- Title
- The role of Schwann cells and nerves in pancreatic cancer
- Creator
- Ferdoushi, Aysha
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2021
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- With a 5-year survival rate of less than 9%, pancreatic cancer (PC) is the 7th leading cause of cancer-related deaths worldwide. The poor prognosis of this cancer is attributed to its highly invasive nature, early onset of metastasis and lack of effective treatments. While current chemotherapy and radiation therapy are largely ineffective in the treatment of this disease, surgical treatment offers the only hope for long term survival. Unfortunately, only ~15% of patients have resectable disease at the time of diagnosis. The tumour microenvironment (TME) of PC is believed to hold a key for overcoming the challenges of treating PC. It has long been known that, in addition to being found in the vascular and lymphatic systems, cancer cells occur in neuronal spaces, which serve as an alternative route for dissemination. Emerging evidence indicates that nerve infiltration in the TME plays a stimulatory role in tumour progression. Some cancers have the ability to invade along nerves, an ominous event termed perineural invasion (PNI) that causes nerve dysfunction and makes the cancer more difficult to eradicate. PNI is one of the most common features of PC that causes severe abdominal and back pain. PNI has repeatedly been shown to be an adverse pathologic finding, heralding more aggressive local disease, higher recurrence rates, and worsened survival. Schwann cells (SCs), the most prevalent glial cell type supporting peripheral nerves, wrap around nerves and facilitate their conduction. SCs are an essential component of peripheral nerves and are implicated in promoting nerve repair but can also be causative in various diseases involving neurodegeneration. Notably, recent studies have shown that these glial cells play an active role in promoting PC progression. SCs have also been reported to be involved in PNI, epithelial to mesenchymal transition, decreased cancer pain sensation and subsequent delayed diagnosis. This dissertation focuses on developing a greater understanding on the role of nerves and supporting SCs in PC progression. We aimed to explore the role of SC-secreted mediators on PC progression and, at the same time, investigate the role of nerve infiltration on PC aggressiveness. We described the proteome of human primary SCs analysed by mass spectrometry-based proteomics liquid chromatography-tandem mass spectrometry (LC-MS/MS). The normal human SC protein dataset that we have reported constitutes a reference for future molecular explorations of physiological and pathological processes where SC are involved. In addition, several novel nociceptors and synaptic proteins were identified. This proteomic dataset may also be of a more direct value in the areas of pain and oncology where the role of SCs has recently been uncovered. Overall, this dataset will serve as a resource for further functional and clinical investigations into the role of SCs in health and disease. To investigate the paracrine function of SCs in the pancreatic TME, we have also profiled the secretome of human primary SCs using LC-MS/MS and explored the role of several identified proteins in PC progression. A total of 13,796 unique peptides corresponding to 1,470 individual secreted proteins were identified. Several proteins that can stimulate PC cell proliferation and invasion were validated by Western blot. The involvement of these secreted proteins was further validated by using blocking antibodies. PC cell proliferation and invasion induced by SC-conditioned media was decreased using blocking antibodies against the matrix metalloproteinase-2, cathepsin D, plasminogen activator inhibitor-1 and galectin-1. Blocking antibodies against the proteoglycan biglycan, galectin-3 binding protein, tissue inhibitor of metalloproteinases-2 decreased proliferation but not the invasion of PC cells. Together, this study delineates the secretome of human SCs and identifies proteins that can stimulate PC cell growth and invasion and could therefore constitute new therapeutic targets. Following on with the study, we investigated the clinicopathological significance of nerves in PC. We have analysed the density and size of nerves in a cohort of 99 PC cases versus 71 normal pancreatic tissues. The presence of nerves was significantly correlated with worse overall survival. In addition, the size of nerves, measured by cross-sectional area, was found to be significantly higher in PC than in the normal adjacent tissue and larger nerves were directly associated with worse patient survival. From these findings, we suggested that the presence and size of nerves in the TME of PC are associated with tumour aggressiveness. Collectively, this dissertation has presented the proteomic and secretomic profiles of human SCs that will also serve as an important resource for further functional and clinical investigations into the role of SCs in oncology. It also investigated the role of several identified SC-secreted proteins in the stimulation of PC growth and invasion, which may represent novel potential targets for the development of future targeted treatments in PC. This work has also provided novel insight in understanding the molecular mechanism of PNI, suggesting that increased nerve infiltration might be a primary event leading to higher PNI levels observed in PC. Results from this work may ultimately develop into novel therapies for PC.
- Subject
- pancreatic cancer; nerves; Schwann cells; thesis by publication
- Identifier
- http://hdl.handle.net/1959.13/1420622
- Identifier
- uon:37621
- Rights
- Copyright 2021 Aysha Ferdoushi
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
|---|---|---|---|---|---|---|---|
| View Details Download | ATTACHMENT01 | Thesis | 51 MB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Abstract | 1 MB | Adobe Acrobat PDF | View Details Download |