Modelling stromal-cancer cell interactions in prostate tumours

Abstract

Prostate cancer is a disease with high incidence and mortality rates. A recent research focus has been on identifying cells of origin which initiate tumourigenesis and cancer repopulating cells responsible for tumour growth and resistance to therapies, as they are an important novel therapeutic target. Our ability to identify these cells in the prostate has been hampered by a lack of human models to study disease progression. Whilst the use of primary human prostate cancer specimens is preferable over commonly used cell and xenograft lines, they display low survival and growth in in vivo assays. It is well established that the stroma plays an important role in prostate biology, however is rarely considered in the use of cancer cell focused approaches. As such this thesis aimed to create models of prostate cancer that are biologically accurate, in order to identify cells of origin and cancer repopulating cells, by providing an enriching stromal environment to primary tissues. Chapter 3 aimed to define potential cells of origin in prostate cancer. Stem cells and transient-amplifying/progenitors from the basal compartment were subjected to in vivo tumour initiation models where the stroma drives malignant transformation. The results confirmed that basal cells were able to initiate tumours, however the tumourigenic potential resided within the transient-amplifying cells, rather than the stem cells. Chapter 4 then examined prostate cancer repopulating cells. Due to observations that the stroma plays an important role in prostate biology, a bioassay was developed where primary localised prostate cancer tissues and cells were combined with inductive mouse mesenchyme to enhance survival and growth in vivo. Mouse mesenchyme did confer a survival and growth advantage of prostate cancer tissues and was essential for the survival and growth of subfractionated cancer cells, thus creating the first assay to study cancer repopulating cells in vivo using primary tissue. Chapter 5 utlised this chimeric xenografting approach to examine cancer repopulating cells in the context of systemic and paracrine androgen signalling, in attempt to identify the cancer repopulating cells which are resistant to current therapies. While androgen deprivation therapy is usually the treatment modality for advanced disease, this model demonstrated castrate-resistant cancer repopulating cells are also present in localised tumours. Furthermore, this study also showed that low stromal androgen receptor levels dampened the response to castration, demonstrating the complex relationship between cancer repopulating cells and the surrounding microenvironment. Overall, this thesis reports the development of models which can be utilised to study cells of origin and cancer repopulating cells in prostate malignancy, using human clinical specimens. This body of work demonstrates the important role that the stroma plays in prostate cancer and maintaining a supportive microenvironment in in vivo models. Future efforts can use these models to further dissect the biology of prostate cancer progression, in particular determine how cancer repopulating cells can be therapeutically targeted to provide better outcomes for patients.