Understanding Prostate Cancer: The Roles of Chronic Inflammation, Diagnostic Biomarkers, and Lifestyle Modifications

Prostate cancer (PCa) continues to stand as a formidable adversary in the world of oncology. As the second most common cancer among men globally and the fifth leading cause of cancer-related deaths, it exerts an alarming toll. In 2020, over 1.4 million new cases were diagnosed, with the heaviest burdens seen in Europe, Asia, and North America. Mortality from PCa, exceeding 350,000 annually, presents an equally concerning pattern, with the highest death rates observed in Asia, Europe, and parts of Latin America. In Portugal alone, PCa represents 20% of newly diagnosed cancer cases, contributing to 10.5% of all cancer-related deaths. Despite these grim statistics, PCa patients generally face an encouraging prognosis, especially when the disease is detected early.

Unraveling the Etiology: Age and Beyond

One of the most significant factors influencing the risk of PCa is age. As men age, their likelihood of developing PCa rises sharply, particularly after age 50. This increased risk is often attributed to chronic inflammation associated with aging, which plays a pivotal role in the development of various cancers, including PCa. This type of inflammation is estimated to be a contributing factor in about 20% of all human cancers.

However, age is just one piece of the puzzle. Other risk factors have been identified, including family history and genetic predispositions. Mutations and alterations in genes such as insulin-like growth factor 1 (IGF-1) have been implicated, further increasing susceptibility to the disease. Racial and ethnic background also play a critical role, with men of black ethnicity showing a higher risk for developing PCa.

In contrast, lifestyle choices can exert a protective effect. Diet and physical activity, in particular, have emerged as key modifiers of cancer risk. Studies consistently show that men who adhere to a Mediterranean diet, rich in fruits, vegetables, and healthy fats, have a lower risk of PCa. Regular physical activity further contributes to this protective effect, improving not only survival rates but also reducing the likelihood of disease progression.

Lifestyle and Cancer Progression: The Double-Edged Sword

While a healthy lifestyle appears to mitigate PCa risk, unhealthy habits contribute to its progression and severity. Obesity is a well-documented risk factor for advanced PCa, with larger waist circumferences and higher body mass indices (BMIs) correlating strongly with more aggressive forms of the disease. Additionally, smoking, alcohol consumption, and even the frequent intake of dairy products high in calcium have all been associated with elevated risks of PCa progression.

Interestingly, medications commonly used to manage other health conditions—such as 5-alpha reductase inhibitors, NSAIDs, and statins—have been found to offer some degree of protection against PCa progression. These medications, though primarily used to manage conditions like benign prostatic hyperplasia (BPH), inflammation, and cholesterol levels, may reduce PCa severity by modulating the same pathways involved in tumor development.

The Role of Inflammation in Prostate Cancer Development

Inflammation, a key factor in numerous chronic diseases, is closely associated with prostate cancer (PCa) development. As men age, inflammation becomes more common in prostate tissue, fostering conditions that support tumorigenesis. Chronic prostatitis, marked by persistent inflammation in the prostate, frequently appears in men who later develop PCa. This ongoing inflammation likely contributes to cellular damage, thereby setting a foundation for malignancy.

The inflammatory process in PCa development is influenced by complex interactions of genetic and environmental factors. For example, elevated serum levels of IGF-1 are known not only to heighten inflammation but also to stimulate cellular proliferation, which accelerates PCa progression.

Chronic inflammation itself has gained recognition as a significant risk factor for PCa, potentially arising from infections, diet, hormonal shifts, or physical injury. Once established, chronic inflammation promotes cancer by driving cell proliferation, immune evasion, tissue remodeling, angiogenesis, and resistance to therapies. In prostate carcinogenesis, proliferative inflammatory atrophy (PIA) serves as an early indicator, often progressing to prostatic intraepithelial neoplasia (PIN) and eventually PCa. Chemokines and cytokines play a central role in this process, either advancing or suppressing cancer depending on specific contexts. Inflammatory markers such as CX3CL1, IL-10, and PDGF-BB have demonstrated associations with PCa and may serve as potential biomarkers for more refined disease understanding.

These interwoven pathways between inflammation and cancer highlight the critical need for early detection and intervention.

Traditional Diagnostic Approaches: The PSA Paradigm

The advent of prostate-specific antigen (PSA) screening in the late 20th century transformed the landscape of PCa diagnosis. PSA, a protein produced by the prostate, is an essential component of semen that plays a crucial role in fertility. Elevated levels of PSA in the blood, however, are often indicative of PCa, prompting further investigation. While PSA screening has led to a marked increase in PCa diagnoses, its use remains contentious due to the risk of overdiagnosis and overtreatment.

