Smoking behavior is associated with increased tumor-associated neurogenesis in prostate cancer

Tumor-associated neurogenesis is being increasingly recognized as a contributor to cancer progression and therapeutic resistance. While tobacco smoking is known to influence inflammation and microvascular remodeling, its relationship with tumor neurobiology remains poorly understood. In this study, we investigated whether smoking behavior is associated with alterations in nerve density within the prostate cancer microenvironment. Prostatectomy specimens from prostate cancer patients with documented smoking history were selected (n=53), and smoking status was categorized as never (n=24), former (n=18), or current (n=11) smoker. The tumor tissues were sectioned and subjected to immunohistochemistry for S100B (Schwann cells) and TUBB3 (neuronal axons). Nerve density was quantified by measuring the number of neural clusters in five random fields, and an average value was calculated for each tumor. The difference in nerve density was compared between current, former, and never smokers using Kruskal-Wallis non-parametric test. Current smokers and former smokers exhibited significantly higher (p < 0.001) intratumoral nerve density compared to never-smokers. However, the difference was not significant (p=0.268) between current smokers and former smokers. In grade-wise comparisons, a significant difference (p < 0.001) between never smokers and current /former smokers was observed in low/medium (Gleason's score ≤7) grade tumors but not in high-grade tumors (Gleason's score >7). Interestingly, nerve mini-bundles at tumor edges were also more frequent in current smokers than in never smokers or former smokers. Altogether, our data demonstrate that the smoking behavior is associated with enhanced neural remodeling in prostate cancer, characterized by increased nerve density and Schwann cell/axon clustering at tumor margins. These findings suggest that host exposure to tobacco smoke promotes a neurotrophic tumor microenvironment, which may be linked to prostate cancer aggressiveness and a higher risk of recurrence.