Departments of Pathology, University of Rochester Medical Center, Rochester, New York 14642, USAUnited States
Department of Integrative Cancer Therapy and Urology, Graduate School of Medical Sci- ence, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, JapanJapan
Departments of Pathology, University of Rochester Medical Center, Rochester, New York 14642, USA; Assistant Professor, Department of Medicine and Pathology, Division of Gastroenterology and Liver Research, Rhode Island Hospital, The Warren Alpert Medical School of Brown University, 55 Claverick St. 4
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Kidney cancer is one of the top ten most common cancers in men and women. There are four types of kidney cancer, including Renal Cell Carcinoma (RCC), Transitional cell carcinoma, renal sarcoma, and Wilm’s tumor. The most common type of kidney cancers is renal cell carcinoma (RCC), with around nine out of ten kidney cancers being RCC (American Cancer Associate). Epidemiology studies have identified several risk factors associated with kidney cancer.1 Among them, male gender is associated with twice incidence rate of RCC as female.2 Androgen and Androgen Receptor (AR) are major factors contributing to malegender-associated-diseases, such as prostate cancer,3 suggesting that androgen and AR might be involved in RCC development and progression
Keywords: malegender; carcinoma; renal sarcoma
NEPHROLOGY ISSN 2380-0445 http://dx.doi.org/10.17140/NPOJ-1-e003 Open Journal Editorial Androgen and Androgen Receptor in * Kidney Cancer Corresponding authors Chiung-Kuei Huang, PhD Assistant Professor 1 2* 1,3* Joshua Cho , Kouji Izumi and Chiung-Kuei Huang Department of Medicine and Pathology Division of Gastroenterology and Liver Research, Rhode Island Hospital 1 Departments of Pathology, University of Rochester Medical Center, Rochester, New York Warren Alpert Medical School of Brown 14642, USA University, Providence RI 02903, USA 2Department of Integrative Cancer Therapy and Urology, Graduate School of Medical Sci- E-mail: ckhuang14623@gmail.com ence, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa, 920-8641, Japan 3Assistant Professor, Department of Medicine and Pathology, Division of Gastroenterology Kouji Izumi, MD, PhD and Liver Research, Rhode Island Hospital, The Warren Alpert Medical School of Brown th Department of Integrative Cancer University, 55 Claverick St. 4th Floor, Providence, RI 02903, USA Therapy and Urology Kanazawa University Graduate School of Medical Science Kidney cancer is one of the top ten most common cancers in men and women. There 13-1 Takara-machi, Kanazawa are four types of kidney cancer, including Renal Cell Carcinoma (RCC), Transitional cell Ishikawa, 920-8641, Japan carcinoma, renal sarcoma, and Wilm’s tumor. The most common type of kidney cancers is E-mail: azuizu2003@yahoo.co.jp renal cell carcinoma (RCC), with around nine out of ten kidney cancers being RCC (American Cancer Associate). Epidemiology studies have identified several risk factors associated with Volume 1 : Issue 2 1 kidney cancer. Among them, male gender is associated with twice incidence rate of RCC Article Ref. #: 1000NPOJ1e003 as female.2 Androgen and Androgen Receptor (AR) are major factors contributing to male- gender-associated-diseases, such as prostate cancer,3 suggesting that androgen and AR might be involved in RCC development and progression.