Many men diagnosed with PCa through PSA screening may never develop symptoms, yet they are subjected to invasive treatments that carry significant risks, such as sexual dysfunction, urinary incontinence, and bowel complications. To address these concerns, healthcare providers have refined their screening strategies, incorporating factors such as patient age, family history, and ethnicity into their decision-making process. For men with PSA levels below 2.5 ng/mL, screening intervals can be extended to every two years, while annual screenings are recommended for those with levels of 2.5 ng/mL or higher.

Digital Rectal Examination: An Adjunctive Tool

In addition to PSA screening, digital rectal examination (DRE) remains a valuable diagnostic tool in detecting PCa. By palpating the prostate through the rectal wall, clinicians can detect abnormalities that may warrant further investigation. Although DRE is often performed in conjunction with PSA screening, it is prone to false positives, which can lead to unnecessary biopsies and overdiagnosis.

Combining PSA screening with DRE, along with a thorough patient history, helps mitigate the risk of unnecessary procedures and improves the overall accuracy of PCa diagnosis. While neither test is perfect, their combined use offers a more comprehensive approach to detecting PCa in its early stages.

Advances in Imaging: The Emergence of MRI and TRUS

In recent years, imaging techniques have made significant strides in enhancing PCa diagnostics. Magnetic resonance imaging (MRI), particularly when combined with transrectal ultrasound (TRUS), has emerged as a powerful tool for detecting clinically significant tumors. This fusion-guided biopsy method offers improved accuracy, especially in patients with previous negative biopsies, reducing the risk of overtreatment.

Multiparametric prostate MRI (mp-MRI) has also garnered attention as a promising modality in PCa diagnostics. This technique allows for the differentiation between significant and insignificant tumors, helping to prevent the overdiagnosis of indolent cancers. While mp-MRI holds great potential, the lack of a standardized reporting system remains a challenge, leading to variability in interpretation.

Nevertheless, integrating MRI and TRUS into the diagnostic pathway offers a significant advantage. According to guidelines from the European Association of Urology, mp-MRI can be used either to guide targeted biopsies or as a triage test prior to biopsy, helping to reduce unnecessary procedures while improving the detection of high-grade cancers.

Molecular Biomarkers: miRNAs and PSMA as Diagnostic Breakthroughs

The identification of molecular biomarkers such as microRNAs (miRNAs) and Prostate-Specific Membrane Antigen (PSMA) represents a major breakthrough in the early detection and monitoring of PCa. miRNAs, which regulate gene expression by binding to messenger RNA (mRNA), play a crucial role in tumorigenesis. These molecules can be detected in prostate tissue as well as in bodily fluids such as serum, plasma, urine, and seminal fluid, offering a non-invasive method for PCa diagnosis. The ability to measure circulating miRNAs could revolutionize the diagnostic process, reducing the need for invasive biopsies.

PSMA, a transmembrane protein found on the surface of prostate cells, has become an increasingly important target for both imaging and therapeutic purposes. When PCa cells become malignant, PSMA is translocated to the surface of the prostate ducts, where it binds ligands, facilitating tumor growth. The increased expression of PSMA in metastatic PCa makes it an ideal target for diagnostic imaging, allowing clinicians to detect cancerous lesions with unprecedented accuracy.

Imaging techniques that target PSMA, such as those using fluorine-18 or 68Gallium-labeled compounds, have already demonstrated superior detection rates compared to traditional imaging modalities, particularly for low-volume lesions. These advances offer new hope for improving early detection and tailoring treatment strategies for PCa patients.

Impact of Lifestyle on Prostate Cancer (PCa) Development

The incidence of prostate cancer (PCa) varies across different racial groups, initially leading researchers to consider genetic variations and polymorphisms as primary risk factors. However, studies on Japanese men who emigrated to Western countries revealed that they had a higher incidence of PCa compared to those who remained in Japan. This finding suggests that lifestyle and environmental factors also contribute to PCa development. These factors include dietary habits, physical activity, alcohol consumption, smoking, medication use, and sexual behavior.

Diet, Physical Activity, and PCa Risk

Diet plays a crucial role in PCa risk. The Western diet, characterized by high consumption of red meat, processed foods, sugary beverages, and low intake of fruits and vegetables, is strongly linked to higher PCa incidence and more severe forms of the disease. Studies have shown that red and processed meats increase the risk of PCa and cancer-related mortality. Refined carbohydrates, abundant in highly processed foods, have also been associated with an elevated risk of PCa due to their effect on insulin resistance and insulin-like growth factors (IGFs). Conversely, unprocessed grains, vegetables, and legumes provide protective benefits, potentially slowing PCa progression.

In contrast, the Mediterranean diet (MedDiet) is associated with a significantly lower risk of various cancers, including PCa. The MedDiet emphasizes plant-based foods, olive oil, and moderate consumption of fish and poultry. Its protective effects are attributed to anti-inflammatory and antioxidant components such as omega-3 polyunsaturated fatty acids and lycopene, which have shown to suppress tumor development and progression.

