Kowalski, K.; Popeda, M.; Richert, J.; Wenta, R.; Szade, J.; Zaczek, A.; Kryczka, T.; Frankiewicz, M.; Miszewski, K.; Matuszewski, M.; Bednarz-Knoll, N.

Abstract Background and objective: Chronic comorbidities like diabetes mellitus can influence cancer incidence and progression. However, their impact on pathological and molecular tumor characteristics and dissemination, especially in prostate cancer (PCa), is not fully understood. Here, we investigated differences in the PCa molecular landscape with coexisting diabetes type 2 and its link to tumor dissemination. Methods: DAmico intermediate- or high-risk PCa patients (n=145), with type 2 diabetes or no diabetes, were analyzed for clinico-pathological features, circulating tumor cell (CTC) presence, yields and phenotypes in tumor-draining vein (TDVB) and peripheral blood (PB), primary tumor characteristics, and selected plasma biomarkers. Key findings and limitations: Diabetes type 2 was found in 20/13.8% patients and associated with more advanced clinical outcomes, i.e. pathological tumor stage (p=0.011) and lymph node involvement (p=0.020). Among patients diagnosed before age 65, diabetes and PCa showed a borderline association with shorter time-to-biochemical recurrence (p=0.032). Diabetic PCa patients had significantly higher total CTC counts in TDVB but not in PB, indicating enhanced tumor cell dissemination from primary tumor (PT). PTs from diabetic PCa patients displayed a borderline association with higher ALDH1 expression (p=0.054) and significantly lower vascular vessel density (p=0.008). Similarly, in patients under 65, PTs from diabetic PCa patients expressed genes linked to decreased angiogenesis. Plasma analyses revealed elevated GDF15 levels in PB (p<0.001), increased TRAP5 concentrations in TDVB (p=0.001), and reduced osteonectin levels in TDVB (p=0.026) in diabetic PCa patients. The study's limitation is the relatively small cohort, especially those with coexisting diabetes type 2. Conclusion and clinical implications: Diabetes in PCa patients associates with advanced tumor stage, enhanced tumor cell dissemination, impaired vascularization, and distinct circulating biomarker alterations. Vascular alterations from diabetes, with systemic factors, especially in PCa patients under 65, may increase tumor dissemination in PCa. However, exact mechanisms need investigation in larger cohorts of patients.