- Title
- ProNGF/NGF, their receptors and nerves in human cancers
- Creator
- Gao, Fangfang
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2020
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Nerve infiltration is emerging as an important process in the tumour microenvironment. Cancer cells release neurotrophic factors that are capable of stimulating nerve infiltration and are increasingly regarded as potential therapeutic targets in oncology. More specifically in this study, nerve growth factor (NGF), its precursor (proNGF) and their receptors that include the neurotrophic tyrosine kinase receptor (TrkA), the common neurotrophin receptor (p75NTR) and the proNGF receptor sortilin, were examined in lung, pancreatic and esophageal cancers. Moreover, we have also investigated how endoplasmic reticulum (ER) stress facilitates neural infiltration during cancer progression. The aims of this thesis were to develop a greater understanding of the role of nerves and neurotrophic growth factors in influencing cancer progression and dissemination. In lung cancers, NGF and its receptor TrkA were found increased in squamous cell carcinoma compared to other malignant histological subtypes and normal lung. ProNGF was increased in both squamous cell carcinoma and adenocarcinoma while sortilin was higher in adenocarcinoma and small cell carcinoma. Nerves in the tumour microenvironment were negative for NGF, proNGF, TrkA, p75NTR and sortilin. This study was published in Scientific Reports. In pancreatic ductal adenocarcinoma (PDAC), sortilin expression was higher in cancer cells compared to normal pancreatic ductal epithelial cells, as demonstrated by both Western blot and mass spectrometry. The increased sortilin level in pancreatic cancer tissues was confirmed by immunohistochemistry in a cohort of PDAC tissues. Sortilin inhibition through utilizing siRNA or pharmacological inhibitor AF38469 could strongly reduce pancreatic cancer cells adhesion and invasion while could not affect cell survival and proliferation. The inhibition of sortilin, however, decreased the phosphorylation level of the focal adhesion kinase (FAK) in Tyr925. This study was published in The American Journal of Pathology. Together, these data suggest the preferential therapeutic value of targeting the NGF-TrkA axis in squamous cell carcinomas of the lung and targeting sortilin in pancreatic adenocarcinomas. We have also investigated nerve infiltration in esophageal cancer tissues and found that the presence of nerves was significantly correlated to squamous cell carcinomas where TrkA was also overexpressed. Nerves were found to express TrkA and p75NTR and an association was observed between high production of NGF by cancer cells and the presence of nerves in the tumour microenvironment. In vitro, NGF production in esophageal cancer cells was demonstrated by Western blot and esophageal cancer cells were able to induce neurite outgrowth in the PC12 neuronal cells. By using anti-NGF blocking antibodies, we observed a reduced neurotrophic activity of esophageal cancer cells. These data demonstrate that innervation is a significant feature in esophageal cancers that may be driven by cancer cell-released NGF. This study was published in The American Journal of Pathology. Furthermore, in cancer cells of various origins, we reported that the release of pro-brain derived neurotrophic factor (proBDNF) by ER stressed-cancer cells, which was controlled by X-box-binding protein 1 (XBP1), induced ER stress in neurons and promoted neuronal outgrowth. Myc-mediated transcriptional upregulation of Egl-9 family hypoxia inducible factor 3 (Egln3) in neurons contributed to receiving ER stress signal and fostering neurite outgrowth. This final part of our study reveals the essential contribution of ER stress to tumour axonogenesis and is currently submitted for publication. Taken together, the work presented in this thesis has provided novel evidence for therapeutic targeting in carcinomas of the lung, pancreas and esophageal. We have highlighted the importance of proNGF/NGF and their receptors in cancers and the association with nerve infiltration, as well as the potential intervention of ER stress in tumour axonogenesis.
- Subject
- nerve infiltration; cancer cells; sortilin inhibition; endoplasmic reticulum (ER) stress
- Identifier
- http://hdl.handle.net/1959.13/1423270
- Identifier
- uon:37909
- Rights
- Copyright 2020 Fangfang Gao
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 7 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 293 KB | Adobe Acrobat PDF | View Details Download |