Physical activity (PA) also influences PCa risk. While studies have shown mixed results, there is substantial evidence that regular exercise reduces the risk of PCa development and improves survival outcomes in patients. For instance, men who engaged in brisk walking for three or more hours per week showed a marked reduction in PCa progression. Exercise may also improve treatment outcomes, particularly in patients receiving androgen deprivation therapy (ADT), and may alleviate treatment-related side effects.

Alcohol, Smoking, and Medication Use in PCa Development

The relationship between alcohol consumption and PCa risk is complex. Earlier studies showed no significant association between alcohol intake and PCa, but more recent research has linked heavy drinking to increased PCa risk, especially for aggressive forms of the disease. Alcohol exposure earlier in life has been associated with a higher risk of developing high-grade PCa.

Similarly, the connection between smoking and PCa is contentious. While some studies report no direct association between smoking and PCa incidence, others suggest that smoking increases the risk of more aggressive and advanced stages of PCa. Smoking may also negatively impact treatment outcomes and increase mortality rates in PCa patients.

Various medications have been studied for their potential to prevent PCa. Proton pump inhibitors (PPIs), statins, nonsteroidal anti-inflammatory drugs (NSAIDs), 5-alpha reductase inhibitors (5-AR inhibitors), and alpha-blockers have shown varied effects. Statins, commonly used to manage cholesterol, have demonstrated a chemopreventive effect, reducing the risk of PCa progression and mortality. Similarly, NSAIDs, particularly aspirin, have been associated with a lower risk of PCa due to their anti-inflammatory properties. However, the evidence regarding these medications remains controversial, and further studies are needed to establish their efficacy in PCa prevention.

Novel Biomarkers for Prostate Cancer: Exploring Diagnostic Potential

With the limitations of current prostate-specific antigen (PSA) screening, there is a growing need for more reliable biomarkers that can differentiate between benign and malignant prostate conditions. Potential biomarkers such as the Prostate Health Index (PHI) and PCA3 have shown promise, with PHI combining total PSA, free PSA, and p2PSA to offer better diagnostic accuracy. Additionally, the 4K score, which incorporates a panel of kallikrein proteins, has demonstrated the potential to prevent unnecessary biopsies and predict high-grade PCa with greater precision. Other promising approaches include metabolomic profiling, exosome analysis, and miRNA studies, all of which are being explored for their diagnostic and prognostic value. Biomolecules like miR-21, miR-182, and miR-101 are under investigation for their roles in PCa progression and hypoxia response, offering new insights into the disease’s underlying mechanisms.

The Influence of Lifestyle Factors on Prostate Cancer Biomarkers

Lifestyle factors, particularly diet and metabolic health, are increasingly being linked to PCa risk. Studies suggest that dietary patterns influencing hyperinsulinemia and inflammation may predict PCa risk. For instance, the Empirical Dietary Index for Hyperinsulinemia (EDIH) and the Empirical Dietary Inflammatory Pattern (EDIP) scores have been used to assess diet-related risks, with high EDIH scores correlating with increased PCa risk. Moreover, irisin, a myokine involved in lipid metabolism, has been identified as a potential lifestyle-associated biomarker, with lower serum levels observed in PCa patients. These findings highlight the importance of further investigating lifestyle-related biomarkers to develop preventive strategies for PCa.

Toward Personalized Prostate Cancer Care

As the understanding of prostate cancer continues to evolve, so too does the approach to its diagnosis and management. From traditional PSA screening to advanced imaging techniques and molecular biomarkers, clinicians now have a wealth of tools at their disposal to detect PCa earlier and more accurately. However, the challenge remains in distinguishing between aggressive and indolent cancers, ensuring that patients receive the appropriate level of care without unnecessary interventions.

The integration of lifestyle factors, pharmacological agents, and personalized diagnostics offers a promising path forward in PCa management. By tailoring interventions to individual risk profiles, clinicians can offer more precise and effective treatments, improving patient outcomes and quality of life.

The Future of Prostate Cancer Diagnostics

Looking ahead, the future of PCa diagnostics lies in the continued refinement of molecular biomarkers and imaging technologies. As clinical trials progress and new data emerge, the integration of non-invasive diagnostic tools such as miRNAs and PSMA-targeted imaging will likely become standard practice. These advances hold the potential to revolutionize PCa care, offering earlier detection, improved risk stratification, and more personalized treatment options.

In this rapidly evolving field, collaboration between researchers, clinicians, and patients will be key to unlocking new insights and improving outcomes for men diagnosed with prostate cancer. The journey toward a new era of PCa care has only just begun, but the future holds immense promise for more effective, patient-centered approaches to managing this complex disease.

Study DOI: https://doi.org/10.3390/jcm11102925

Engr. Dex Marco Tiu Guibelondo, B.Sc. Pharm, R.Ph., B.Sc. CpE

Editor-in-Chief, PharmaFEATURES

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