Cancer incidence and mortality rapidly grow despite significant drug discovery and clinical practice advances. Lung cancer is the most frequent cancer and the leading cause of cancer death among males, followed by prostate and colorectal cancer (for incidence) and liver and stomach cancer (for mortality) [1]. In the last decade, incidence remained high, with an estimated 1.1 and 1.4 million men worldwide diagnosed with prostate cancer in 2012 and 2021, respectively. However, the magnitude of increasing incidence and decreasing prostate cancer mortality has been attenuated [2]. The high number of cases in more developed nations could be due to the already common practice of prostate-specific antigen (PSA) screening and subsequent biopsy [3]. In the United Kingdom, prostate cancer contributed to 46,690 (13%) of new cases and 11,287 deaths annually. In addition, 54% of prostate cancer cases in the UK are diagnosed in males aged 70 and over every year [4]. According to the statistics provided by the National Cancer Registry [5] of Malaysia, prostate cancer ranked ninth overall and is the fourth most frequent cancer (7.3% of all cancers) diagnosed in men. Although the incidence of prostate cancer is more prevalent in Western countries, the number of prostate cancer cases has also grown in different parts of the world. Genome-wide association studies have identified around 100 genetic loci associated with prostate cancer risk in Western populations but only a dozen in Japanese and the Chinese populations [6], thus reflecting a specific baseline protection for male Asians.

Chromosomal abnormalities associated with prostate cancer include the deletion of 8p, 10q, 13q, and 16q, as well as the gains of 7p, 7q, 8q, and Xq chromosomes. These allelic abnormalities have been reported by Nupponen and Visakorpi ^[7][23], Hughes and co-workers ^[8][24], and Shi and co-workers ^[9][25]. Further allelic loss has been reported by Rubin and Rubin ^[10][26], Shen and Abate-Shen ^[11][27], and Fraser and co-workers ^[12][28], which include the loss of 6q, 7q, 17p, and 18q.

The MYC is a well-known oncogene that plays an essential role in regulating cellular proliferation, differentiation, and apoptosis. This oncogene is located at 8q24 and another amplified region of 8q ^{[13][14][15][16]}[29,30,31,32]. The overexpression and amplification of this oncogene have been detected in prostate cancer cells, especially in the metastatic stage ^[16][17][18][32,33,34]. Besides MYC, the RAS family of oncogenes are the most common oncogenes in human cancer. However, in prostate tumors, mutations in the ras genes (HRAS, KRAS, and NRAS) are relatively uncommon ^[19][20][35,36], except in the rare ductal form of the disease. Morote and co-workers ^[21][37] have reported that overexpression of the ERBB2 gene is a frequent event in prostate cancer. The ERBB2 gene, or Her-2/neu, is from a family of genes that provide instructions for producing growth factor receptors. These growth factors are essential in stimulating cell growth and division. ERBB2 gene amplification will result in the overproduction of ErbB2 protein, which can cause cells to grow and divide continuously, leading to uncontrolled cell division, one of the hallmarks of cancerous tumor progression ^[22][23][38,39]. Another oncogene that plays a significant role in the progression of prostate cancer is Bcl-2. Several authors have reported the overexpression of Bcl-2, especially in recurrent tumors ^{[24][25][26][27][28]}[40,41,42,43,44]. However, this event did not seem to happen due to the amplification of the genes ^[7][27][23,43]. Bcl-2 inhibits apoptosis of the prostate cancer cells subjected to androgen deprivation, allowing the cancerous cells to survive without the required hormone.

