The impact of zinc and testosterone co-treatment on tumourigenesis in prostate cancer: a novel model.

[BACKGROUND] Pre-clinical models play a key role in prostate cancer research, helping to understand the mechanism of the disease. The unavailability of suitable animal models in under-resourced areas, such as in sub-Saharan African (SSA) countries, presents a major barrier for them to contribute meaningfully to developing effective treatments and preventive strategies in this global effort against prostate cancer. This study investigated the use of a combination of high-dose zinc and testosterone to induce carcinogenesis in Wistar rats.

[METHODS] The histopathological assessment of the model prostate was carried out. In addition, the relative gene expression of common genes that are deregulated in prostate cancer such as Tmprss2, Akt1, Pdgfrβ and Tp53 were validated in the model.

[RESULTS] We could show that, intramuscular administration of testosterone alone causes epithelial hyperplasia but did not result in abnormal glandular patterns or patterns associated with prostate carcinoma. However, administration of high dose zinc alone (10-100 mg/kg) resulted in epithelial dysplasia in all prostate lobes and was associated with papillary and tufting patterns of glandular architecture indicative of HGPIN. Moreover, administration of testosterone together with 100 mg/kg zinc resulted in tumour formation, characterized by glands with central necrosis, loss of glandular architecture and occasional presence of luminal cells in stroma. The induction significantly increased Tmprss2 expression by 789.8-fold and Akt1 expression by 2.93-fold compared to the naïve control. Combination treatment also led to a 15.89-fold rise in Pdgfrβ expression. Additionally, Tp53 expression increased 2.23-fold in the group treated with the combination.

[CONCLUSION] In summary, the zinc-testosterone model induced lesions characteristic of HGPIN with the possibility of early microinvasive adenocarcinoma, most importantly in the dorsolateral lobes, mimicking human disease characteristics.