Molecular diagnosis of prostate cancer

The history of biomarker diagnostics of prostate cancer (PC) spans three quarters of a century. In their studies, A.B. Gutman et al. (1938) noted a significant increase in the activity of acid phosphatase in the blood serum of men with metastases of PC. Later, a more accurate method for determining the prostate-specific subfraction of acid phosphatase (PAP) was developed. Despite the low sensitivity and specificity (an increase in PAP in 70-80% of cases accompanied metastatic prostate cancer and only in 10-30% - localized), this biological marker was the main one in the urologist's "arsenal" for almost half a century.

M.S. Wong et al. (1979) described a protein specific to the prostate gland and subsequently named prostate-specific antigen (PSA). They demonstrated that PSA is exclusively localized to the prostate, and its level was elevated in both benign hyperplasia and prostate cancer. The introduction of screening programs using PSA yielded positive results: the frequency of disease detection increased by 82%, specific mortality decreased from 8.9 to 4.9%, and the occurrence of distant metastases decreased from 27.3 to 13.4%.

The imperfection of the method for determining the PSA level is due to its low specificity, a large number of false negative results at the lower threshold value (4 ng/ml). Currently, many other markers of prostate cancer have been discovered.

[ 1 ], [ 2 ], [ 3 ], [ 4 ]

E-cadherins

Cadherins are membrane glycoproteins that play an important role in Ca+-dependent intercellular adhesion. It is known that the loss of intercellular "bridges" and connections with neighboring epithelial cells is one of the first stages of tumor development. Reduced E-cadherin expression, often observed in prostate cancer, correlates with survival, clinical and morphological stage of the disease.

[ 5 ], [ 6 ], [ 7 ], [ 8 ], [ 9 ], [ 10 ]

Collagenase type IV (MMP-2 and MMP-9)

As numerous studies have shown, the main enzymes produced by the tumor and destroying components of the intercellular matrix are collagenases type IV (metalloproteinase-2, -9; MMP-2 and MMP-9). In this regard, it is believed that the degree of increase in collagenase production reflects the aggressiveness of the tumor and its ability to further local spread.

[ 11 ], [ 12 ], [ 13 ], [ 14 ], [ 15 ], [ 16 ]

Genes p53 and p63

The p53 gene, localized in the cell nucleus, is considered a tumor growth suppressor. It prevents cells with damaged DNA from entering the synthetic phase of the division cycle and induces apoptosis. The loss of normally functioning p53 leads to uncontrolled cell division. The p63 gene is a functional homologue of p53. Its production is characteristic exclusively of the basal layer of the prostate epithelium, in the formation of which it plays an important role. In prostate cancer, p63 expression is significantly reduced, which is detected by immunohistochemical examination.

P21Cip1 and p27Kip1

Proteins p21Cip1 and p27Kip1 are tumor suppressors that inhibit all types of cyclin-dependent kinase (CDK) and prevent the cell from entering the next phase of the division cycle. Mutations in the genes encoding p21 (CDKN1A) and p27 (CDKN1B) are found quite often in prostate cancer, indicating a poor prognosis for the disease.

Telomerase

The vast majority of human cells have a programmed number of divisions, after which they undergo apoptosis or enter the G0 phase of the cell cycle. Telomeres, the end sections of chromosomes containing repeating short nucleotide sections (TTAGGG), are considered to be the "counter" of cell divisions. Telomeres are shortened with each cell division. However, telomeres can also be extended with the help of the ribonucleoprotein telomerase. There is a relationship between telomerase activity, the degree of adenocarcinoma differentiation according to the Gleason scale, and the local aggressiveness of the tumor. Currently, the possibility of creating telomerase inhibitors for the treatment of prostate cancer is being actively studied.

DDZ/RSAZ

It is assumed that this gene affects the development and differentiation of tissues, but its function has not yet been reliably established. Gene expression in prostate adenocarcinoma tissue is a highly specific indicator. In various types of gland pathology, its normal content is exceeded by up to 34 times. Insignificant expression of DD3/PC3A is noted only in renal tissue. To date, a method for assessing the expression of DD3/PC3A determined in urine has been developed. Its sensitivity is 82%, specificity is 76%, the prognostic significance of negative and positive results is 67 and 87%, respectively (the corresponding indicators for PSA are 98, 5, 40 and 83%).

[ 17 ], [ 18 ], [ 19 ]

Ki-67 (MIB-1) and PCNA (proliferating cell nuclear antigen)

Ki-67 and PCNA are detected in cell nuclei during immunohistochemical examination in any active phase of the cell cycle (G1, S, G2, M), but they are absent in the G0 phase, which allows them to be used as effective markers of cell proliferation and determination of the growth fraction of the cell population. Studies have shown that Ki-67 and PCNA allow for high-accuracy differentiation of prostatic and intraepithelial neoplasia grade II-III and adenocarcinoma. A correlation was found between this indicator and the Gleason score, PCa stage, and PSA level, but the data regarding its prognostic significance are contradictory. Currently, there is no convincing evidence of the effectiveness of Ki-67 and PCNA detection for assessing the risk of local invasion, metastasis, or biochemical recurrence after radical prostatectomy.

CD44

The mechanisms underlying the formation of bone metastases from prostate cancer are still poorly understood. It is assumed that adenocarcinoma cells use the same mechanisms as lymphocytes and circulating progenitor cells to penetrate the endothelium of bone marrow vessels. One of the necessary conditions for adhesion to the endothelium and extravasation is the presence of the CD44 receptor on the cell surface. CD44 expression is found in 77.8% of prostate adenocarcinoma cases, which correlates with the frequency of metastasis,

[ 20 ], [ 21 ], [ 22 ], [ 23 ]

α-Methyl acyl-CoA racemase (AMACR)

Racemase is an enzyme that catalyzes the transition of branching fatty acids from R- to S-stereoisomers. When peroxisomal oxidases act on them, free radical processes are enhanced and cell DNA is damaged. Determination of the activity of α-methylacyl-CoA racemase in immunohistochemical studies allows us to differentiate cancer from other processes and more accurately determine the stage of the disease (including when examining biopsies).