- Title
- Tetraspanins as biomarkers and causative proteins in prostate cancer
- Creator
- Copeland, Ben Troy
- Relation
- University of Newcastle Research Higher Degree Thesis
- Resource Type
- thesis
- Date
- 2013
- Description
- Research Doctorate - Doctor of Philosophy (PhD)
- Description
- Prostate cancer (PCa) is the most commonly diagnosed solid cancer and the cause of the second highest mortality rates in men in the majority of western counties. There are two major unmet needs in dealing with prostate cancer. Firstly, since the majority of deaths from prostate cancer are attributed to the largely untreatable late stage metastatic forms of the disease, understanding molecules involved in the metastatic cascade of PCa may prove beneficial in regards to therapeutic options. Secondly, PCa is a very heterogeneous disease and in many cases follows an indolent course. There are currently no reliable biomarkers to gauge which patients will progress on to advanced disease. Hence, biomarkers that can be implemented into the diagnostic process to stratify patients diagnosed with PCa in regards to their likely outcome allowing the assignment of the most effective and less invasive treatment options are urgently needed. Tetraspanins are membrane bound proteins that associate with motility related molecules such as integrins. In vivo and in vitro experimental studies have indicated tetraspanins may be important regulators of tumour invasion and metastasis in a number of cancers. Furthermore clinical studies have shown that high expression levels of the tetraspanins CD82 and CD9 have been correlated to good prognosis, while in contrast increased expression of the tetraspanins CD151 and Tspan8 have been correlated with more aggressive cancers and poor outcomes. In this study, for the first time the effects of gene ablation of the pro- and anti-tumourigenic/metastatic tetraspanins, Cd151 and Cd9 respectively, have been evaluated in a de novo developing and spontaneously metastasising murine model of prostate cancer. In addition analysis of clinical tissue microarrays containing a cohort of various prostate tissue samples have been assessed by immunohistochemistry for CD151, Tspan8, CD82 and CD9 expression levels. The Cd9 and Cd151 knock-out mouse models were independently crossed onto the TRansgenic Adenocarcinoma of Mouse Prostate (TRAMP) mouse model. We report here for the first time that development of primary prostate tumours was not affected by ablation of either Cd9 or Cd151. However ablation of Cd9 resulted in an increase of metastatic lesions (number of foci and total area) to the liver. Conversely ablation of Cd151 resulted in a decrease of metastatic lesion (number of foci and total area) to the lungs. No change in average area of individual metastases was observed in either case. Normal and matched PCa tissue samples on tissue micro-arrays obtained from the Australian Prostate Cancer Consortium (APCC) were analysed by IHC. The expression of CD151 and Tspan8 was shown to be positively correlated to PCa progression. In contrast, CD9 and CD82 expression was shown to be negatively correlated to cancer progression. Our results showed weaker correlation with prognosis than previous reports and possible reasons are discussed. In adjunct to the classical pathological IHC manual scoring method, automated digital pathology (Aperio) systems were evaluated in an attempt to standardise IHC scoring. The automated scoring showed similar trends with manual scoring, in regards to tetraspanin expression and cancer progression, however resulted in less significant associations. In summary, the tetraspanins Cd9 had anti-metastatic effects while conversely Cd151 had pro-metastatic effects. Both Cd9 and Cd151 had no effect on the development of primary prostate tumours in the TRAMP model. These molecules may be beneficial therapeutic options as metastatic modulators. More extensive evaluation the tetraspanins CD151, Tspan8, CD9 and CD82 as prognostic markers that can delineate PCa patients whose disease may remain indolent and those who will progress is needed.
- Subject
- oncology; prostate cancer; tetraspanin
- Identifier
- http://hdl.handle.net/1959.13/1039255
- Identifier
- uon:13633
- Rights
- Copyright 2013 Ben Troy Copeland
- Language
- eng
- Full Text
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| Thumbnail | File | Description | Size | Format | |||
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| View Details Download | ATTACHMENT01 | Abstract | 576 KB | Adobe Acrobat PDF | View Details Download | ||
| View Details Download | ATTACHMENT02 | Thesis | 9 MB | Adobe Acrobat PDF | View Details Download |