It is now generally accepted that the burden of disease due to prostate cancer has tremendously increased globally. Current data indicates that prostate cancer is the most common form of cancer in men in the United State of America, and the second leading cause of death due to cancer [1], (see Figure 1). Approximately 100 men are being diagnosed of this disease daily in the United Kingdom [2]. In both American and British studies, men of African descendant or who emigrated from Africa to either USA or Britain had increased risk of being diagnosed with this disease [3]. Factors contributing to the development of prostate cancer have been suggested. The most outstanding of them are environmental and genetic inheritance [4].

For men with localized prostate cancer, common treatment options include watchful waiting, surgery to remove the prostate gland (radical prostatectomy), external beam radiation therapy EBRT, cryotherapy, androgenablation therapy [8-13]. Advanced localised prostate cancer is usually treated by androgen ablation therapy [14,15]. In this treatment protocol, at least three recognised agents have been used; among them is bicalutamide, which has been shown to be most efficacious and the first line drug for patients with localised prostate cancer.

AAT involves the use of androgen blockades or antagonists such as flutamide, bicalutamide or casodex and nilutamide to competitively and directly block the androgen receptors in the cytosol of the prostate cells. These agents are generally—used either as intermittent therapy—to prevent the flare phenomenon commonly associated with GnRH agonists or monotherapy, in men in whom GnRH agonist could not effectively control their disease [16]. Patients treated with this drug have temporal benefits in symptoms and quality of life over a period of 2 years and subsequently develop androgen independent state which is commonly characterised with treatment resistance and cancer cells spread to bone and lymph node (Figures 2 and 3) and death due to these complications [14-22]. Mechanisms leading to development of androgen independent state and poor treatment outcome in prostate cancer patients are yet to be fully explained.

Patel et al. [23] studied the characteristic changes that lead to the development of androgen independence in prostate cancer cells earlier dependent on androgens using LNCap cell and sublimes CL1. They transfected the androgen independent sublines CL1 with a green fluorescence protein and injected them into the Mice, and observed extensive local invasion and metastasis to distant organs. In a slightly similar experimental design, Tso et al. [24] observed that the androgen deprived LNCap cells were fast growing, and had ability of potentiating the growth of endothelia cells, and were resistant to both chemotherapy and radiotherapy, with high metastatic potential. The works of Freedland et al. [25] revealed three different growth pattern of androgen refractory cells when transfected and implanted into the Severe Combined Immunodeficiency Disease SCID Mice. And showed that the androgen refractory prostate cancer cells were fast growing with widespread to metastasis. Zhou et al. [26] found that androgen independent prostate cancer cells had decreased apoptosis and acquired higher proliferation rate than the androgen dependent cells. Common to all these studies are increased invasiveness and malignant metastasis, loss of apoptosis and chemotherapeutic resistance. It is not clear what molecular and cellular changes are responsible the transformation to androgen refractory phenotype following androgen ablation therapy.

Evidence has shown that androgen dependent prostate cancer cells required the presence of both epidermal Growth Factor EGF and androgens for optimal cell proliferation, whereas androgen independent or refractory prostate cancer cells exhibited significant growth without these molecules [27]. Freedland et al. [25] observed heterogeneous growth response in prostate cancer cells exposed to androgen ablation, and suggested that there were various alteration in the genes expressions profile of rapidly proliferating prostate cancer cells. Many studies have shown androgen receptor gene over expression following androgen ablation and progression to androgen refractory phenotype, see Figure 4 [23,26,28].

It has been established that androgen ablation therapy induces initial reduction in the androgen receptor protein before progression to androgen independent state [23] and [26]. Hughe et al. [29] demonstrated that this treat-

ment intervention might induce some structural changes or mutation in the androgen receptor causing androgen independence. However, in a study involving 44 mutant androgen receptor prostate tumours; 15.9% had loss of function, 6.8% had wild type function, 31.8 % had partial function and 45.5% demonstrated a gain of function [29]. Also, Marceili et al. [31] investigated androgen receptor mutations in 137 specimens of prostate cancer from primary tumour of stage B and D, and observed that only 8% had mutation on in the androgen receptor and that there was no mutation in the 99 patients with stage B prostate cancer. Put together, there may some changes in the androgen receptors of androgen independent prostate cancer cells, but the extent of such changes may not the solely responsible for the development of refractory state. Thus progression to androgen refractory prostate cancer state may not be due to mutations in the androgen recaptors.

