normal thyroid tissue. Targeting TrkA, p75NTR and sortilin in vitro using a pair of anaplastic thyroid cancer cell lines decreased cell survival and features of metastasis (migration and invasion), thus highlighting their potential are novel therapeutic targets in this devastating subtype of thyroid disease. Taken together, the work portrayed in this thesis has provided new evidence highlighting the importance of nerve infiltration in human carcinomas of the breast and thyroid, elucidated a role for NGF as a potential regulator of neurogenesis in the breast tumour microenvironment, as well as implicated NGF, its precursor proNGF and their receptors (TrkA, p75NTR and sortilin) as novel targets for therapeutic intervention.
- Subject
- ProNGF; NGF; tumour; breast cancer; thyroid cancer; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1383729
- Identifier
- uon:31979
- Rights
- Copyright 2018 Sam Faulkner
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
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| View Details Download | ATTACHMENT01 | Thesis | 31 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 397 KB | Adobe Acrobat PDF | View Details Download |