The androgen receptor (AR) is a type of nuclear receptor that is encoded by a single copy gene located on the X-chromosome (Xq11.2-q12), which consists of 919 amino acids in length, but this can vary depending on the poly-glutamine, poly-glycine, and poly-proline repeats of variable lengths ^[29][45]. AR signaling is crucial as it plays a critical role in prostate function and differentiation in the growth and progression of prostate cancer ^[29][30][45,46]. AR activity is regulated by two major ligands, testosterone, and dihydrotestosterone (DHT). DHT, which has a ten times higher binding affinity to the AR, is the primary androgen bound to the AR. The binding of DHT to the AR promotes the recruitment of protein kinases, which leads to the phosphorylation of several serine residues. This process is essential as it serves many functions, such as protection from proteolytic degradation, stabilization, and transcriptional activation ^[30][46]. The transactivation of the AR is vital as it regulates specific gene targets involved in cell growth and survival ^[31][47]. The rate of cell proliferation and the rate of cell apoptosis are balanced in normal prostate epithelium. However, this balance is lost in prostate cancer, leading to the formation of tumor cells ^[32][48]. Since prostate cancer growth is highly dependent on androgen, androgen-ablation therapy has always been the most effective treatment for prostate cancer at an early stage. However, this therapy only manages to delay tumor progression by 18–24 months, followed by the development of a lethal drug-resistant stage known as castration-resistant prostate cancer (CRPC). Visakorpi and co-workers ^[15][31] have reported that in CRPC patients, the frequent amplification of chromosome Xq in recurrent tumors has led to the overexpression of the AR after androgen deprivation therapy. This type of chromosomal amplification is rarely seen in primary tumors. The overexpression of the AR overcomes the decreased levels of circulating androgens in hormone-independent prostate cancer, thus allowing the cancer cells to continue growing even in a deficient level of androgen left in serum after castration ^[15][33][31,49]. The overexpression of AR also produces a receptor that is more sensitive to a low androgen level, or that can be activated by other types of steroids, such as adrenal androgens, estrogens, progestins, and anti-androgens used in the management of the disease ^[34][50].

Prostate cancer is one of the most malignant types of cancer in men. It can spread to distant sites, including bones, lymph nodes, lungs, liver, and brain. However, prostate cancer frequently metastasizes to the bone marrow ^[35][51]. Almost 90% of advanced prostate cancer patients suffer from pathologic fractures, spinal cord compression, and pain due in part to deregulated cycles of osteoblastic and osteolytic resorption/formation driven by the growing tumor mass ^[36][37][52,53]. Although the mechanisms that account for the tendency of prostate cancer cells to metastasize to the bone have not yet been elucidated, they may include direct vascular pathway, highly permeable sinusoids, chemotactic factors produced by bone marrow stromal cells, and the synthesis of growth factors necessary to support cell survival and the proliferation of ‘seeded’ cancer cells ^[38][39][54,55]. Taichman and co-workers hypothesize that metastatic prostate carcinomas may use the hematopoietic model to localize to the bone barrow. In this model, chemokines, a group of molecules known to play significant roles as activators and chemoattractants, including CXC chemokines such as CXCL12 and its receptor CXCR4, appear to be critical molecular determinants for the events in this model ^[40][41][56,57]. They also showed that the CXCL12/CXCR4 chemokine axis was activated in prostate cancer metastasis to the bone ^[42][58]. They also confirmed that CXCR4 expression is related to increasing tumor grade and showed that CXCL12 signaling through CXCR4 triggers the adhesion of prostate cancer cells to bone marrow endothelial cells ^[43][59]. Similar studies by other researchers also suggest that the CXCL12/CXCR4 axis plays a similar role in other tumors metastasizing to the marrow. For example, Mueller and co-workers ^[44][60] reported that the CXCL12/CXCR4 axis plays a central role in regulating metastasis by showing that normal breast tissues express little CXCR4 receptors compared to breast neoplasms, which express high levels of CXCR4. Furthermore, this research also shows that using an antibody that could block the CXCR4 receptor could prevent the spread of tumor cells to the lungs and lymph nodes.

Apart from that, the metastatic progression of prostate cancer is also closely associated with two genes, namely E-cadherin (CDH1) and KAI1 genes. The expressions of both genes are significantly reduced in metastatic prostate cancer cells ^[45][46][61,62]. However, this was not caused by allelic loss but rather by post-transcriptional events regulated by p53. Therefore, a loss of p53 function in the late stages of tumor progression could cause the downregulation of these two genes with subsequent metastasis ^[47][63].

Besides the abnormalities in chromosomes, the presence of oncogenes, and the overexpression of specific receptors, cancer cells commonly overexpress key enzymes of the arachidonic acid metabolism (mainly COX-2 and 5-LOX). COX-2 is overexpressed in practically every premalignant and malignant condition involving the colon, liver, pancreas, breast, lung, bladder, skin, stomach, head, neck, and esophagus ^{[48][49][50][51][52][53][54][55]}[64,65,66,67,68,69,70,71]. Interestingly, human prostate cancer cells are known to generate 5-lipoxygenase (5-LOX) instead. 5-LOX is a type of enzyme in humans encoded by the ALOX-5 gene. Ghosh and Myers ^[56][72] reported that chemical constituents such as arachidonic acid, omega-6, and polyunsaturated fatty acid stimulate prostate cancer cell growth via the 5-LOX pathway. This has been corroborated by Yang and co-workers ^[57][73], who also point towards 12-LOX. The expression of 5-LOX is usually restricted to specified immune cells such as neutrophils, eosinophils, basophils, and macrophages.

