Use of nude mouse xenograft models in prostate cancer research

Abstract

BACKGROUND. Our understanding of the mechanisms of (progressive) growth of prostatic cancer has been largely obtained through the study of experimental animal models. To be able to validate new concepts, representative model systems of human origin that mimic the clinical process of the disease in patients are essential. Unfortunately, the limited number of human prostate tumor models has considerably hampered research. METHODS. Various research groups have put much effort in the development of human prostate tumor xenograft models, and large numbers of clinical prostate tumors were heterotransplanted in immune-deficient host animals. This huge effort has resulted in a number of tumor lines which are reviewed here. RESULTS. Up to now, approximately 25 xenograft models of human prostate cancer have been established and reported in the literature. The available xenografts seem to represent the various stages of clinical prostate cancer, such as early progression and transition from androgen-dependent to androgen-independent growth. In addition, recent efforts are concentrating on the establishment of in vitro cell lines from these xenografts as well as on the development of (bone) metastatic variants. KEY WORDS:xenograft models; human prostate cancer; immunodeficient mice INTRODUCTIONWith the increasing life expectancy of men, prostatic cancer has become a major medical problem. Although (advanced) prostate cancer is in most cases initially treatable by antiandrogen therapy, the indefinite escape from hormonal control and consequently the relapse in tumor growth is one of the main clinical problems [1]. In addition, metastatic spread of prostate cancer towards bone is the main cause of morbidity among prostate cancer patients [2]. To improve the present treatment modalities, new therapeutic targets, related to these issues, have to be identified. Representative animal models are needed to develop and test new concepts of properties and prostate cancer growth regulation.Research on human prostate cancer has for many years been hampered by the very limited availability of experimental model systems. The most important reason for the lack of representative models is the very poor growth potential of human prostate tumor tissue in culture or in nude mice. Also, animal models of prostatic cancer are hardly available since other mammal species (e.g., laboratory animals), in contrast to men, do not, or only rather poorly, develop prostatic cancer spontaneously upon aging [3]. The spontaneous occurrence of prostate carcinoma in aging dogs and ACI/Seg and Lobund-Wistar rats has been used in model sytems. In addition, different hormonally and/or chemically induced rodent model systems have been developed successfully. In recent years, a number of transgenic mouse models of prostate cancer have been established [4]. Although these model sys-

Differential androgen receptor signals in different cells explain why androgen-deprivation therapy of prostate cancer fails

“…PC346C cells: AR functions as proliferation stimulator and suppressor PC346C, established from a human primary tumor through xenograft (van Weerden et al, 1996;van Weerden and Romijn, 2000), is an androgen-dependent prostate cancer cell line expressing wild-type AR and CK8/18 (van Bokhoven et al, 2003). After long-term androgen ablation, another androgen-independent subline, PC346DCC, with a 95% decrease in AR expression, was generated from PC346C cells.…”

Dietary n-3 Polyunsaturated Fatty Acids Enhance Hormone Ablation Therapy in Androgen-Dependent Prostate Cancer

“…There are very few human prostatic cancer cell lines that are truly AD. 26 The CWR22 xenograft model has been well characterized in this regard and responds to androgen withdrawal in the same manner as AD tumors in men, with increased apoptosis, reduced cell proliferation, and tumor regression accompanied by decreasing levels of circulating prostate-specific antigen (PSA). 27 These xenografts also progress (relapse) to AID growth (CWR22R) when subjected to the same selective forces (hormone ablation) that cause this change in men with the disease.…”

The diverse and contrasting effects of using human prostate cancer cell lines to study androgen receptor roles in prostate cancer

“…PC346C cells isolated from a human prostate primary tumor through xenograft [52,53] are CK5-negative and CK8/18-positive [9]. The PC346C cells are androgendependent, with the expression of wild-type (wt) AR [9,54].…”