Induced Bph Models

Spontaneous models of BPH are closer to human pathology, but these models are difficult to obtain due to the slow aging process. BPH pathogenesis can be induced or accelerated in dogs, as well as in standard laboratory rodents like mice and rats. Dogs have an androgen responsive prostate tissue; thus the application of androgens can induce BPH. It has been experimentally shown that a regime involving androstanediol and estradiol application induced BPH. DHT and testosterone were not able to induce BPH in dogs if applied alone. Combinational treatment with DHT and estradiol applied subcutaneously daily usually during 14 or 28 days induces BPH in dogs (Yokota et al., 2004). Similarly, eight-months-long daily treatment with testosterone and androstenedione induced a canine BPH even in young animals (Ito et al., 2000). The problematic anatomy of canine prostate described earlier is still a problem in modeling the human BPH using hormonal induction. This problem can be overcome using a surgical approach, where the canine prostate is enveloped by a mesh that does not allow growth into the peritoneal cavity. This is currently the only way to induce BPH in dogs that is accompanied with urethral obstruction seen in human BPH.

The rodent prostate differs considerably from the human prostate in anatomy and physiology. Rodent prostate consists of anterior, ventral, and dorsolateral lobes. Only the dorsolateral lobe has been reported to be comparable to human prostate. The main factor in BPH induction is the long-term application of high doses of androgens and estrogens. Some studies report an induction of BPH using only chronic testosterone treatment, but this model suffers from several limitations (Mitra et al., 1999). The response is strain specific; however, some rat strains do not develop BPH after this treatment, and classic strains like Wistar or Sprague-Dawley are responsive. Except for sex hormones, chronic applications of prolactin or sympathomimetic phenylephrine also lead to BPH in rodents (Van Coppenolle et al., 2000; Marinese et al., 2003). However, this model is used only sporadically as the use of sympathomimetic drugs affects not only the urogenital system, but notably other systems as well (Golomb et al., 1998). Reports of spontaneous development of BPH in rodents are lacking; normal rodent prostate tissue even undergoes an age-dependent atrophy. Exceptions are the brown Norway rats (Banerjee et al., 1998; Banerjee et al., 2001) and spontaneously hypertensive rats (Zhang et al., 2004). However, the mechanism of BPH etiology in these strains is specific and does not resemble the multifactorial origin of human BPH.

Besides hormonal treatment there is an additional approach for the induction of BPH—the so-called mouse prostate reconstitution model. Fetal urogenital tissue is transplanted into the prostate of an adult animal. Without androgen treatment only epithelial proliferation is induced, but additional androgen application results in BPH (Guo et al., 2004). It can be expected that specific growth factors in the transplanted tissue are responsible for the induction of proliferation, but the identification of the active compounds is not complete. Nevertheless, previously mentioned growth factors like FGF, IGF, and TGF might be involved. Xenografting of human BPH tissue into immunodeficient mice or rats is also possible. However, the survival of this tissue is limited, and the use of such models is currently questionable, although biochemically the transplants produce prostate-specific enzymes. Another possibility is to implant prostate tissue cell lines ectopically (e.g., under the renal capsule) in recipient animals (Takao et al., 2003). This model however, resembles in vitro more than in vivo models.

Transgenic Models

Transgenic animals present a totally new approach for modeling human diseases. They are very important for the study of the pathogenesis of diseases, mostly the role of specific genes and gene products. However, their use in finding and evaluating potential therapeutics is limited, and the results of such studies must be taken with caution. BPH, like most other so-called civilization diseases, has a multifactorial etiology and thus cannot be reduced to a deficiency or overexpression of one protein. Nevertheless, transgenic animals represent an invaluable tool for BPH research. Based on the known pathophysiology of BPH, these animals are genetically modified to overexpress growth factors like FGF and IGF in a more or less prostate-specific manner. The organ specificity of expression is guaranteed by the use of prostate-specific promoters. Interestingly, another endocrine factor can be added to the pathogenesis of BPH after research using transgenic mice—prolactin. Mice overexpressing prolactin have been shown to develop BPH with high histological similarity to human BPH (Dillner et al., 2003). The role of prolactin in BPH remains uncertain, as its overproduction was associated with higher androgen levels and an altered expression of several metabolic genes in the transgenic rodents (Dillner et al., 2002).

In vitro studies show that prolactin alone can have a proliferative or at least antiapoptotic effect on prostate tissue. As mentioned previously, the tumor suppressor protein p27Kip1 might be involved in the pathogenesis of BPH. This has been shown on p27Kip1 knock-out mice that develop an enlarged prostate. This model might also explain the puzzling relationship between BPH and prostate cancer (Cordon-Cardo et al., 1998). Of the transgenic animals currently described as models of BPH prolactin, overexpressing mice seem to develop a histological picture that is closest to the human BPH, though with several shortcomings. The generation of mice with prolactin overexpression restricted to the prostate tissue has improved the potential of this model considerably (Kindblom et al., 2003).

In vitro Models

In part due to the pressure from ecologic organizations, cell culture models are used more and more by researchers. It is difficult to study BPH in Petri dishes, but it is possible. The advantages are the generally assumed advantages of all cell culture models—easy reproducibility, virtually unlimited material for experiments, very good control over the cell growth conditions, no ethical problems. On the other side, cell cultures, especially in the case of BPH, are a very distant model. The biggest problem is the interaction between epithelial and stromal cells that plays a crucial role in the BPH pathogenesis in vivo. This interaction is lacking in classic pure cell culture models. Most cultures are derived from clinical specimens obtained during prostatectomy or transurethral resection. An important issue in the evaluation of cell cultures for research is the ability of the cells to express the androgen receptor, 5-alpha reductase, and the prostate-specific antigen. On the functional level, this means that the cells must retain their androgen responsiveness. Caution must be paid to cell cultures derived from prostate carcinoma. These tumor cell lines have a different phenotype, and research on these cells is difficult to interpret for BPH, although many studies have been published using these cell lines. Nontumorigenic cell cultures are few, and some of them are prepared from prostate tissue of various experimental animals. Similar to the in vivo models, cell cultures from rats or mice differ considerably from canine or primate cell lines.

Some problems of classic mono-layer cell cultures can be overcome by using a 3D histoculture—sponge-gel-supported or the so-called total-immersion histoculture (Olbina et al., 1998). The problem of a lacking interaction between different cell types is partially solved by using a coculture model where primary cell lines of prostate fibroblasts and epithelial cells are cultured together, separated by a porous membrane that enables the diffusion of soluble factors produced by the one or the other cell type. It must be noted that this— although definitely an improvement—is still a virtual interaction that only partially resembles the situation in vivo. A detailed description of such a coculture model was published repeatedly (Bayne et al., 1998; Habib et al., 2000).

Conclusion

The wide spectrum of available models shows that there is still no ideal model for BPH research (see Figure 52.9 and Table 52.3).

On one site, there is the need to make the model as close as possible to the human pathology; this is true for the spontaneous model of BPH in chimpanzees. On the other site, there is a need for simple, reproducible, and relatively cheap models; this is true for some of the cell culture models. It is probable that an ideal model will never exist and the knowledge about BPH will be composed of numerous puzzle pieces from many studies on various models as is the case today. One possibility to get closer to the ideal is to generate transgenic animals

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