From the Guidelines
Prostate cancer develops when normal prostate cells undergo genetic mutations that lead to uncontrolled growth and proliferation, with androgen receptor signaling playing a central role in the disease's development and progression. The disease typically begins in the peripheral zone of the prostate gland with abnormal changes in prostate epithelial cells, as noted in the NCCN guidelines insights: prostate cancer, version 1.2021 1. These mutations affect key cellular pathways, including androgen receptor signaling, which is crucial for prostate cancer development. Most prostate cancers are androgen-dependent initially, requiring male hormones like testosterone for growth. Common genetic alterations include PTEN loss, MYC amplification, and TMPRSS2-ERG gene fusions, which occur in approximately 50% of prostate cancers.
Key Pathways and Progression
As the disease progresses, cancer cells may develop androgen independence, allowing them to grow without hormonal stimulation. This castration-resistant state often involves amplification or mutation of the androgen receptor gene. Prostate cancer typically spreads first to regional lymph nodes, then preferentially metastasizes to bone through complex interactions between tumor cells and the bone microenvironment, as discussed in the context of castration-resistant prostate cancer (CRPC) management 1. The disease progression is generally slow, often taking years to develop from precancerous lesions (prostatic intraepithelial neoplasia) to invasive cancer, which explains why it's predominantly diagnosed in older men and why many men die with prostate cancer rather than from it.
Clinical Implications
The understanding of prostate cancer's pathophysiology has significant implications for its management, including the use of androgen deprivation therapy (ADT) for localized and advanced disease, as well as the sequential application of additional systemic therapies for men with CRPC 1. The incorporation of bone-modifying drugs for men with bone metastases and CRPC further highlights the complexity of managing the disease's progression. The central role of androgen receptor signaling in prostate cancer development and progression underscores the importance of therapies targeting this pathway, alongside the consideration of the disease's potential to become castration-resistant and the need for sequential treatment strategies.
From the Research
Pathophysiology of Prostate Cancer
- Prostate cancer is a complex disease that involves the interaction of genetic and environmental factors, including infectious agents and dietary carcinogens, as well as hormonal imbalances 2.
- Chronic inflammation is thought to play a key role in the development and progression of prostate cancer, driving prostate carcinogenesis and neoplastic progression 2.
- Genetic variants in genes involved in signaling innate immune/inflammatory and steroid metabolism pathways may modify the genetic susceptibility to prostate cancer and clinical disease outcome 2.
- Single-nucleotide polymorphisms (SNPs) may operate in combination to create a 'risk profile' for prostate cancer, and combinations of inflammatory and sex steroid hormone pathway SNPs are found in prostate cancer patients 2.
Mechanisms of Prostate Cancer Initiation and Progression
- Prostate cancer is a major health problem, and understanding the mechanisms of its initiation and progression is crucial for the development of novel therapeutic approaches 3.
- Recent studies have identified critical genetic and epigenetic changes that drive prostate cancer initiation and progression, including changes in signaling pathways and molecules 3.
- These discoveries may help concentrate efforts on key pathways and molecules, and translate knowledge from mechanistic studies into effective treatments 3.
Diagnosis and Detection of Prostate Cancer
- Digital rectal examination (DRE) and prostate-specific antigen (PSA) testing are commonly used for the early detection of prostate cancer 4, 5.
- PSA testing is more effective than DRE for detecting prostate cancer, and the combination of both methods provides a more complete evaluation of the prostate gland for malignant involvement 4, 5.
- However, a systematic review and meta-analysis found that DRE has a low diagnostic value for prostate cancer detection, and its use as a screening test may not be necessary 6.