Prostate Cancer (PCa) is the most commonly diagnosed non-cutaneous
cancer in males and the fifth leading cause of death worldwide. The majority of PCas are
androgen-sensitive, with a significant up-regulation of
Androgen Receptor (AR) that causes a stimulatory effect on growth and progression of
cancer cells. For this reason, the first-line
therapy for PCa is
androgen ablation, even if it ultimately fails due to the onset of
hormone-refractory state, in which the malignant cells do not sense the
androgen signal anymore. Besides
androgens, a growing number of evidence suggests that
Thyroid Hormones (THs) mediate
tumor-promoting effects in a variety of human
cancers, as Epithelial-to-Mesenchymal Transition (EMT), invasion and
metastasis and also stimulation of angiogenesis and
tumor metabolism. Moreover, epidemiological studies demonstrated an increased risk for PCa in patients with lower levels of
Thyreotropin (TSH). Here, we investigated if intracellular TH metabolism affects
Benign Prostatic Hyperplasia (BPH) and PCa formation and progression. We found that the intracellular TH metabolism is a crucial determinant of PCa behavior. We observed that a dynamic stage-specific expression of the THs modulating
enzymes, the deiodinases, is required for the progression of BPH to PCa
malignancy. By acting simultaneously on epithelial
cancer cells and fibroblasts, THs exert a proliferative and pro-inflammatory effect cooperating with
androgens. These findings suggest that
androgens and THs may interplay and mediate a coordinate effect on human PCa formation and progression. In light of our results, future perspective could be to explore the potential benefits of THs intracellular modulators aimed to counteract PCa progression.