Data from microarray analyses studies of prostate cancer cells progressing to androgen refractory phenotype indicated that the onset of androgen independence did not require any alteration in the status of androgen receptors, even though too many genes were dysregulated [32]. The gene profiling analysis of androgen refractory prostate cancer cells [33], further threw more lights on the nature of the dysregulations, indicating that the following genes were up regulated; PCDH7, TPTE, TSP4, EPHA3, HGF, MET, EGF, TEM8 while HTAT1P2, CDKN2A, CDKN2B, CDKN1C, PPP2CA, SPRY, etc, were down regulated [33]. Also P53, P21, bax, bcl-2, VEGF, waf1 were all up regulated in the androgen refractory prostate cancer cells in a separate study [26]. Furthermore, the changes responsible for progression to androgen independence in prostate cancer have characterised using real time polymerase chain reaction (RT PCR) [23]. Thus, the androgen independent cells had over expression of phosphatise and tensin homolog gene PTEN, interleukin 6, interleukin 8, transforming growth factor beta, vascular endothelial growth factors VEGF, epidermal growth factor receptors EGFR, bcl-2 and low level of P53 [23], also see Figure 4. In addition, the functions of these genes have been reviewed elsewhere [4,29]. However, a full functional genomics of these delineated perturbed genes may further open a new window into the complex multifactoral acquisition of androgen independence following androgen ablation therapy.

The emergence of cells refractory to androgen ablation and radiation therapy is often the major cause of death in men treated with prostate cancer. It is not yet known the actual initiators of the emergence of these resistant cells. Currently, some hypotheses have evolved to explain the changes that lead to the progression to androgen independence. These include;

1)         Increased in the sensitivity of the androgen receptors [5,30,34-37].

2)         Decreased and/or loss of specificity of the androgen receptors [4,35].

3)         Outlaw pathways [5,33,37].

4)         involvement of neuroendocrine cells [37-39].

5)         involvement of prostate cancer stem cells [2,36].

6)         increasing level of tumour hypoxia [21,40,41].

The peculiar nature of microenvironment of prostate tumour is characterised by irregular supply of oxygen, PH, and nutrients [39]. The consequences of this alteration are development of irregular vasculature, genetic and epigenetic changes, alterations in gene expression and cellular functions, see Figure 4 [40]. Tumour hypoxia has been recognised as one of the pivots of development and progression of prostate cancer through the activation of three major oxygen sensitive pathways; including hypoxia inducible factor-1 (HIF-1), Mammalian target of Rapamycin mTOR kinase, and the Unfolded protein response (UPR), see Figure 4, [40]. These three pathways are independent but may also act in an integrated manner, with some level of influence on each other and leading to a common cumulative effects on gene expression, cell survival and tumourigenesis [40]. Hence, long time androgen deprivation has been suggested to induce tumour hypoxia and the consequent transition from androgen dependence to independence state, culminating in resistance to therapy.

Additionally, tumour hypoxia induces the generation of radical oxygen species (ROS), which beyond a certain threshold may cause adaptive responses and loss of: 1) PTEN, the function of PTEN in a normal cell is induction of apoptosis and its loss in androgen refractory prostate cancer causes cell survival [37]; 2) Glutathione S-transferase GST-Pi; 3) androgen regulated specific home box NKX3, 4) over expression of bcl-2 and loss of apoptosis, 5) activation of hypoxia inducible factor-1 HIF-1, see Figure 4, and activation of nuclear factor (NFkB). NFkB is an innate molecule which has a central role in the activation of both innate and adaptive immunity. In this case, its activation results in production of pro-inflammatory cytokines. Put together, these molecular signalling above may result in the increased level of inflamematory cytokines and oxidative damage to the DNA and epimutation; this may be responsible for acquisition of aggressive and more malignant phenotype, and invasive regional and distant spreading and resistance to treatment, see Figure 4.

In conclusion, development of androgen resistance is an established consequence of therapeutic intervention using androgen ablation approach. Various mechanisms involveing the alteration of gene expression, through yet unclear signalling pathways results in various molecular and cellular changes which may independently and synergistically induce transformation to androgen resistant phenoltypes. The perturbation of gene expression profile that drives development of androgen independence has been discussed in this study. A wide range of genomic perturbations in the gene expression profile of androgen independent prostate cancer tumours have been high-lighted. In addition, some specific mechanisms that may result in development of androgen independent state have been discussed. However, more studies involving perhaps functional genomics may be important—this may provide evidence for molecular targeting of some hit and lead genes that drive prostate cancers towards malignant progression. This in turn may serve as potent therapeutic targets for overcoming treatment failures in patients with prostate cancer.

The authors declare that no part of this work has been published else where or is awaiting publication anywhere.

I declare no conflict of interest, and that no fund from any funding body or the University was made available for this work. This study was funded by the authors only.