Nintedanib treatment delays prostate dorsolateral lobe cancer progression in the TRAMP model: contribution to the epithelial-stromal interaction balance.

Prostate cancer (PCa) progression mechanism has been linked to epithelial proliferation, tumor invasion ability, and growth factors. Nintedanib (BIBF 1120) has been reported as being FGF and VEGF pathway inhibitors, exhibiting antitumor activity. Thus, the objective herein was to characterize the early Nintedanib treatment effects on the structure and molecules involved in the basal membrane, the extracellular matrix (ECM) maintenance, in addition to the angiogenesis and mitogenic processes at different grades of prostatic tumor development in TRAMP mice. Therefore, 45 male TRAMP mice were divided into control groups: 8-week-old mice (TC8), 12-week-old mice (TC12), and 16-week-old mice (TC16); and treated groups with 10 mg/kg/day Nintedanib dose for 4 weeks. The treated groups were euthanized at 12 (TN12) and 16 (TN16) weeks of age. Samples from the dorsolateral lobe were collected and processed for light microscopy, immunohistochemistry, Western blotting, and microvessel density analysis. The results showed that early Nintedanib treatment led to an increase of healthy epithelium frequency and a reduction of LGPIN and a maximum vascularization density in the TN12 group. Also, treatment led to a well-differentiated adenocarcinoma decrease and an α and ß dystroglycan and also laminin 1 increase in the TN16 group. IGFR1 decreased in the TN16 group. To conclude, early Nintedanib treatment led to a reduction in cancer severity, interfering in both ECM compounds and angiogenesis process to then contribute to a balance, not only in the prostatic epithelium and stroma, but also in the epithelial-stromal interaction during PCa progression.

Nintedanib antiangiogenic inhibitor effectiveness in delaying adenocarcinoma progression in Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP).

BACKGROUND: In recent times, anti-cancer treatments have focused on Fibroblast Growth Factor (FGF) and Vascular-Endothelial Growth Factor (VEGF) pathway inhibitors so as to target tumor angiogenesis and cellular proliferation. One such drug is Nintedanib; the present study evaluated the effectiveness of Nintedanib treatment against in vitro proliferation of human prostate cancer (PCa) cell lines, and growth and progression of different grades of PCa lesions in pre-clinical PCa transgenic adenocarcinoma for the mouse prostate (TRAMP) model. METHODS: Both androgen-independent (LNCaP) and androgen-dependent (PC3) PCa cell lines were treated with a range of Nintedanib doses for 72 h, and effect on cell growth and expression of angiogenesis associated VEGF receptors was analyzed. In pre-clinical efficacy evaluation, male TRAMP mice starting at 8 and 12 weeks of age were orally-fed with vehicle control (10% Tween 20) or Nintedanib (10 mg/Kg/day in vehicle control) for 4 weeks, and sacrificed immediately after 4 weeks of drug treatment or sacrificed 6-10 weeks after stopping drug treatments. At the end of treatment schedule, mice were sacrificed and ventral lobe of prostate was excised along with essential metabolic organ liver, and subjected to histopathological and extensive molecular evaluations. RESULTS: The total cell number decreased by 56-80% in LNCaP and 45-93% in PC3 cells after 72 h of Nintedanib treatment at 2.5-25 µM concentrations. In pre-clinical TRAMP studies, Nintedanib led to a delay in tumor progression in all treatment groups; the effect was more pronounced when treatment was given at the beginning of the glandular lesion development and continued till study end. A decreased microvessel density and VEGF immunolocalization was observed, besides decreased expression of Androgen Receptor (AR), VEGFR-1 and FGFR-3 in some of the treated groups. No changes were observed in the histological liver analysis. CONCLUSIONS: Nintedanib treatment was able to significantly decrease the growth of PCa cell lines and also delay growth and progression of PCa lesions to higher grades of malignancy (without inducing any hepatotoxic effects) in TRAMP mice. Furthermore, it was observed that Nintedanib intervention is more effective when administered during the early stages of neoplastic development, although the drug is capable of reducing cell proliferation even after treatment interruption.