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Saleh et al. Improvement of prostate cancer detection

6.6% of overall male deaths. In the United States, clinical value of early detection of PCa has induced
[3]
about 161,000 new PCa cases are anticipated in the search of many novel PSA-based diagnostic
2017 along with approximately 26,700 PCa deaths. markers that might, singly or in combination, improve
[4]
Radical prostatectomy and radiotherapy are still discrimination between PCa and BPH leading to help
curative therapeutic options for PCa, but are restricted minimize the frequency of unnecessary and invasive
to organ-confined tumors. Therefore, the successful biopsies. [10]
treatment of PCa depends on detection of the
disease at its earliest stages. There is a necessity to The cell cycles of common human cells are tightly
improve current methods for early detection and/or controlled and coordinated by intra-and extracellular
diagnosis of PCa and to distinguish men at risk for signals, working in harmony and congruence to
carcinogenesis. Screening can detect disease in its appropriately regulate cell proliferation, deterioration
[5]
early or asymptomatic stage; in addition, screening and apoptosis. As the combined signals of growth
tests of malignant tumors must have high sensitivity to and inhibition boost proliferation, the cell attains
detect the disease with sufficient specificity to protect mitosis. Insulin-like growth factors (IGFs) are
[11]
patients with false-positive results from uncalled-for important moderators of growth, development,
diagnostic interventions. [6] and survival. They are synthesized by virtually any
bodily tissue, and their action is accomplished by a
A single polypeptide, prostate specific antigen (PSA), network of complex molecules, including binding
exists in diverse molecular forms. It occurs in either proteins, proteases and receptors, which all comprise
normal or malignant prostatic tissue. About 70-90% of the IGF system. [12] IGF-1 and IGF binding protein-3
serum PSA combines with serum protein inhibitor, alpha (IGFBP-3) play a pivotal function in the regulation of
1 antichymotrypsin, and the rest remains unbound in growth; controlling cellular proliferation and apoptosis.
free form (fPSA). Measurements of total and free/total Circulating IGF-1 binds to the IGF-1 receptor and
PSA ratio are common analyses in diagnosing PCa. acts as a stimulus of signal transduction reactions,
The lower the f/tPSA ratio, the higher the likelihood promoting proliferation and increased survival of
of malignancy. The protocol for PCa screening may cells. Such signalling components and reactions are
involve PSA analysis and digital rectal examination. fundamental to the tumorigenesis processes. The
[13]
Trans-rectal ultrasonography has been associated IGFBPs family exists in six different types; all with
with an increased false positive rate, making it not high affinity for IGF-1. IGFBP-3 is the superabundant
ideal screening tool. It has been recommended that, type that influences serum levels of IGFs and has
starting at age 50 years, a routine check-up with PSA the highest affinity to IGF-1. Although IGFBPs are
[11]
analysis and digital rectal examination be carried out mainly synthesized in the liver, they can be expressed
annually for men at high risk. Single polypeptide PSA in many other normal and cancerous tissues such
is expressed in normal, benign and malignant prostatic as lung, breast, and ovarian cancers. IGFBPs may
tissues but not in any other human tissue. Although impact carcinogenesis by various mechanisms. They
[7]
the introduction of PSA related PCa screening and PSA regulate bioavailability of circulating IGF-1/2 as well
has become the best and most valuable biomarker as their activity and transportation mechanisms to
for screening, detection, staging and monitoring of target tissues. In many types of cancers, IGF-1 and
[14]
PCa; there are challenges. For example, elevated IGFBP-3 have been related to tumor grade and stage
levels of PSA can reflect the presence of malignant as well as disease progression. Most circulating
[15]
cells but can also be related to non-malignant prostate IGF-1 (99%) is bound to IGFBPs; less than 1% is
disorders like benign prostatic hyperplasia (BPH), carried in the unbound state in the circulation. IGFBP-3
infection or chronic inflammations. Increased serum is the most abundant IGFBP in the circulation and is
[8]
PSA levels have been seen in patients with PCa, as produced by many types of cells, and is believed to
well as in BPH and prostatitis, producing a high rate regulate the availability of IGF-1 by impairing IGF
[16]
of false-positive cases. There also remains a wide action and inhibiting cell growth by blocking free
overlap between PCa and BPH, particularly in patients IGFs or through IGF-independent mechanisms.
[17]
with marginally increased PSA concentrations, in the Moreover, IGFBP-3 has been found to elevate levels
range of 4-10 ng/mL, a range which is said to be a of the cell-cycle inhibitor p21/WAF1, leading to growth
“grey zone” where there is a dilemma in differentiation arrest in PCa cells. Many studies have shown the
[18]
between benign and malignant prostatic diseases; correlation between IGF-1 and PCa risk, and they have
this dilemma has strengthened the necessity to demonstrated the inclusion of the IGF network in the
improve PCa specificity by developing, combining early stages of prostate carcinogenesis and other
[19]
and validating other diagnostic biomarkers with studies have found increased circulating IGF-1 and
consideration of the sensitivity. Consequently, the decreased IGFBP-3 levels correlated with an excess
[9]
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ May 24, 2017 83