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Abstract
Prostate cancer (CaP) is a major health problem in males in western countries. Although early-stage CaP can be controlled using conventional therapies, almost all CaP patients invariably progress to recurrent castration resistant CaP and eventually die from secondary disease. Targeting tumour-associated antigens is fast emerging as an area of promise for late stage CaP. This thesis provides an overview of literature regarding CaP-related issues, with emphasis on the putative roles of the tumour microenvironment and selected tumour-associated antigens, i.e. CD44 and CD147 in CaP. The aims of the study were to: 1) investigate the expression of CD44 and CD147 in primary CaP tissues and various metastatic CaP cell lines, and identify whether CD44 and CD147 are related with CaP progression, whether they are related with multidrug-resistance proteins, and whether these two proteins are inter-related; 2) develop CaP cell lines with down-regulated CD44 and CD147 expression, study the in vitro functions of these molecules in CaP, and the potential mechanisms involved; and 3) develop CaP animal models with CD44/CD147-knock-down (KD) xenografts, and look at the roles of CD44 and CD147 in vivo in respect of tumour growth, metastasis, and drug resistance.
The results indicated that CD44 and CD147 are both associated with CaP progression. CD44 and CD147 are co-expressed and interact in CaP cells. KD of CD44 or CD147 enhanced docetaxel sensitivity, reduced CaP invasive potential, and down-regulated main signal modulators associated with cell growth and survival. In vivo, CD44 or CD147-KD PC-3M-luc subcutaneous xenografts showed suppressed tumour growth with increased docetaxel responsiveness compared to control xenografts. Preliminary studies of an intracardiac model showed metastatic spread of PC-3M-luc cells imaged using bioluminescence, indicating this is an appropriate model for future studies assessing the in vivo roles of CD44 and CD147 in tumour spread.
These findings suggest that CD44 and CD147 are both closely related with CaP metastasis and drug resistance. Selective targeting of CD44/CD147 alone or combined with docetaxel may limit CaP metastasis and increase chemosensitivity, indicating promise for future CaP treatment. To date, these studies appear to be the first to show that CD44 and CD147 are collaborators in CaP.