CD24 expression is important in male urothelial tumorigenesis and metastasis in mice and is androgen regulated

Abstract

Overexpression of CD24, a glycosyl phosphatidylinositol-linked sialoglycoprotein, is associated with poor outcome in urothelial carcinoma and contributes to experimental tumor growth and metastasis. However, the requirement for CD24 ( Cd24a in mice) in tumorigenesis and spontaneous metastasis from the orthotopic site remains uncharacterized. Using N -butyl- N -(4-hydroxybutyl) nitrosamine induction of invasive and metastatic bladder cancer, we show that Cd24a -deficient male mice developed fewer bladder tumors than C57BL/6 control male mice. Evaluating only mice with evidence of primary tumors, we observed that Cd24a- deficient male mice also had fewer metastases than wild-type counterparts. In parallel observations, stratification of patients based on CD24 immunohistochemical expression in their tumors revealed that high levels of CD24 are associated with poor prognosis in males. In female patients and mice the above observations were not present. Given the significant role of CD24 in males, we sought to assess the relationship between androgen and CD24 regulation. We discovered that androgen receptor knockdown in UM-UC-3 and TCCSUP human urothelial carcinoma cell lines resulted in suppression of CD24 expression and cell proliferation. Androgen treatment also led to increased CD24 promoter activity, dependent on the presence of androgen receptor. In vivo, androgen deprivation resulted in reduced growth and CD24 expression of UM-UC-3 xenografts, and the latter was rescued by exogenous CD24 overexpression. These findings demonstrate an important role for CD24 in urothelial tumorigenesis and metastasis in male mice and indicate that CD24 is androgen regulated, providing the foundation for urothelial bladder cancer therapy with antiandrogens.

Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity

“…CD24, a RAL GTPase-regulated glycosyl phosphatidylinositol (GPI)-linked sialoglycoprotein, is required for metastatic bladder cancer colonisation in mice and shows increased expression in human bladder cancer metastases 183 . Interestingly, prognostic value seems to be confined to male patients and in Cd24-null mice, reduced carcinogen-induced tumour incidence was seen only in males 184 . As CD24 is androgen-responsive, if these data are confirmed, androgen ablation could have therapeutic impact in males 184 .…”

“…Interestingly, prognostic value seems to be confined to male patients and in Cd24-null mice, reduced carcinogen-induced tumour incidence was seen only in males 184 . As CD24 is androgen-responsive, if these data are confirmed, androgen ablation could have therapeutic impact in males 184 .…”

The emerging role of the androgen receptor in bladder cancer

“…Ablation of CD24 resulted in fewer metastases than in control animals. Interestingly, this result was restricted to male mice, suggesting a role for androgens (Overdevest et al 2012). In cell culture studies, an AR knockdown resulted in decreased CD24 expression and cell proliferation, while treatment with androgens increased CD24 levels, arguing that CD24 is androgen regulated in urothelial cells (Overdevest et al 2012).…”

“…Interestingly, this result was restricted to male mice, suggesting a role for androgens (Overdevest et al 2012). In cell culture studies, an AR knockdown resulted in decreased CD24 expression and cell proliferation, while treatment with androgens increased CD24 levels, arguing that CD24 is androgen regulated in urothelial cells (Overdevest et al 2012). Others have found that androgen stimulation of AR positive bladder cancer cells promoted a mesenchymal phenotype, migration and invasion in vitro, and metastasis in vivo (Jing et al 2014).…”

Biodistribution of gold nanoparticles in BBN-induced muscle-invasive bladder cancer in mice

“…Macrophage in tumors, generally known as tumor-associated macrophage (TAMS), are often upregulated urethra. Since the BBN model only produces tumors in male mice, 34 direct instillation of AuNPs into the bladders of male mice is challenging, but could be done surgically. Further, transitional human bladder tumors could be injected into in the stromal compartment of solid tumors and participate in their growth, angiogenesis, and metastasis.…”