As the most common noncutaneous malignancy in American men, prostate cancer currently accounts for 29% of all diagnosed cancers, and ranks second as the cause of cancer fatality in American men. Prostatic cancer is rarely symptomatic early in its course and therefore disease presentation often implies local extension or even metastatic disease. Thus, it is extremely critical to detect and diagnose prostate cancer in its earliest stages, often prior to the presentation of symptoms. Three of the most common techniques used to detect prostate cancer are the digital rectal exam, the transrectal ultrasound, and the use of biomarkers. This review presents an update regarding the field of prostate cancer biomarkers and comments on future biomarkers. Although there is not a lack of research in the field of prostate cancer biomarkers, the discovery of a novel biomarker that may have the advantage of being more specific and effective warrants future scientific inquiry.
Prostate cancer is the most common noncutaneous malignancy in American men. It currently accounts for 29% of all diagnosed cancers, and ranks second as the most common cause of cancer fatality in American men, accounting for 13% of all cancer fatalities (
Approximately 98% of prostate cancer cases are glandular in origin (
Prostatic cancer is rarely symptomatic early in its course, as the majority of malignancies arise in the peripheral portion of the gland away from the prostatic urethra. Symptomatic presentation often implies local extension or even metastatic disease. As the cancer begins to involve the urethra and/or bladder neck, obstructive voiding symptoms often develop; these can include hesitancy, slowing of the urinary stream and intermittent flow. Irritative voiding symptoms, like frequency and urgency, may also occur although these are more difficult to attribute to cancer, as they are also associated with benign prostatic hyperplasia (BPH). With tumor progression, patients may also notice sexual symptoms such as hematospermia and/or decreased ejaculatory volume secondary to ejaculatory duct obstruction. Erectile dysfunction may also be observed if there is local encroachment on neurovascular bundles.
Bony pain is often a sign of metastatic involvement of the skeleton; human prostate cancer is one of the rare cancers that repeatedly produces osteoblastic metastases to the bone in 95% of cases (
In terms of biochemical markers, the first to be used routinely in the diagnosing and staging of prostate cancer was PAP. PAP hydrolyzes esters under acidic conditions to yield inorganic phosphates. Although identified in numerous organs such as the liver, brain and lungs, the highest concentration of PAP is identified in the prostate. Prostate epithelial cells secrete PAP into the glandular lumen and can be measured by either immunoassay or enzymatic assay.
A 1938 study showed PAP to be elevated in the prostates of patients with metastatic prostate cancer (
PSA, or human kallikrein 3 (hK3) is a 33-kDa serine-protease of the tissue kallikrein family that was identified in prostatic extracts in the 1970s (
PSA is widely used to screen for prostate cancer. PSA screening is less expensive than transrectal ultrasound (TRUS), and it can detect more prostate cancers than digital rectal examination (DRE) or TRUS, and is more likely to be organ-confined compared to those cancers discovered by DRE alone (
The analysis of multiple preoperative variables to predict the ultimate pathological stage of patients undergoing radical prostatectomy was first developed by Oesterling
Although certain studies showed that PSA expression in prostate cancer tissue decreased with increasing Gleason score, serum PSA levels remained proportional to the volume, Gleason score and stage of the prostate cancer (
Although PSA is the most popular biomarker for prostate cancer, it is one of the most controversial. A recent study recognized the disadvantage of PSA for the early detection of prostate cancer. It was found that multiple men must be screened, biopsied and diagnosed to prevent one fatality (
hK2 is a member of the same family as PSA and exhibits ~80% homology in the amino acid sequence with PSA. Similar to PSA, the highest level of hK2 is in prostatic tissue (
A recent study reported on the use of a porous silicon antibody immunoassay platform for the detection of serum levels of total hK2 (
IGF-1 and IGFBPs are associated with tumor prognosis and progression in patients with colon, breast, lung and prostate cancers (
