Prostate Cancer Review: Genetics, Diagnosis, Treatment Options, and Alternative Approaches

Abstract

Prostate cancer is one of the malignancies that affects men and significantly contributes to increased mortality rates in men globally. Patients affected with prostate cancer present with either a localized or advanced disease. In this review, we aim to provide a holistic overview of prostate cancer, including the diagnosis of the disease, mutations leading to the onset and progression of the disease, and treatment options. Prostate cancer diagnoses include a digital rectal examination, prostate-specific antigen analysis, and prostate biopsies. Mutations in certain genes are linked to the onset, progression, and metastasis of the cancer. Treatment for localized prostate cancer encompasses active surveillance, ablative radiotherapy, and radical prostatectomy. Men who relapse or present metastatic prostate cancer receive androgen deprivation therapy (ADT), salvage radiotherapy, and chemotherapy. Currently, available treatment options are more effective when used as combination therapy; however, despite available treatment options, prostate cancer remains to be incurable. There has been ongoing research on finding and identifying other treatment approaches such as the use of traditional medicine, the application of nanotechnologies, and gene therapy to combat prostate cancer, drug resistance, as well as to reduce the adverse effects that come with current treatment options. In this article, we summarize the genes involved in prostate cancer, available treatment options, and current research on alternative treatment options.

Keywords: gene therapy; genetics of prostate cancer; prostate cancer; prostate cancer diagnosis; prostate-specific antigen (PSA); traditional medicine.

Figure 1

A schematic depicting the development of prostate cancer. The stages of the cancer onset and progression are indicated by the molecular processes, genes, and signaling pathways which are important in different stages of cancer. The first sign of prostate cancer is an inflammation of the prostate gland as a result of uncontrollable cell division. This uncontrollable cell division is caused by mutations that arise due to damaged DNA. At a chromosomal level, the initiation of prostate cancer begins with the shortening of telomerase at the end of the chromosome. Oxidative stress from prostate gland inflammation can shorten prostatic telomeres [78]. Research on the Nkx3.1 homeobox gene has shown the impact of the gene on the prostate cancer initiation phase in mice. No tumor suppressor gene has been solely given a role in prostate cancer initiation or progression. However, several genes such as MYC, PTEN, NKX3.1., and TMPRSS2-ERG gene fusions are implicated in prostate cancer initiation. TMPRSS2-ERG gene fusions are responsible for the main molecular subtype of prostate cancer. The gene fusion activates the ERG oncogenic pathway, which contributes to the development of the disease. Metastasis of prostate cancer is conserved by the reactivation of pathways involved in cell division, which results in uncontrolled cell division and cell proliferation, leading to metastasis of the cancer [79]. Gene expression profiling results have indicated an overexpression in EZH2 mRNA and proteins present in metastatic prostate cancer. Due to the functions of EZH2 involving apoptosis and proliferation, EZH2 is a novel target for prostate cancer [80].

Figure 2

The function of AR signaling in prostate cancer and development: (A) Prostate homeostasis is maintained in a healthy prostate via reciprocal signaling between the stromal and epithelial layers; (B) normal prostate cells are converted into cancer initiating cells by unknown mechanisms, histological evidence of prostatic intraepithelial neoplasia and early cancer lesions appears, cells at the basal layer express higher levels of AR in response to this event; (C) cellular and molecular alterations occur in prostate adenocarcinoma, resulting in luminal cells with the AR transcriptional pathway; (D) Prostate cancer cells in CRPC maintain AR activity through other mechanisms (including upregulation of AR and its splice variants, intra-tumoral androgen synthesis, cross communicate with other signal pathways, and increased/altered expression of AR cofactors) as the availability of androgen from the blood steam becomes limited [134].

Figure 3

The androgen receptor gene encodes a 110 kD protein composed of 919 amino acids that are classified by an androgen-binding domain (ABD), a conserved DNA-binding domain (DBD), and an N-terminal transactivation domain, which has two polymorphic trinucleotide repeat segments. These repeated segments, consisting of variable numbers of polyglycine repeats and polyglutamine, highly influence the androgen receptor transcription activity. The gene transcript consists of eight exons in total: exon 1 codes for the N-terminal domain, exons 2–3 code for the DBD, and exons 4–8 code for the ABD [135].