Genetic Mechanisms of Prostate Cancer

^*Correspondence: Jenifer Catherine, Department of Molecular Cell Biology, University of Brasília, Federal District, Brazil, Email:

Keywords

Oncogenes • Malignancy • Genetic alterations • Cancer stem cells

Introduction

With an estimated 1,600,000 new cases and 366,000 deaths every year, prostate cancer is the most often diagnosed non-skin cancer and the second most common reason for cancer-related deaths among males. Prostate cancer remains a major medical concern for afflicted men despite recent advancements. It is imperative to increase the effectiveness of current treatments for metastatic illness and to lessen the overtreatment of more benign disease. A lot of patients with prostate cancer show an aggressive disease with progression and metastases, whereas some patients show an indolent disease with little tendency to advance.

Description

Surgery and radiotherapy are the standard treatments for this cancer; however, patients who cannot undergo radiotherapy or surgery are given androgen ablation therapy, which successfully shrinks androgen-dependent tumours. Unfortunately, androgen-independent prostate cancer that frequently metastasizes returns after this treatment is frequently used. An estimated 1,600,000 cases and 366,000 deaths from prostate cancer occur in males each year, making it the most prevalent noncutaneous cancer in men globally. The overtreatment of an inherently benign condition and the lack of adequate treatments for metastatic prostate cancer mean that prostate cancer remains a substantial medical problem for the affected individuals despite recent advancements. The human prostate is made up of three different cell types: basal cells, which are localised at a lower level and express markers like cytokeratin 5 but only weak levels of androgen receptor and rare neuroendocrine cells. Luminal cells are columnar epithelial cells that express secretory proteins, differentiation antigens like cytokeratin 8 and prostatespecific antigen and high levels of the androgen receptor (characterized by the expression of endocrine markers). Human prostate tumours can be classified into three stages of development: (a) intraepithelial neoplasia, which can be thought of as a precancerous state and is characterised by hyperplasia of luminal cells and progressive loss of basal cells; (b) adenocarcinoma androgendependent (divided into two stages, adenocarcinoma latent and clinical), which is characterised by the complete loss of basal cells and the strong luminal phenotype: the tumour is androgen-dependent at this stage and androgen deprivation can inhibit tumour growth; and (c) An adenocarcinoma that is androgen-independent (also known as castration-resistant) and indicates the progression of the disease without relying on androgens for growth.

The luminal compartment grows as the prostate cancer progresses and basal cells are lost. According to both immunophenotypic and genotypic data, this corresponds to a luminal phenotype. Basal cell and stem cell genes are more prevalent in advanced stages of disease, which are characterised by metastases and castration-resistant prostate cancer. The histological assessment of prostate malignancies, as well as other solid tumours, is crucial for determining the biology, stage of development and prognosis of the tumour. For clinical purposes, the histological assessment of these tumours is expressed in terms of the Gleason score, which is a grading system that assesses how much the bioptic prostatic specimen resembles a normal prostate gland (low score, 1 corresponding to normality) or is honestly tumorigenic (high score, 5 corresponding to a lack of normal glands and the presence of sheets of frankly abnormal tumour cells); between these two extreme grades, there are intermediate grades underlying a progression.

High-grade prostatic intraepithelial neoplasia (HGPIN), which corresponds to a proliferation of prostate glandular epithelial cells demonstrating obvious cytological atypia within the tissue boundaries of prostatic ducts and acini, is a possible precursor lesion of prostate cancer. The epidemiological data linking HGPINs to tumour glands and the later occurrence of invasive carcinoma during tumour surveillance, the morphological similarities between the epithelial cells of HGPINs and invasive cancer, the colocalization of HGPIN with invasive prostate cancer and their shared genetic rearrangements and other genetic alterations are the two main reasons why HGPIN is considered a precursor lesion of prostate cancer.

