Importance of Biomarkers in Predicting Prostate Cancer Recurrence

Introduction:

The prostate gland is the largest accessory gland of the male reproductive system. This wall-nut-shaped gland is situated at the base of the urinary bladder. The primary function of the prostate gland is to secrete proteolytic enzymes. These enzymes help in breaking down the factors responsible for coagulation of semen. This maintains the fluidic state of the semen and helps in its movement. The cancerous growth of the epithelial cells of the prostate gland is known as prostate cancer. This is one of the most common cancers seen in men. It is the fifth leading cause of death among men in the world. Traditional treatment options like surgery, radiation therapy, and chemotherapy can be used for the treatment of such cases. But in 40 percent of cases, recurrence of prostate cancer can be seen. Different biomarkers can be used for predicting the recurrence of prostate cancer.

What Is Prostate Cancer?

The cancerous growth of the prostate gland usually arises from the peripheral zone and spreads quickly to the periphery due to its proximity to the neurovascular bundle. Epithelial to mesenchymal transition is considered the main factor behind the formation of prostate cancer. This transition leads to stem-cell-like phenotypic changes in cancer cells. The proliferation of cancer cells is aided by this change. Circulating tumor cells and disseminated tumor cells can be identified through this type of transition. On the other hand, metastatic stem cells colonizing in other areas show mesenchymal to epithelial transition. The commonest type of prostate cancer is adenocarcinoma of the prostate (cancer arising from glands). Small cell carcinoma, neuroendocrine tumors, transitional cell carcinoma, and sarcoma are other types of prostate cancers.

1. Etiology of Prostate Cancer:

The etiological factors associated with prostate cancer are:

• Genetics is one of the most common causes of prostate cancer. Genetic mutation is related to genes like BRCA, RNASEL, HOXB13, and ATM genes.

• Increased age is another risk factor. This type of carcinoma is mainly seen in men who are older than 40 years. Familial history is another important etiological factor related to prostate cancer. The incidence of prostate cancer in fathers and brothers increases the risk factor of prostate cancer by sixfold.

• The androgen receptors bind to testosterone and dihydrotestosterone (DHT), which leads to the supply of secretory proteins to the prostate gland, such as prostate-specific antigen (PSA). Also, the transcriptional activity of the androgen receptors is maintained by these hormones. The activation of androgen receptors leads to the growth and proliferation of prostate epithelial cells. Androgens play a pivotal role in the activation of androgen receptors.

• Infection conditions are also related to the increased incidence of prostate cancer. Infection caused by the human papillomavirus (HPV) is linked to an increased risk of prostate cancer.

• A higher incidence of prostate cancer is seen in black people of African descent. The severity of disease and mortality is high in those individuals.

• Excessive smoking, alcoholism, and obesity are also considered etiological factors for prostate cancer.

Symptoms:

The symptoms of prostate cancer are:

• Increased frequency of urination.

• Urine flow is weak, and it's hard to maintain a steady urinary flow rate.

• Presence of blood in the urine.

• Pain in the lower back region.

• Pain and burning sensation during urination.

• The prostate gland becomes swollen up, hard, and irregular on palpation. The prostate gland is usually palpated through digital rectal examination.

• Unexplained weight loss, pain in the low back region, and tiredness can also be found.

• A high level of prostate-specific antigen is linked to the hyperactivity of the prostate cells and prostate cancer.

What Are the Mechanisms of Prostate Cancer Recurrence?

The cancer cell which spreads toward various parts of the body through metastasis is known as disseminated cells. Most of the disseminated cells die due to the defense mechanism of the body and because of shear stress in circulation. But certain cells overcome this defense mechanism and lodged in the target organs. Different external and internal factors are responsible for the transformation of these cells from dormant states to cancerous cells. This causes a recurrence of prostate cancer. The recurrence can be local or distant sites like bones, muscles, and lymph nodes. The factors associated with recurrence are:

1. Mesenchymal to Epithelial Transition: This type of change leads to morphological and functional changes in cellular characteristics. Changes observed in cellular characteristics are cell polarity, cell motility, cell-to-cell contact, and cellular organization.
2. Reactivation of Androgen Signaling: It is established that increased levels of androgen receptors and their co-activators are associated with recurrent disease. In such cases, amplification and mutation of the androgen receptor gene can be seen.
3. Loss of Metastasis Suppressor Genes: Genes like KAI1, RKIP, and NDRG1 help to prevent the metastasis of prostate cancer and maintain its dormancy. These genes maintain the cell cycle of the metastatic cell. Suppression of these genes leads to the activation of cancerous cells. The involvement of p38 is also important and is associated with the arrest of cell growth.

What Are the Roles of Biomarkers of Prostate Cancer Recurrence?

The biomarkers that are associated with the recurrence of prostate cancer are:

1. Prostate-Specific Antigen: This is the most widely used diagnostic marker for prostate cancer. The quantification of prostate-specific antigen level (PSA) in predicting prostate cancer is known as biochemical recurrence. PSA values of more than 4 nanograms per milliliter are associated with the recurrence of prostate cancer. Tests based on prostate-specific antigens, such as the prostate health index and the 4Kscore, can be useful in predicting the malignancy presence. These tests analyze factors like total PSA, free PSA, and precursor PSA.

2. Circulating Tumor Cells: This is one of the important biomarkers for the detection of prostate cancer cells. FDA-approved Veridex Cell Search platform identifies EPCAM-positive and CD45-negative cancer cells. The value of the circulating tumor cells determines the prognosis of prostate cancer treatment and overall survival rate. Also, the number of circulating tumor cells is correlated with the amount of PSA level.

3. Inflammatory Proteins as Biomarkers: Recurrence of the prostate cancer is associated with inflammation or generation of proinflammatory cytokines. Factors like IL-8, TNF-α, and MCP-1 are elevated in recurrent cases of prostate cancers.

Conclusion:

Prostate cancer is one of the most commonest cancers seen in men. It is one of the leading causes of death among men. But the recurrence of prostate cancer is seen in almost one-third of cases. Prediction of recurrence can be done through the assessment of biomarkers like prostate-specific antigen.