Surgery (Austin & Northern Health) - Theses
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ItemThe role of zinc in prostate cancer( 2018)Prostate cancer (PCa) is the most common cancer amongst Australian men. Zinc is an essential metal and is vital for normal function of the prostate gland. Castrate-resistant prostate cancer (CRPC) is becoming increasingly resistant and treatment options are limited in number and often associated with poor clinical outcomes. Therefore a pertinent clinical issue is to develop more effective treatment regimes. Zinc appears to play a role in PCa, but a true understanding leading to therapeutic developments is yet to be achieved. In particular evidence regarding cell proliferation and zinc uptake and levels in PCa cells is conflicting. HIF1α is a well-known prognostic marker in PCa associated with poor prognosis, resistance to treatment and development of metastatic disease, however the cause over-expression in CRPC remains a mystery. Therefore the ability of PCa cells to uptake and store zinc, and the role of zinc in PCa cell proliferation, tumour growth and HIF1α mediated survival was investigated in this thesis. CRPC-like human PC3 cells are significantly resistant to docetaxel chemotherapy and overexpress HIF1α protein, compared to normal prostate epithelial control cells (PNT1A). Cell proliferation assays (MTT) demonstrated that physiological zinc administered to PC3 cells significantly slowed growth compared to normal PNT1A and androgen-sensitive PCa (LNCaP) cells. The effect of zinc supplementation or zinc chelation (by TPEN) does not affect macroscopic growth in PC3 xenograft tumours. There is no significant difference in baseline total zinc concentration (measured by ICP-MS) between cell lines normal (PNT1A), androgen sensitive (LNCaP) and CRPC (DU145 and PC3) cells. However, CRPC-like PC3 cells contain significantly higher unbound free Zn2+ and Immunofluorescence Microscopy (IFM) subcellular distribution of Zn2+ in PC3 cells is unlike that seen in normal prostate epithelial cells. PC3 cells are resistant to oxidative stress injury. Zinc strongly induces HIF1α protein expression in these cells in a time and dose dependent manner. Zinc mediated oxidative protection in PC3 cells is a HIF1α dependent as demonstrated in a PC3 HIF1α-KD model. No such zinc protection was seen PNT1A cells. Zinc could be essential in the resistant nature of CRPC cells as Zn2+ ions rescue HIF1α protein expression and are implicated in the normoxic stabilisation of the HIF1α protein by competing with Fe2+ ions at the PHD binding sites. Therefore zinc dysregulation in CRPC cells is an important factor in the development of resistance, as well as potentially progression to metastatic disease and poor prognosis in PCa.
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ItemGastrin-mediated adaptive responses to hypoxia in colorectal cancer( 2014)Over the past two decades the potential biological activities exerted by gastrin precursors on colorectal tumourigenesis have gradually widened to include mitogenesis, apoptosis resistance, stimulation of angiogenesis and promotion of cell migration and invasion. However, the molecular mechanisms underlying this plethora of biological effects are unclear. Furthermore, the interplay between gastrin precursors and the colorectal tumour microenvironment has been a relatively neglected area of gastrin research. This thesis investigates these two important areas of gastrin biology and is the first study to report that hypoxia-inducible gastrin gene expression in colorectal cancer cells mediates resistance against hypoxia-inducible cell death in vitro and in vivo and may contribute to the development of distant metastatic disease.
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ItemHypoxia and angiogenesis in renal cell carcinoma( 2009)Hypoxia is one of the hallmarks of cancer. It was first postulated to occur in solid tumours by Thomlinson and Gray in 1955.1 The presence of hypoxia has been demonstrated in different types of solid tumours.2 Intratumoral hypoxia is caused by the lack of functional blood vessels in proliferating tumour tissue, resulting in low intratumoral oxygen concentrations. If hypoxia is severe or prolonged, cell death occurs.3 Malignant cells can undergo genetic and adaptive changes that allow them to escape from dying of oxygen deprivation. These changes are associated with a more aggressive malignant phenotype 4,5 conferring resistance to radiation 6,7 and chemotherapeutic agents.3,8,9 Hence hypoxia is known to be a key factor responsible for tumour resistance in humans. Invasive polarographic oxygen sensor measurements have demonstrated hypoxia in solid tumours and it is generally defined to occur at an oxygen tension less than ten mmHg.10 Perhaps of more importance is that hypoxia has been demonstrated to be a prognostic indicator for local control after treatment with radiotherapy in glioma, head and neck and cervical cancers.11-13 It has also been able to predict for survival and the presence of distant metastases in soft tissue sarcomas.14 Finally, the significance of hypoxia in the activation and induction of functional molecules such as hypoxia inducible factors (HIFs) and VEGF, the modulation of gene expression (e.g. carbonic anhydrase IX), increased proto-oncogene levels, activation of nuclear factors and accumulation of other proteins (e.g. TP53) although progressing, is yet to be defined.15,16 Thus, it is of clinical interest to understand the levels of hypoxia and numbers of hypoxic cell populations in tumours, particularly those resistant to radiation and chemotherapy. In doing so clinicians and researchers may formulate more accurate prognostic information and develop treatments targeting hypoxic cells. Renal cell carcinoma (RCC) is a tumour resistant to radiation and chemotherapy that is yet to have its oxygen status investigated. Although the “gold standard” of oxygen tension measurement is the Polarographic Oxygen Sensor (POS or Eppendorf pO2 histograph), non-invasive means of measuring oxygen status via imaging, immunohistochemistry or serum tumour markers are more practical. As highlighted by Menon and Fraker, it is imperative that reliable, globally usable, and technically simplistic methods be developed to yield a consistent, comprehensive, and reliable profile of tumour oxygenation. Until newer more reliable techniques are developed, existing independent techniques or appropriate combinations of techniques should be optimized and validated using known endpoints in tumour oxygenation status and/or treatment outcomes.17 Hanahan and Weinberg 18 surmised that the field of cancer research has largely been guided by a reductionist focus on cancer cells and the genes within them- a focus that has produced an extraordinary body of knowledge. Looking forward in time, they believe that progress in cancer research would come from regarding tumours as complex tissues in which mutant cancer cells have conscripted and subverted normal cell types (endothelial cells, immune cells, fibroblasts) to serve as active collaborators in their neoplastic agenda. The interactions between the genetically altered malignant cells and these supporting coconspirators will prove critical to understanding cancer pathogenesis and to the development of novel, effective therapies.18 Essentially, the background outlined here not only highlights the core aim of this thesis: to better understand the oxygen status of renal cell carcinoma and the relationship of this to angiogenesis so that better targeted therapies may be pursued in the future; but it also places this research in the context of the future proposed by Hanahan and Weinberg,18 by clearly focusing on collaborators in the neoplastic agenda, rather than just tumour cells themselves, to better understand RCC.