Androgen-Regulated And Highly Tumorigenic Human Prostate Cancer Cell Line Established From A Transplantable Primary CWR22 Tumor

Main Category: Prostate / Prostate Cancer
Also Included In: Urology / Nephrology;  Cancer / Oncology
Article Date: 15 Nov 2008 - 1:00 PDT

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UroToday.com - The molecular mechanisms underlying development of androgen-independent growth of prostate cancer are largely unknown, and no effective therapies for hormone-refractory prostate cancer exist at present. One of the key problems in conducting studies to identify growth factors and signaling pathways that can replace androgens in the growth control of prostate cancer cells is the lack of androgen receptor (AR)-positive human prostate cancer cell lines that are regulated by androgens and tumorigenic in nude mice.

We have established and characterized a new androgen-dependent, highly tumorigenic human prostate cancer cell line, CWR22Pc, from the primary CWR22 human prostate xenograft tumors. The primary CWR22 prostate tumors are highly responsive to androgen deprivation with marked tumor regression after castration, mimicking the course of the human disease.

Comparative genomic hybridization and DNA fingerprinting analysis show that the CWR22Pc cell line genetically originates from the primary CWR22 tumors. The growth of CWR22Pc cells is strictly regulated by androgens, and CWR22Pc cells express high levels of androgen receptor with H874Y mutation but without the exon 3 duplication. Transcription factors Stat5a/b and Stat3, which are highly activated in prostate cancers of high histological grade, are activated by prolactin and IL-6 respectively in CWR22Pc cells and Akt and MAPK signaling pathways are constitutively active in CWR22Pc cells.

The CWR22Pc cells form androgen-regulated, rapidly growing tumors at high incidence in nude mice. Importantly, when androgens were withdrawn from the established CWR22Pc tumors grown in nude mice, the tumors initially shrank but re-grew back as androgen-independent tumors. CWR22Pc cells produce PSA in an androgen-regulated manner, and the serum prostate-specific antigen levels correlate with the CWR22Pc xenograft tumor volumes in mice.

The CWR22Pc cell line provides a useful research tool to address a number of key questions pertinent to the basic biology of prostate cancer as well as clinical management of the disease. First, because growth of CWR22Pc cells in culture is strictly regulated by androgens, CWR22Pc cells will be able to provide critical information about androgen-regulated growth mechanisms in a prostate-specific cell context. Second, the CWR22Pc cell line provides a model system where significance of different protein kinase signaling pathway activation can be tested for their ability to replace androgens for growth promotion and maintenance of prostate cancer cell viability in vitro and in vivo. Third, CWR22Pc cells have the H874Y mutation in the AR gene without additional genetic changes and will therefore enable studies of AR (H874Y) transcriptional activity in a biological setting where prostate specific co-activators and co-repressors are expressed and present. Importantly, the regrowth of CWR22Pc tumors in vivo in nude mice after androgen deprivation mimics the course of development of hormone-refractory prostate cancer in humans. Future studies need to characterize genetically and epigenetically the cell clones that recur when CWR22Pc cells are grown as xenograft tumors under the biological pressure of androgen deprivation.

Finally, it will be important to establish whether CWR22Pc cells metastasize when inoculated orthotopically in nude mice.

Written by Ayush Dagvadorj,1 Shyh-Han Tan,1 Zhiyong Liao1, Luciane R. Cavalli,2 Bassem R. Haddad,2 and Marja T. Nevalainen1 as part of Beyond the Abstract on UroToday.com

1Dept. of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107.
2Dept. of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20057.

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