*5.2. Endocrine FGFs*

Endocrine FGFs have two different characteristics, a growth factor and a metabolic regulator. Investigating endocrine FGFs might clarify the molecular link between the progression of cancer and metabolism. Among endocrine FGFs, the association between FGF19 and malignant diseases such as liver cancer, colon cancer, and prostate cancer was demonstrated [56–59]. FGF19 induces the expression of markers of epithelial mesenchymal transition in hormone-sensitive prostate cancer cells [60,61]. Consistent with the results, accumulation of FGF19 in cytoplasm was shown in poorly differentiated prostate cancer cells in human prostate cancer tissues derived from radical prostatectomy, and the presence of FGF19-positive tissues correlated with positive immuno-histochemical staining with N-cadherin in prostate cancer tissues [60]. The bRFS rate in cases with FGF19-positive tissues was significantly lower than in cases with FGF19-negative tissues [60]. In prostate cancer cells, FGF19 stimulates cell proliferation and cell invasion through activation of MAP kinase and AKT pathways [62]. Expression of FGF19 increased in castration-resistant cell lines compared with castration-sensitive ones or immortalized normal prostate cells [62]. According to these reports, FGF19

might be associated with the risk of post-operative recurrence by enhancement of cell proliferation and epithelial-mesenchymal transition of PCa cells.

Since endocrine FGFs that include FGF19 act as circulating hormones related to several metabolic diseases, the impact of their serum concentration for metabolic diseases was investigated. These molecules are expected to be a potential serum biomarker for PCa. We measured serum FGF19 and beta-klotho level in cases with PCa. While there was no relationship between the serum klotho level and pathological findings, the results showed that patients with a high Gleason score had higher serum FGF19 levels than those with a low Gleason score [60]. This data indicates that FGF19 might be a potential serum biomarker in PCa. One limitation to using endocrine FGFs that include FGF19 as a serum biomarker is the change of serum concentration according to dietary conditions and blood sugar level because endocrine FGFs act as a metabolic regulator and their level is also regulated by a feedback mechanism. Further study will clarify the optimal timing and conditions for measuring endocrine FGFs to apply them as a serum biomarker for PCa. Besides FGF19, the increased expression of FGF23 in many PCa cell lines and PCa tissues was reported. FGF23 enhances proliferation, invasion through activation of AKT, and the MAPK pathway in PCa cell lines. These findings indicate that it can promote PCa progression in an autocrine, paracrine, and/or endocrine manner [63].
