Prostate Cancer

Summary

1 Introduction

1 Introduction

Prostate cancer is a highly heterogeneous disease, both in terms of its pathology and clinical presentation. It is the second leading cause of cancer-related deaths in Western males, yet because prostate tumors can take decades to progress to clinically significant disease, they are difficult to diagnose and treat. Latent prostate cancer is common, with many older men showing localized prostate tumors upon autopsy that died from other causes [1]. In contrast, once metastasis has been detected by imaging, the vast majority of patients will likely die from prostate cancer. Over the past two decades, serum PSA screening has provided a valuable tool for prostate cancer surveillance, however the age-adjusted incidence of mortality has remained relatively constant, therefore new tools are needed to guide prognosis and treatment.

Research into the genetic origins of prostate cancer has accelerated dramatically in recent years, aided by the availability of new high-throughput microarray and sequencing technologies. Numerous gene expression studies have been conducted to characterize prostate cancer initiation and progression, and many of them have shown correlation with clinical outcome. However, molecular associations with prostate cancer phenotypes continue to be fragmentary, and in some cases are poorly substantiated by follow-up investigations [2]. Early studies that profiled cancerous versus benign tissues have now been supplemented by micro-dissection procedures, revealing differences in gene expression patterns across individual tumor foci isolated from the same specimen [3]. Guided by such observations, investigators are now directing their attention to underlying molecular features that could be associated with gene expression alterations, toward a more comprehensive understanding of prostate cancer initiation and progression. These include genetic polymorphisms and epigenetic modifications, alternative splicing, and post-translational regulation involving non-coding RNA. This review surveys studies that have been conducted in each of these areas.

1 Introduction

Prostate cancer is one of the most commonly diagnosed cancers in men of developed Western countries. Globally, it is the 2nd most commonly diagnosed and 6th leading cause of cancer death in men [1]. Several risk factors such as family history, race, obesity, diet and other environmental factors have been associated with prostate cancer. The best established risk factor for prostate cancer is age, whereby there is an estimated incidence of 80% in men by 80 years of age [2]. Hence, prostate cancer is globally a major health and economic burden in our current aging population.

When diagnosed at an early organ-confined stage of the disease, prostate cancer is potentially curable by radical prostatectomy, which involves the removal of the prostate gland, and/or radiotherapy. However, it has been estimated that approximately 30% of patients relapse after the initial treatment. Since the discovery in the 1940s that prostate cancer is dependent on the male sex hormones androgens [3], the main therapy for patients diagnosed with metastatic disease or progressive disease, _targets androgen production and its mediator, the androgen receptor (AR). These therapies, called hormonal or androgen ablation therapy, refers to the administration of anti-androgens that block the functional action of AR [4]. After an initial period of tumor regression, prostate cancers become unresponsive to these therapies and eventually progress to the “castrate-resistant” state. Currently, there is no curative treatment available for castrate-resistant prostate cancer, and chemotherapy has limited benefits in improving survival.

8.12.9 Prostate cancer

Prostate cancer is a slowly progressing type of cancer with cell propagation occurring before its clinical appearance. According to a report published by US National Cancer Institute, an estimated 238,590 individuals were affected by prostate cancer and 29,720 cases of deaths were recorded due to prostate cancer in the year 2013 (Brawley, 2012). It has been established that prostate cancer antigen 3 is a key molecule associated with prostate cancer located on 9q21–22 chromosome. It was characterized molecularly as a specific gene for prostate cancer because it is overexpressed in prostate cancer metastasis and prostate tumor specimens in 90% of cases (Neves et al., 2013).

A novel _targeted SWCNT-based system for SiRNA delivery was developed by Li et al. for prostate cancer therapy. This system was functionalized with polyethylene imine chemically and bound with 1,2-distearoyl-sn-glycero-3-phosphorylethanolamine–PEG-2000 maleimide to further conjugate it with Asn–Gly–Arg (NGR) peptide for _targeting tumors. This system efficiently penetrated into the cell and crossed the cell membrane of human prostate cancer cells (PC-3 cells) in vitro, where it caused more severe apoptosis and suppressed proliferating cancerous cells division. The combined application of RNAi and near-IR photothermal therapy sufficiently amplified the anticancer potential of the system without inducing any toxic effect on other vital organs (Wang et al., 2013).

4.2.3 Prostate cancer

Prostate cancer is a common malignancy of males. The normal growth and function of the prostate gland is dependent on androgens, but also members of the TGFβ superfamily. It has been shown that there is loss of inhibin α subunit expression in high-grade prostate cancer (Mellor et al., 1998), and evidence that promoter methylation and loss of heterozygosity is associated with the down-regulation of the INHA in prostate cancer cell lines, which is consistent with its tumour suppressive role (Balanathan et al., 2004).

Prostate Cancer (PC)

PC is the most common noncutaneous cancer in men and the second leading cause of cancer death, constituting a global public health challenge. Unlike benign disease, prostate cancers usually arise in the peripheral zone of the gland and some men will have both BPH and prostate cancer. PC is a relatively slow growing disease that usually takes many years to progress. Most men are diagnosed with early stage localized prostate cancer and either considered to be at low risk of progressing and go onto active surveillance, or at high risk of progressing, requiring active treatment (removal of gland at radical prostatectomy or radiotherapy). About 1/3rd of men treated are not cured, the tumor recurs and the disease becomes advanced and/or metastatic. Men with advanced disease typically undergo androgen deprivation therapy via medical castration that initially reduces tumor burden and symptoms, but castrate-resistant prostate cancer (CRPC) develops resulting in death (Fig. 3).

Fig. 3. Schematic of prostate cancer disease progression.

Key points