Molecular diagnosis of prostate cancer

The history of biomarker diagnostics of prostate cancer (PCa) is three quarters of a century. In his studies, A.B. Gutman et al. (1938) noted a significant increase in the activity of serum acid phosphatase in men with PCa metastases. Later, a more accurate method for determining 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 by metastatic prostate cancer and only 10-30% - localized), this biological marker for almost half a century was the main one in the "arsenal" of the urologist.

M.S. Wong et al (1979) described a protein specific for the prostate gland and subsequently called a prostate-specific antigen (PSA). They have been shown that PSA, is characterized exclusively by the prostatic localization, and its level has been elevated in both benign hyperplasia and prostate cancer. The introduction of screening programs using PSA has yielded positive results: the detection rate of the disease has increased by 82%, the specific mortality has decreased from 8.9 to 4.9%, and the emergence of distant metastases - from 27.3 to 13.4%.

The incompleteness of the method for determining the level of PSA is associated with its low specificity, a large number of false negative results with a 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, which play an important role in Ca + -dependent intercellular adhesion. It is known that the loss of intercellular "bridges" and the connection with neighboring epithelial cells is one of the first stages of tumor development. The decrease in E-cadherin expression, which is often observed in prostate cancer, correlates with the survival, clinical and morphological stage of the disease.

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

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

As shown by numerous studies, the main enzymes produced by the tumor and destroying the components of the intercellular matrix are type IV collagenase (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]

The genes p53 and p6S

The p53 gene, localized in the nucleus of the cell, is considered a suppressor of tumor growth. It prevents the entry of a cell from the damaged DNA into the synthetic phase of the fission cycle and induces apoptosis. Loss of normally functioning p53 leads to uncontrolled cell division. The p5S gene is the functional homologue of p53. Its products are peculiar only to the basal layer of the epithelium of the prostate gland, in the formation of which it plays an important role. In prostate cancer, the expression of pB3 is significantly reduced, which is found in immunohistochemical studies.

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 fission cycle. Mutations of genes encoding p21 (CDKN1A) and p27 (CDKN1B) are detected with prostate cancer frequently enough, indicating a poor prognosis of the disease.

Telomerase

The overwhelming majority of human cells have a programmed number of divisions, after which they are apoptotic or go to the G0 phase of the cell cycle. The "counters" of cell divisions are telomeres - terminal chromosome sections containing repeated short nucleotide patches (TTAGGG). With each division of the cell, the telomeres shorten. However, telomeres can also be completed with the help of ribonucleoprotein telomerase. There is a relationship between the activity of telomerase, the degree of differentiation of adenocarcinoma on the Gleason scale and local aggressiveness of the tumor. Currently actively exploring the possibility of creating telomerase inhibitors for the treatment of prostate cancer.

DDZ / RSAS

It is believed that this gene affects the development and differentiation of tissues, but its function has not been established to date. Expression of the gene in the prostate adenocarcinoma tissue is a highly specific indicator. For various types of pathology of the gland, the excess of its normal content is noted up to 34 times. Minor expression of DDZ / RSAZ is noted only in the kidney tissue. To date, a method for estimating the expression of DD3 / RSAZ, determined in urine, has been developed. Its sensitivity is 82%, the specificity is 76%, the prognostic significance of the negative and positive results is 67% and 87%, respectively (the corresponding values for PSA are 98, 5, 40 and 83%).

[17], [18], [19],

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

Ki-67 and PCNA are detected in immunohistochemical studies in the nuclei of cells 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 cellular population. Studies have shown that Кi-67 and РСNА allow to differentiate with high accuracy prostatic and intraepithelial neoplasia of II-III degree and adenocarcinoma. Correlation of this indicator with Gleason scale data, stage of PCa and PSA level was found, however, with respect to its prognostic significance, the data are inconsistent. At present, there is no conclusive evidence of the effectiveness of detection of Ki-67 and PCNA for assessing the risk of local invasion, metastasis, or biochemical recurrence after radical prostatectomy.

CD44

The mechanisms underlying the formation of bone metastases of prostate cancer have so far been little studied. It is suggested that adenocarcinoma cells for permeation through the endothelium of bone marrow vessels use the same mechanisms as lymphocytes and circulating progenitor cells. 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 cases of prostatic adenocarcinoma, which correlates with the frequency of metastasis,

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

α-Methylacyl-CoA-racemase (AMACR)

Racemaz is referred to enzymes that catalyze the transition of branching fatty acids from R- to S-stereoisomers. When peroxisome oxidases are activated, free radical processes are strengthened and the DNA of the cell is damaged. Determination of the activity of α-methylacyl-CoA racemase in immunohistochemical studies allows differentiation of cancer from other processes and more accurately determine the stage of the disease (including in the study of biopsy specimens).