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Title: Mechanism of invasion by prostate cancer
Author: Ünlü, Ali
ISNI:       0000 0001 3541 6194
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 1998
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The prostate is normally under the control of sex steroids and endocrine therapy is the most effective first line therapy in prostate cancer. Prostate carcinoma is characterised by eventual loss of hormonal sensitivity with increased aggressive behaviour of the tumour. Prostate carcinoma has an initial slow growing non- invasive phase, but, mostly, is invasive by the time of diagnosis. As the tumour progresses, tissue growth factors, such as epidermal growth factor (EGF) and transforming growth factor-beta (TGFbeta) appear to be more effective than hormones in the control of the cancer cells. Increased tyrosine kinase activity, related to the increased activity of growth factor receptors, has been shown in many prostate cancers. Plasminogen activators (PA) , particularly urokinase plasminogen activator (uPA), have been implicated in extracellular proteolysis in invasiveness, metastasis and angiogenesis. PA are highly substrate specific enzymes which convert the inactive zymogen plasminogen to plasmin. Plasmin, a proteolytic enzyme of broad specificity, degrades laminin and fibronectin, and activates various tissue metalloproteinases. Degradation of these extracellular proteins facilitates the migration and metastasis of tumour cells to different biological sites. Regulation of uPA activity and pericellular proteolysis, at protein level, is controlled by the combination of PA inhibitors, PAI-1 and PAI-2 which are responsible for the negative regulation and uPA receptor (uPAR) which binds latent uPA. uPA plays a critical role in the invasion and migration of prostate cancer cells and provides a marker of the aggressive phenotype. This study investigated the regulation by androgen, EGF, and TGFbeta of the release and function of uPA, PAI-1 and PAI-2 using hormone-insensitive invasive prostate cancer cells, PC-3 and DU145. These studies include measurement of EGF receptor function, in terms of its sensitivity to a "specific" inhibitor and assay of the various proteases at mRNA, protein and functional levels. The PC3 and DU145 cells both possess EGF receptor (EGFR). Growth of PC3 cells was stimulated by exogenous EGF but not that of DU145 cells (figs 3.5 and 3.6). However, EGFR-specific tyrosine kinase inhibitors significantly inhibited growth of both cell types (figs 3.7 and 3.8). On the other hand, both cell types were found to be growth insensitive to exogenous TGFbeta (figs 4.1 and 4.2). Both cell lines expressed uPA, uPAR and PAI-1 transcripts. uPA, tPA, PAI-1 and PAI-2 proteins were all detectable in the PC3 cells whereas only uPA and PAI-1 proteins (PAI-1 protein was hardly detectable in the control group) were found in DU145 cells. EGF increased the production of uPA, at both transcriptional and protein level (figs 3.11, 3.15 and 3.16) in addition to increasing uPAR at transcriptional level (figs 3.12 and 3.14) in both cell lines. uPA activity was enhanced by EGF in both cell lines (figs 3.18 and 3.19). The matrigel invasion of the PC3 cells was increased by exogenous EGF in an in vitro invasion assay (fig 3.20). The tyrosine kinase inhibitors inhibited all stimulations caused by EGF. uPA production and activity were suppressed well below that in the control group. The tyrosine kinase inhibitor (ZM26060S) also reversed the EGF stimulated matrigel invasion by the PC3 cells. TGFbeta also stimulated uPA and PAI-1 production in both cell lines (figs 4.8 and 4.9). The TGFB-induced increase in PAI-1 production in both cell lines (figs 4.10 and 4.11) was remarkable (2087 % in PC3, 1433 % in DU145). TGFbeta also stimulated PAI-2 protein in the PC3 cell line. uPA activity was found to be inhibited by TGFbeta in the PC3 cell cytosol whereas it was increased in the DU145 cells (figs 4.12 and 4.13). In the matrigel invasion assay TGFbeta treated PC3 and DU 145 cells showed a similar invasion in comparison to the control group. Overall, EGF is a potent stimulative agent for both growth and invasion in prostate cancer cells. The contribution of TGFbeta to prostate cancer cell growth and invasiveness still seems to be controversial. The effect of TGFbeta on the immune system, on angiogenesis and on colony formation by cancer cells all suggest that TGFbeta plays a positive role in favour of cancer invasiveness and provides a new target for therapy. As can be seen from the results, targetting the EGFR function inhibits not only tumour growth but also its invasiveness. On the basis of these results, inhibition of EGFR-related tyrosine kinase activity may open a new era in the treatment of drug-resistant prostate cancer.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Cancer treatment; Sex steroids; Endocrine therapy