HCB operates to national and international standards. All HCB tissue specimens are validated against original pathological diagnosis to confirm accuracy and assure quality. HCB has supported 14 cancer research projects supplying more than 11 000 tissue sections.
Some of the exciting projects currently supported by HCB are:
Associate investigators: Leonie Ashman
Dr. Weidenhofer is studying how the altered expression of tetraspanins in cancer cells affects their behaviour. Previous studies in prostate carcinomas have shown that the levels of tetraspanins CD151 and CD9 are differentially altered: CD9 appears to be downregulated while CD151 frequently displays high levels. Both CD151 and CD9 can regulate aspects of tumour cell invasion and metastasis, properties that are important for cancer progression. Using cell culture models the team has identified that certain microRNAs are able to control the expression of CD151 and CD9. The question is what regulates these regulators? The next step is to validate these findings in prostatic cancer tissues. Towards this, HCB supplied sections of prostate cancer tissues of varying grades with validation performed by our pathologist. This ensures that the pathology of the tissues supplied genuinely reflects their classification. The annotated images will then be used to dissect out cancer cells from within these sections using laser-capture micro-dissection. The level of expression of miRNAs will be measured by qPCR with serial sections from the same tissue will be stained for the CD151 and CD9 proteins using immunohistochemistry. Employing the Aperio AT2 Digital Pathology scanner and HALO image analysis software the intensity of staining will be quantified. Comparing qPCR data for microRNAs with the levels of CD151 and CD9 proteins will confirm whether the regulatory relationships exist in patient's cancers. If confirmed this will identify particular microRNAs as novel therapeutic targets to control cancer metastasis.
Associate investigators: Leonie Ashman, Hubert Hondermarck
Despite improved treatment options for breast cancer, advanced cases of the disease remain near untreatable. To improve outcomes for these patients, more aggressive and targeted treatment strategies are required. However identifying which patients require this at an early stage is not yet possible. Our work focuses on the tetraspanin proteins CD151, CD9 and CD82 which are altered in breast cancer and display promise as prognostic markers and therapeutic targets. This project will identify which mechanisms are involved in the de-regulation of CD151, CD9 and CD82 expression in breast cancer and how this may affect cancer cell function. Our preliminary work suggests that the ubiquitin pathway may be an important regulator of tetraspanin expression in breast cancer. This concept will be further investigated in a panel of breast cancer cell lines representing major groupings of the disease. These experiments will define which of the 'ubiquitin' enzymes (E3 ligases) are required for regulating tetraspanins. Transposing this knowledge to breast cancer tissues (provided by HCB) we will determine if aberrant ubiquitination is a key mechanism leading to altered expression of tetraspanins in breast cancer. This knowledge will advance the development of prognostic biomarkers, allowing better patient stratification for treatment, thereby improving outcomes and quality of life. Importantly this study will identify the most effective way in which to target CD151, CD9 and CD82 with novel therapeutic strategies and therefore potentially inhibit the progression and metastasis of breast cancer.
Unlike other cancers, testicular cancer is the disease of young men and mainly occurs during peak age of their professional and family life. In last decade, the incidence rate of testicular cancer has significantly increased in Australia and the reasons for this increase are currently unknown. Cisplatin-based chemotherapy combined with surgery is the standard and highly effective treatment for this cancer. However, long term follow up studies in large cohorts of testicular patients revealed that this treatment regimen results in infertility and neurotoxicity in 50%, hearing loss and renal impairment in 30%, and pulmonary fibrosis in 10% of the testicular cancer survivors. The risk of getting secondary cancers such as leukemia, urinary bladder cancer, and cardiovascular diseases (due to widespread damage to the endothelial cells of blood vessels by cisplatin) is doubled in testicular cancer survivors treated with cisplatin-based therapy. These studies show that the cisplatin-based treatment leads to serious and life-threatening side-effects highlighting the need for development of targeted therapies based on molecular understanding of the disease. This proposed research will establish the role of mTOR signalling in the initiation and progression of testicular cancer and will provide a strong scientific rationale for using mTOR inhibitors in treatment of this disease in human testicular patients. We hypothesized that sustained activation of mTOR is the key event required for the development of testicular defects in mutant mouse models of testicular cancer and human patients (hereditary and sporadic testicular cancer patients). The mechanistic understanding of mTOR signalling in mammalian testis will allow us to identify novel therapeutic targets and thus develop innovative means of treating testicular cancer. The study will analyze mTOR signalling in human testicular tissue samples supplied by HCB.
Associate Investigators: Kirsty Pringle, Yu (Eric) Wang, Eugenie Lumbers
Endometrial cancer is the most commonly diagnosed gynaecological cancer with the majority of cases being endometrioid adenocarcinomas. There is increasing evidence suggests that local renin angiotensin systems (RAS) contributes to the regulation and progression of tumourigenesis in a variety of tissues, including the endometrium. In support of this notion, recent studies have demonstrated that high levels of Angiotensin II (the predominant effector of RAS) are associated with increased incidence and poor prognosis for endometrial cancers. Therefore established anti-hypertensive drugs such as those that target RAS through blocking Angiotensin II receptors (e.g. losartan, captopril) are strong candidates for inclusion as adjuncts in cancer therapy. RAS broadly encompasses a number of receptor-ligand pathways (e.g. AT1R, AT2R, Angiotensin-(1-7)/MasR) that balance growth promotion with growth inhibition. We postulate in endometrial cancer that RAS pathways are tilted towards proliferative and angiogenic pathways. However more needs to be known about the patterns of expression of these RAS pathways in endometrial cancer. To address this, samples of endometrial cancer tissue and adjacent normal endometrium were provided by HCB to enable analyses of RNA and protein. These findings will be correlated with the histological classification, FIGO, surgical grading and clinical outcome (survival). The project will define whether there are different RAS profiles in tumours of different stages/histopathology. This information will help guide the development of specific adjuvant therapies for various grades and stages of endometrial cancer.