In contrast, most non-immune body cells do not express 5-LOX unless at the onset of certain diseases such as asthma, arthritis, psoriasis, and cancer ^{[58][59][60][61]}[74,75,76,77]. The 5-LOX plays a significant role in chemotaxis in these cells ^[58][74]. Ghosh and Myers ^[56][72] reported that the inhibition of 5-LOX would block the production of 5-LOX metabolites and trigger apoptosis in prostate cancer cells. The expression of 5-LOX in normal prostate glands is almost undetectable but is augmented in prostate tumor tissues. Therefore, this finding is significant for developing future therapeutic approaches for prostate cancer, as 5-LOX plays a critical role in the survival of prostate cancer cells. All this leads to the concept that 5-LOX may play a major role in the development and progression of prostate cancer and could be used as a promising target in prostate cancer therapy. Other abnormalities, including the amplification and overexpression of certain genes mentioned earlier, could also be used as a potential target in future prostate cancer therapy.

The tumor typically consists of cancer cells and stromal cells. These stromal cells face a hostile metabolic environment characterized by acidosis and hypoxia. Therefore, tumor development requires the supply of oxygen and nutrition, usually provided by the nearby blood vessels ^[62][78]. With this, the tumor growth is only limited to 1–2 mm in diameter (avascular phase) ^[63][79]. Therefore, the tumor needs an increased blood supply mainly provided by forming new blood vessels from pre-existing capillaries and venules to exceed the size limit. This process is called angiogenesis ^[63][79]. Like other tumor cells, prostate tumors overexpress the vascular endothelial growth factor (VEGF) ^[64][80]. The VEGF is a homodimeric glycoprotein that belongs to the first group of pro-angiogenic factors ^[65][81]. Other important pro-angiogenic factors include the fibroblast growth factor (FGF) ^[66][82], platelet-derived growth factor B (PDGF-B) ^[67][83], angiopoietins ^[66][67][82,83], growth-related oncogenes ^[68][84], tumor growth factor β (TGFβ) ^[69][85], and matrix metalloproteases (MMPs) ^[70][86].

The overexpression of the VEGF in prostate tumors will promote the development of tumor neovascularization, and this overexpression also correlates with increasing grade, vascularity, and tumorigenicity. Besides that, the receptor for the VEGF, VEGFRs, and α₅β integrin were expressed by prostate cancer cells in vitro and prostate tumors in vivo, and their expression was elevated at sites of bone metastasis compared to the original prostate tumor. He and co-workers ^[71][87] reported that the angiogenic effect of the VEGF in the prostate tumor could be blocked by the inactivation of its receptor, the VEGFR. Without the VEGF or VEGFR, the prostate tumor cells would not be able to form sprouting capillaries. Therefore, this could be a potential target to stop the development and progression of prostate cancer.

Prostate-specific membrane antigen (PSMA) serum levels have been proposed to be a better prognostic value than PSA to evaluate the effectiveness of prostate cancer treatments, either via surgery, hormones, radiation, or chemotherapy ^[72][88]. Interestingly, PSMA overexpression is observed in the neovasculature of solid tumors but not in the vasculature of normal tissues ^[73][89]. The correlation between PSMA and VEGF expression in LNCaP-induced tumors reinforced its value as a marker for angiogenesis. Mechanistically, PSMA may modulate integrin ^[74][90] and the nuclear factor kappa B ^[75][91] signaling pathways. Some authors later attributed this correlation to the Mouse double minute 2 (MDM2), a negative regulator of the p53 tumor suppressor, which regulates VEGF expression and angiogenesis, after gene profiling studies suggested a signalling interplay between MDM2 and PSMA ^[76][92]. This view has been recently expanded after Watanabe and co-workers experimentally showed how PSMA-positive vesicles secreted from prostate cancer cells have the potency to transform vascular endothelial cells into an angiogenic state ^[77][93]. This has been followed by preliminary results on how they can induce PSMA-negative cells to secrete VEGF ^[78][94]. These new data open new views on how PSMA may induce pro-tumoral changes in the tumor microenvironment, thus supporting tumor progression.