Article History th Received: June 24th, 2015 th In contrast to the results of current epidemiological study, hormonal therapy had Accepted: June 26 , 2015 4-8 th been evaluated in clinical trials for RCC patients in early decades. Despite the discovery of Published: June 26 , 2015 the therapeutic effects of both progesterone and androgen in RCC patients, their therapeutic outcomes had not been appreciated.9 Since androgen and AR are involved in male-gender- Citation associated diseases, recent studies have switched the focus to target androgen and AR signaling Cho J, Izumi K, Huang CK. Andro- in RCC. It was first disclosed that high AR expression is correlated with poor prognosis for gen and androgen receptor in kidney RCC patients; signifying shorter overall survival, relapse-free survival, and cancer-specific cancer. Nephrol Open J. 2015; 1(2): 10 survival. However, another study suggests that AR is actually expressed in more than 90% of e7-e8. doi: 10.17140/NPOJ-1-e003 normal kidney human samples and that there are no differential AR expressions in normal male and female kidneys.11 In addition, AR expression levels are inversely correlated with pT Stage and Fuhrman’s Grade in RCC patients. This surprising result leads to further investigation of the transactivation activity of AR, as AR mainly exerts its function through transcriptional regulation of target genes.12 Androgen treatment does not promote the transactivation activity of AR in commonly used RCC cell lines, such as CAKI-2 and OSRC-2, although AR expression could be detected in these cells. These interesting results bring up novel questions. How does male gender predispose RCC development if AR expression is reduced in RCC samples? Can AR be the therapeutic target even if RCC has AR expression without transactivation activity? It has been demonstrated that targeting AR can be a potential therapy for RCC in pre- clinical model.13 With in vitro malignant transformation assay, AR has been shown to promote normal human kidney epithelial cell transformation with more colony numbers and larger colo- Copyright ny in the presence of carcinogen, ferric nitrilotriacetate. In addition, AR promotes cell growth of ©2015 Huang CK, Izumi K. This is an open access article distributed transformed kidney epithelial cells but not that of normal kidney epithelial cells. Furthermore, under the Creative Commons At- AR involves in cancer migration, invasion, and proliferation in RCC cell lines as determined tribution 4.0 International License by using overexpression and/or knockdown of AR in RCC cells with cancer progression assays. (CC BY 4.0), which permits un- Using cancer-specific cDNA array, hypoxia-induced factor 2α (HIF2α) and Vascular Endothe- restricted use, distribution, and reproduction in any medium, pro- lial Growth Factor (VEGF) were identified to be the AR downstream targets responsible for vided the original work is properly AR-mediated RCC progression. By challenging RCC cells with HIF2α and VEGF inhibitors, cited. AR-mediated RCC progressions could be abolished, suggesting that AR might modulate RCC NEPHROLOGY ISSN 2380-0445 http://dx.doi.org/10.17140/NPOJ-1-e003 Open Journal progression through HIF2α and VEGF signaling pathways.
8. Poster DS, Bruno S, Penta JS, Pinna K, Vilk P, Macdonald JS. Current status of chemotherapy, hormonal therapy, and im- To determine whether targeting AR can be a potential munotherapy in the treatment of renal cell carcinoma. American ® therapy for RCC, an AR degradation enhancer, ASC-J9®, was journal of clinical oncology. 1982; 5: 53-60.
used to determine the effects of targeting AR on RCC progres- sion in in vitro cell culture and in in vivo preclinical models, sub- 9. Raghavaiah NV. Hormone treatment of advanced renal cell cutaneous and orthotopic xenograft mouse tumor models. ASC- carcinoma. Urology. 1982; 19: 123-126. doi: 10.1016/0090- ® J9® treatment substantially reduces RCC proliferation, colony 4295(82)90563-5 formation, migration, and invasion in in vitro cell assays. Tar- ® geting AR with ASC-J9® in RCC preclinical models also shows 10. Noh SJ, Kang MJ, Kim KM, et al. Acetylation status of significant suppression of RCC tumor progression. In addition, p53 and the expression of dbc1, sirt1, and androgen recep- ASC-J9 inhibits the expression of AR, HIF2α, and VEGF, sug- tor are associated with survival in clear cell renal cell carci- gesting that targeting AR may be a novel therapeutic approach noma patients. Pathology. 2013; 45: 574-580. doi: 10.1097/ for RCC patients.
PAT.0b013e3283652c7a Although androgen and AR signaling may be a poten- 11. Zhu G, Liang L, Li L, et al. The expression and evaluation tial therapy for RCC patients, it remains unclear as to why RCC of androgen receptor in human renal cell carcinoma. Urology.
have significantly less AR expression than normal kidney and 2014; 83: 510 e519-524. doi: 10.1016/j.urology.2013.10.022 why AR is negatively associated with RCC tumor stage. Future studies will be needed to explain these controversial observa- 12. Heinlein CA, Chang C. Androgen receptor (ar) coregulators: tions.
An overview. Endocrine reviews. 2002; 23: 175-200.
DISCLOSURE 13. He D, Li L, Zhu G, et al. Asc-j9 suppresses renal cell carci- noma progression by targeting an androgen receptor-dependent There is no conflict of interest for authors to disclose.
hif2alpha/vegf signaling pathway. Cancer research. 2014; 74: 4420-4430. doi: 10.1158/0008-5472.CAN-13-2681