Regulatory mechanism

As many, genetically diverse foci of the illness are present in primary tumors at the time of diagnosis, prostate cancer is a multifocal disease. In fact, exome sequencing of prostate cancer foci showed that the same prostate contained somatically distinct cancers. This was further supported by more recent research that showed distinct tumour origins by comparing the genomic landscape of related and geographically separated areas within prostates. Up to 80% of men who get a radical prostatectomy for clinically localized prostate cancer are thought to have multifocal disease. Prostatic intraepithelial neoplasia (PIN), localized prostate cancer, advanced prostate adenocarcinoma with local invasion and ultimately metastatic prostate cancer are the many stages of the multistep process that leads to the malignant alteration of the prostate. The most extensively used grading system for determining the aggressiveness of prostate cancer is the Gleason grading system, which was developed by Donald Gleason and was initially based on the histological patterns of prostate adenocarcinoma. The majority of deaths related to prostate cancer are caused by metastatic illness. The liver, lungs and bones are the next most common sites for metastases to form after the lymph nodes close to the initial tumours. Human prostate cancer bone metastases typically manifest as mixed osteolytic and osteoblastic lesions that are extremely painful, hypercalcemic and prone to fractures. Understanding the biology of bone metastasis has received a great deal of attention in an effort to uncover more potent cures for this deadly condition. Prostate cancer metastasis has been linked to epithelial-mesenchymal transition (EMT), which has been suggested to be important. Prostate cancer cells go through EMT, circulate as circulating tumour cells (CTCs) and overcome a number of physical obstacles to establish bone metastasis. They pass through sinusoid walls and bone marrow stroma before moving via sinusoids within the bone marrow cavity to the endosteal bone surface. Mechanistic research intended to comprehend cancer cell dispersion to distant organs have focused on the molecular and phenotypic characterisation of CTCs, an exceedingly rare cell type with significant heterogeneity that may be crucial in metastasis.

Once prostate cancer cells have colonised the bone marrow, they interact with the bone microenvironment to create and destroy bone in a "vicious cycle" that promotes cancer cell survival and tumour growth. Endothelin 1 (ET-1), adrenomedullin, fibroblast growth factors (FGFs), platelet-derived growth factor (PDGF) and bone morphogenetic proteins (BMPs) are growth factors generated by prostate cancer cells that can induce osteoblast activation to create new bone through paracrine signalling. To further encourage osteoblast differentiation from mesenchymal stem cells, tumor-secreted proteases like matrix metalloproteinases, prostate-specific antigen (PSA) and urokinasetype plasminogen activator stimulate the release of osteoblast-inducing growth factors like transforming growth factor (TGF-), insulin-like growth factors and PDGF. The cornerstone for identifying disease subgroups and related therapeutic approaches has been the cataloguing of the genetic factors that contribute to prostate cancer. Numerous extensive genomic investigations have discovered recurrent DNA copy number variations, mutations, rearrangements and gene fusions in both primary prostate cancers and mCRPC. While showing only slightly elevated mutations, primary prostate cancers and mCRPC demonstrate noticeably increased genome-wide copy number changes.

In a large percentage of primary prostate tumours as well as nearly all metastatic prostate cancers, distinctive genetic changes target the DNA repair, PI3K-PTEN, WNT and AR pathways. Translocations involving androgenregulated promoters and the ETS family of transcription factors, including the ERG and the ETV genes, are the most frequent genetic changes in prostate cancer. The formation and operation of the prostate are fundamentally influenced by AR signalling. Most primary and metastatic prostate cancers have genomic changes in the androgen signalling pathway, such as AR amplification/mutations, gain of the AR coactivator NCOA1/2 and loss of the AR corepressor NCOR1/2, which contribute to castration resistance, according to studies using conventional methods and next-generation sequencing (discussed further below). Additionally, one-third of mCRPC tumours had AR genomic structural rearrangements, which led to aberrant expression of numerous AR variant species lacking the ligand-binding domain and persistent activation of AR signalling, including AR variant 7 (AR-V7), which seems to be responsible for disease progression [1-5].

Conclusion

The field is in a position to save and improve the lives of many men with this disease thanks to a deep understanding of prostate cancer biology and genomics, the development of sophisticated profiling technology, the use of artificial intelligence in decision-making systems and the ability to conduct multiple-armed adaptive clinical trials with longitudinal profiling. The creation of efficient mashups of conventional medicines, targeted therapies and immunotherapies faces difficulties: The efficacy, toxicity and tolerability of combination therapies must be determined through optimization of dosing regimens and sequencing and strategies for prioritising various combination therapies must be developed. Comprehensive understanding of the effects of these therapies on the patient's immune system is lacking. However, as this transcription factor may play both tumor-suppressive and oncogenic roles, it is unclear how exactly gene changes contribute to the development of prostate cancer.

References

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