ONCOTHESIS

Evans blue as a diagnostic tool for non-muscle-invasive bladder cancer: a preclinical study

Summary

The diagnosis of non-muscle-invasive bladder cancer using the standard white-light cystoscopy technique is not optimal and leads to underdiagnosis of some of the tumours. Therefore, in this thesis, the use of Evans blue dye as a diagnostic tool to aid bladder cancer detection during white-light cystoscopy was investigated using a rat orthotopic bladder cancer model. The results show that Evans blue might have great potential to assist detection of bladder cancer in a clinical setting.

(BELG J MED ONCOL 2016;10(7):281–284)

Genomic analysis of high-risk prostate cancer

Summary

Whole exome sequencing was performed on 38 high-risk prostate cancer samples. We confirmed recurrent mutations in prostate cancer-specific genes, but also identified genes not reported to be mutated, like TET1. This DNA hydroxymethylase converts methylcytosines to hydroxymethylcytosines as a first step in DNA demethylation. By immunohistochemistry, we detected decreased TET1 protein levels in tumour compared to surrounding non-tumour tissue. DNA hydroxymethylation followed the same course. Furthermore, TET1 mRNA expression levels are an independent predictor of metastasis-free survival in a larger retrospective cohort, indicating an important role for TET1 and hydroxymethylation in prostate cancer.
The LNCaP and C4-2B cell lines form an excellent preclinical model to study the development of metastatic castration-resistant prostate cancer. Both exome and transcriptome sequencing was performed: more than half of the mutations found in the exomes were confirmed in the RNA-sequencing data. Combining C4-2B-specific mutations with differentially expressed genes allowed the detection of changes in focal adhesion and ECM-receptor interactions, which might contribute to the metastatic potential of C4-2B cells.

(BELG J MED ONCOL 2016;10(4):139–142)

Radiation-induced collateral damage: impact on metastasis

Summary

Experimental conditions show that radiotherapy-induced damage of normal tissues induces a pro-metastatic environment; and our research focussed on the factors associated with these pro-metastatic effects, which can be used as potential therapeutic targets.

(BELG J MED ONCOL 2016;10(3):105–107)

Biomimetics of the peritoneal tumour-environment create new therapeutic opportunities

Summary

The peritoneal tumour-environment plays an important role in the adhesion of disseminated cancer cells into the peritoneal wall. Disseminated cancer cells can be deceived to adhere to an ecological trap instead of the peritoneal wall through biomimetics of the peritoneal tumour-environment. Encapsulated carcinoma associated fibroblasts trap free cancer cells in the peritoneal space. Removal of the traps results in a delay of tumour formation and a prolonged survival in mouse models.

(BELG J MED ONCOL 2016;10(2):73–75)

Towards an evidence-based approach for diagnosis and management of adnexal masses: findings of the International Ovarian Tumour Analysis (IOTA) studies

Summary

Large numbers of patients with ovarian cancer do not receive the appropriate care in specialist oncological centres. This compromises their outcome of disease. Improving the accuracy of existing triaging protocols will lead to more appropriate selection of patients with malignant adnexal tumours for such specialist care.

The ultrasound-based LR2 prediction model and Simple Rules developed by the International Ovarian Tumour Analysis study are currently the best tools to discriminate between cancer, including borderline tumours and benign conditions in women with adnexal tumours that require surgery. These diagnostic tests offer more accurate triage in the hands of examiners with various levels of ultrasound expertise when compared to existing protocols using the Risk of Malignancy Index.

Predicting whether a tumour is benign or malignant is not the only thing that we need to know before deciding on appropriate treatment. To know the specific histopathology (i.e. borderline, invasive or metastatic disease) of a mass tailors further management and treatment options to the individual patient. The use of a novel International Ovarian Tumour Analysis multiclass risk prediction model Assessment of Different NEoplasias in the adneXa incorporating both serum CA-125, clinical, and ultrasound variables, enables clinicians to differentiate between different subtypes of malignant disease when cancer is suspected in an ovary.

So far the International Ovarian Tumour Analysis study has provided significant progress in relation to the preoperative classification of adnexal masses. Evidence-based guidelines by professional societies on management of ovarian cancer should be updated in order to reflect these improvements in preoperative diagnosis.

(BELG J MED ONCOL 2016;10(1):38–40)

Changes in the periductal stroma of ductal carcinoma in situ (DCIS) of the breast yield potential biomarkers for recurrence risk prediction

Summary

Ductal carcinoma in situ is regarded as a non-obligate pre-invasive precursor of invasive ductal carcinoma. Up to one in four patients will recur locally after breast-conserving surgery alone, and approximately half of these recurrences will be invasive. Recurrence prediction is still not satisfactorily accurate and could be improved by identifying additional prognostic markers.

As the role of the tumour microenvironment in cancer progression is increasingly acknowledged, this PhD research project aimed to explore the prognostic potential of stromal features in ductal carcinoma in situ. The presence of periductal myxoid stroma was identified as an adverse prognostic factor for both overall and invasive recurrence risk. This myxoid stromal architecture correlated with reduced stromal decorin expression and increased periductal versican expression. The cytokines bFGF and TGF-β1 were identified as potent modulators of stromal protein expression. We hypothesise that certain preinvasive ductal carcinoma in situ lesions modulate the composition of their surrounding stroma through cytokine release. This invasion-permissive and tumour-promoting microenvironment is mirrored in the presence of a myxoid stromal architecture. Further studies are required to validate the value of stromal changes as prognostic markers for recurrence in ductal carcinoma in situ.

(BELG J MED ONCOL 2015;9(7):296–98)

Biomarkers for an effective and cost-effective use of anti-EGFR biotherapeutics for the treatment of head and neck cancer

As the epidermal growth factor receptor is expressed in up to 90% of all head and neck squamous cell carcinomas and initiates important signalling pathways in carcinogenesis, this receptor has emerged as a promising therapeutic target. Nevertheless, the challenge of drug resistance alongside treatment with epidermal growth factor receptor inhibitors remains. New results from our research group provide evidence that the RAS-MAPK signalling pathway is still activated despite upstream epidermal growth factor receptor blocking by cetuximab, an epidermal growth factor receptor targeting monoclonal antibody. DUSP5, DUSP6, AURKB, HB-EGF, IL8 and the transcription factor AP-1 were among the genes identified by us as likely contributing to cetuximab resistance. These novel findings provide new insights in the underlying mechanisms of anti-epidermal growth factor receptor therapeutic resistance in head and neck squamous cell carcinomas. Furthermore, these observations can form a solid basis for further in vivo and clinical studies on this topic, making advances in the treatment of head and neck squamous cell carcinomas.

(BELG J MED ONCOL 2015;9(2):74–6)