However, plasma concentrations of IGFBP-2 and IGFBP-3 were associated with disease progression; IGFBP-3 was found to be lowest in patients with bony metastasis, progressively higher in patients with localized disease and highest in healthy subjects (
The cytokines in the TGF-β1 family of polypeptides have been implicated in numerous steps of tumor development and elevated levels of TGF-β1 have been found in patients with various cancers (
IL-6 has a role in various cellular activities, including regulation of immune function and bone turnover. Studies using immunohistochemistry have demonstrated that protein concentrations of IL-6 are increased 18-fold in localized prostate cancer tissue when compared with normal prostate cancer tissue. In addition, concentrations of IL-6 receptors are increased 8-fold in prostate cancer tissue when compared with normal tissue (
PCR is a molecular technique that amplifies minute amounts of DNA using sequence-specific primers and heat-stable bacterial DNA polymerase. When RNA is the starting material, reverse transcriptase is used to transcribe it into DNA prior to initiating the reaction. RT-PCR is extremely sensitivity in detecting tissue-specific mRNA of tumor markers such, as PSA (
PSMA is a 100-kDa transmembrane glycoprotein identified in all types of prostatic tissue, but particularly elevated in carcinomas. PSMA levels have been used (
Epstein
EPCA, a nuclear structural protein associated with prostate cancer, was identified (
In a study by Bolduc
Other promising research involves glutathione s-transferase (GSTP), a cytosolic enzyme that converts certain toxic compounds to glutathione (
A novel protein that has shown much evidence in the diagnosis of prostate cancer is PCA3. Multiple studies (
The analysis of multiple urinary proteins, rather than one specific protein, is also a novel idea. Instead of simply studying PSA or PCA3 levels, it has been proposed that combinations of proteins, such as TMPRSS2-ERG and PCA3, be analyzed for early detection (
Combining mulitple genes used as biomarkers, such as GalNac-T3, PSMA, hepsin and PCA3, in RT-PCR analysis can be a powerful new method to distinguish between prostate cancer and BPH (
Prostasomes have also recently been linked to the incidence of prostate cancer. A previous study has shown that malignant prostate cancer cells produce and secrete prostasomes (
While the PSA test is the current standard in blood-based diagnostic tests for prostate cancer, research is currently being performed to find an alternative and improved blood-based diagnostic test.
Chavarro
Gann
The field of prostate cancer biomarkers is extensive; however, the search for a more rapid and accurate marker continues. Recent study has utilized genomic testing as a biomarker for aggressive prostate cancer. A recent discovery of the long noncoding RNA SChLAP1 in the prostate has provided a novel biomarker that not only adds to the ability to identify prostate cancer, but also to conventional risk stratification (
Exosomes have proved to be non-invasive cancer biomarkers as tumor-specific molecules can be found in exosomes isolated from biological fluids. A recent study has explored the proteome of urinary exosomes by utilizing mass spectrometry to identify proteins that are expressed differentially in prostate cancer patients (
The present review explored a portion of current and future biomarkers used in the detection of prostate cancer. A study from 1938 showed PAP to be elevated in the prostates of patients with metastatic prostate cancer, thus identifying the first biomarker used routinely in diagnosing and staging of prostate cancer. In the 1970s, PSA, also known as hK3, was discovered and today it remains the most widely used, and controversial, biomarker in prostate cancer.
The search for a more rapid, specific marker for the detection of prostate cancer has lead to numerous laboratories examining biomarkers. Although a number of markers have been acknowledged, there is yet to be one that is widely accepted and used. Research now concentrates on genomic factors. For example, SChLAP1 has been validated for the prognosis of aggressive prostate cancer and it is suggested that the integration of genomic tests may advance the diagnosis of prostate cancer through early identification of high-risk patients. Furthermore, the potential of using urinary exosomes in the diagnosis and clinical management of prostate cancer has been explored. Understanding the biochemical and genetic aspects of prostate cancer biomarkers not only has the ability to more efficiently detect prostate cancer, but it may also provide an insight into how and why prostate cancer arises, and may suggest a method to manage or even cure it.