Archives

  • 2018-07
  • 2019-08
  • 2019-09
  • 2019-10
  • 2019-11
  • 2019-12
  • 2020-01
  • 2020-02
  • 2020-03
  • 2020-04
  • 2020-05
  • 2020-06
  • 2020-07
  • 2020-08
  • 2020-09
  • 2020-10
  • 2020-11
  • 2020-12
  • 2021-01
  • 2021-02
  • 2021-03
  • 2021-04
  • 2021-05
  • 2021-06
  • 2021-07
  • 2021-08
  • 2021-09
  • 2021-10
  • 2021-11
  • 2021-12
  • 2022-01
  • 2022-02
  • 2022-03
  • 2022-04
  • 2022-05
  • 2022-06
  • 2022-07
  • 2022-08
  • 2022-09
  • 2022-10
  • 2022-11
  • 2022-12
  • 2023-01
  • 2023-02
  • 2023-03
  • 2023-04
  • 2023-05
  • 2023-06
  • 2023-08
  • 2023-09
  • 2023-10
  • 2023-11
  • 2023-12
  • 2024-01
  • 2024-02
  • 2024-03
  • 2024-04
  • 2024-05
  • Previous studies have thus demonstrated that AR activation

    2024-04-01

    Previous studies have thus demonstrated that AR activation generally correlates with the promotion of urothelial carcinogenesis and cancer growth. In this article, we review available data suggesting their modulation through the AR pathway as well as correlations of AR signals with sensitivity to conventional therapy for urothelial cancer and highlight underlying molecular mechanisms (Fig. 1).
    AR signaling and its physiological functions in the bladder The physiological functions of androgens are mainly dependent on their binding to AR, a 110 kDa protein and a member of the nuclear receptor superfamily that functions as a ligand-inducible transcription factor, in target cells (Cano et al., 2013, Chen et al., 2015, Heinlein and Chang, 2004, Rahman et al., 2004, Singer et al., 2008). AR signals thus mediate the biological effects of androgens in a wide range of physiological and pathological processes. In the absence of ligand as an inactive form, AR resides in the cytoplasm coupling with heat shock proteins. Binding of androgens to AR triggers a series of conformational and structural changes, resulting in a release from the heat shock proteins, formation of a homodimer, and translocation into the nucleus. The AR, along with co-regulators, then binds to an androgen-response element (ARE) allowing target genes to be transcribed. Alternative mechanisms of AR activation independent of androgen binding include phosphorylation via cytokines and kinases [e.g. epidermal growth factor receptor (EGFR)] as well as gene mutations or alternative splicing that make the receptor constitutively active (Antonarakis et al., 2016, Lamont and Tindall, 2011, Knudsen and Penning, 2010). Male internal genitalia, including urothelium, as well as the prostate whose differentiation/development requires the induction of AR signaling (Thomas et al., 2008), are derived from the urogenital sinus endoderm. It is therefore conceivable that AR signaling is involved in Gliotoxin development. Indeed, AR expression has been documented in human or rodent urothelium as well as bladder submucosa such as smooth muscle cells and neurons (Celayir et al., 2002, Pelletier, 2000, Rosenzweig et al., 1995, Salmi et al., 2001, Wilson and McPhaul, 1996). Nonetheless, physiological functions of androgen/AR in the bladder remain unclear, and only a few animal studies have demonstrated that AR signaling contributes to the regulation of urine storage and urinary tract functions. Castration in male animals was found to significantly reduce the activity and expression of tissue enzymes closely related to cholinergic and non-cholinergic nerve functions (Filippi et al., 2007, Juan et al., 2007). Androgen supplementation in castrated male rats also re-augmented the thickness of urothelium, the quantity of smooth muscle fibers, and the number of vessels in their bladders (Madeiro et al., 2002). In addition, androgen deprivation resulted in the induction of bladder fibrosis and the reduction of bladder capacity and compliance in male rats (Zhang et al., 2012). A recent study confirmed a decrease in bladder capacity with no change in the amplitude or duration of bladder contractions or voiding efficiency in castrated male rats (Cheng and de Groat, 2016). In accordance with these observations in animals, a few studies have shown clinical data suggesting that androgen treatment contributes to improving/maintaining bladder functions (Holmäng et al., 1993, Yassin et al., 2008). Conversely, testosterone was shown to have an impact on neurogenic and chemogenic responses in the rat bladder, resulting in the inhibition of detrusor muscle contraction (Hall et al., 2002). To the best of our knowledge, however, there are no recent clinical studies further assessing whether androgen treatment is beneficial to men with lower urinary tract symptoms.
    AR alterations in urothelial cancer AR expression has been examined in human bladder cancer cell lines and urothelial tumor tissue specimens. In several cell lines, such as UMUC3 and TCCSUP (Miyamoto et al., 2007), AR mRNA and protein have been found to be expressed. In tissue specimens, immunohistochemistry has detected AR protein signals in bladder (12.9–53.4%) or upper urinary tract (11.3–55.4%) urothelial tumors, which were significantly lower than the positive rates in normal/non-neoplastic tissues (57.5–86.5%) reported in at least 4 comparative studies (Table 1). Thus, the levels of AR protein expression appear to be considerably reduced in urothelial tumors, compared with corresponding non-neoplastic urothelial tissues. Of note, a polymerase chain reaction-based method could detect AR mRNA signals in all 33 fresh non-muscle-invasive bladder tumor specimens examined (Miyamoto et al., 2007). In contrast, 3 immunohistochemical studies have demonstrated no detectable AR in normal urothelial tissues [vs. 52.9% (Birtle et al., 2004), 51.1% (Tuygun et al., 2011), and 21.7% (Mashhadi et al., 2014) urothelial tumors]. These conflicting findings might be due to differences in tissue preservation (e.g. formalin fixation), staining protocol (e.g. antibody), and/or scoring criteria. So-called cancer field effect might also have affected the immunoreactivity because “normal” urothelium was obtained from patients with urothelial tumor in most of these studies. Interestingly, 3 studies in upper urinary tract specimens showed significant or marginal increases in AR positivity in ureteral tumors, compared with renal pelvic tumors (Kashiwagi et al., 2016a, Shyr et al., 2013, Wirth et al., 2017). In our studies using the same antibody/staining protocol and scoring criteria, the positive rates of AR expression were 11.1% in 45 renal pelvic tumors, 28.0% in 50 ureteral tumors, and 42.0% of 188 bladder tumors or 33.0% of 91 high-grade muscle-invasive bladder tumors (Kashiwagi et al., 2016a, Miyamoto et al., 2012b). Moreover, these immunohistochemical studies have failed to identify significant sex-related differences in the expression of AR in normal or cancerous urothelial tissues.