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الرئيسية > A New Insight into Wilms’ Tumo...>الوصف

A New Insight into Wilms’ Tumorigenesis Describing A Novel Model for Wilms’ Tumor Progression

المؤلف الرئيسي: Townsi, Nada Ibrahim (Author)
مؤلفين آخرين: Charles, Adrian (Advisor)
التاريخ الميلادي: 2011
موقع: بيرث
الصفحات: 1 - 127
رقم MD: 752780
نوع المحتوى: رسائل جامعية
اللغة: الإنجليزية
الدرجة العلمية: رسالة ماجستير
الجامعة: Western Australia University
الكلية: School of Pathology and Laboratory Medicine
الدولة: أستراليا
قواعد المعلومات: +Dissertations
مواضيع:
الأورام
السرطان
رابط المحتوى:
صفحة العنوان     
المستخلص     
قائمة المحتويات     
24 صفحة الأولى     

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المستخلص: Tumorigenesis or cancer progression is a complex multistep process that occurs as a consequence of the sequential accumulation of genetic and epigenetic alterations at the cellular level. Epidemiological, histological and molecular evidence has indicated that cancers develop in a multistep pattern in which the transformational progression of normal cells into cells with various degrees of invasive and aggressive neoplastic behaviour is driven by the accumulation of molecular events followed by a subsequent selection and clonal expansion of the selected sub-clone or clones. A broad spectrum of pre-neoplastic lesions lies between the completely normal and the highly malignant phenotype in which each lesion represents a branching of a new border between normalcy and malignancy. Like many cancers, Wilms’ tumour is presumed to arise in a multistep pattern as a consequence of the progression and the clonal expansion of persistent pluripotent embryonic renal precursors that are known as Nephrogenic Rests (NRs). These lesions are considered as true precursors as they are capable of progressing into Wilms’ tumour by accumulating several genetic and epigenetic alterations in a multistep pattern analogous to the Voglegram model of tumorigenesis. The current model of Wilms' tumour progression presumed that the progression of persistent embryonic blastemal cells, that fail to follow their normal developmental pathway of differentiation into developed kidney, or disappearing through apoptosis, instead progress into hyperplastic rests or nodules occurs as a consequence of molecular events that endow these cells with selective growth and survival advantages to proliferate, out-compete other clones and dominate the tumour microenvironment. Similarly, the progression of these hyperplastic rests into full blown Wilms' tumour also requires additional genetic or epigenetic alterations. However, in this study we hypothesized a new model of progression in which persistent NRs with a tendency to mature and produce growth factors could progress into hyperplastic nodules as a result of the autocrine and paracrine effects of secreted growth factors without the need for further genetic or epigenetic alterations. This paracrine-mediated model of progression was explored by using mathematical, immunohistochemical and cytogenetic approaches which all indicated that hyperplastic rests or nodules may represent a nursery or a fertile field for additional genetic events rather than being caused by a genetic event as has been generally thought. Such a model may provide an insight into the development of a novel therapeutic approach targeting the growth factor-producing cells or alternatively antagonising or at least suppressing the paracrine effect of this secreted molecule.

In a separate part of this project a small pilot comparative study was conducted as a series of immunohistochemical experiments in order to investigate whether two different pathogenetic pathways, the ILNRs and PLNRs associated pathways, for Wilms’ tumour progression could be identified. This study concluded that both ILNRs and PLNRs associated with Wilms’ tumours are characterised by different cellular expressional levels and patterns for the different biomarkers included in this study. Thus, a larger comparative study could be worthwhile as these findings may facilitate the distinguishing of different pathogenetic pathways for Wilms’ tumorigenesis which may allow more pathway specific treatment for these tumours.

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