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Experimental Biology and Medicine 230:520-526 (2005)
© 2005 Society for Experimental Biology and Medicine

MINIREVIEW

Hormone-Refractory Prostate Cancer in the Lobund-Wistar Rat

Morris Pollard1 and Mark A. Suckow

Lobund Institute, University of Notre Dame, Notre Dame, Indiana 46556

1To whom requests for reprints should be addressed at 400 Freimann Life Science Center, University of Notre Dame, Notre Dame, IN 46556. E-mail: mpollard{at}nd.edu


   Abstract
Top
 Abstract
Introduction
 Rodent Models of Prostate...
 The LW Rat Model...
 Discussion
 References
 
Research on cancer prevention and therapy must focus on the refractory disease, the fatal end-stage of cancer that develops in patients with organ-related solid tumors. Refractory cancers develop spontaneously in advanced-stage tumors or in relapsed cases after failed therapy. Because neither prevention nor therapy is currently feasible, refractory cancer is a major impediment to survival. There is a great need for an animal model of prostate cancer (PC), one that develops cancer from initial premalignant to the terminal refractory stages. We describe here a model of hormone-refractory prostate cancer (HRPC) that develops spontaneously through two stages by endogenous mechanisms in the Lobund-Wistar (LW) rat. The early premalignant, testosterone (T)-dependent stage is promoted by high levels of endogenous T, and up to age 12 months is reversible by T deprivation; without this intervention, the tumorigenic process progresses to the refractory stage, which is highly aggressive and does not respond to T deprivation or to a wide range of therapies. Initial refractory tumors are palpable at approximately 18 months of age. As they continue to grow, the tumors express characteristics seen in refractory cancers in humans (i.e., hypoxia, expression of hypoxia-inducible factors, and metastasis). Chemically induced HRPCs in LW rats manifest the same two developmental stages, but with shorter latency periods. A transplantable, metastasizing cell line (PAIII) was derived from a germfree LW rat with advanced-stage cancer. Both spontaneous and chemically induced autochthonous HRPC model systems serve as outstanding models for studies on the prevention and therapy of refractory cancer.

Key Words: hormone-refractory cancer • prostate cancer • rat • animal model • testosterone


   Introduction
Top
 Abstract
 Introduction
Rodent Models of Prostate...
 The LW Rat Model...
 Discussion
 References
 
In the evolution of the neoplastic state, progression moves from dependence to autonomy (1). The latter (refractory) stage, manifested in a wide variety of solid tumors, including hormone-refractory prostate cancer (HRPC), is a major impediment to survival. If untreated, or in the event of relapse after failed therapy, patients develop irreversible, aggressive, therapy-resistant metastatic disease.

It was observed that when rapidly replicating tumor cells propagate beyond their optimal supply of oxygen, cells most distant from the source of oxygen suffer anoxic necrosis (2), and adjacent surviving pimonidazole-stained hypoxic cells (3) manifest changes related to the refractory disease. Hypoxia is a key regulatory factor in tumor growth, causing hypoxia-inducible factors (HIF) to activate the transcription of genes with crucial roles in tumor biology, including those influencing growth factors, altered glucose metabolism, genomic instability and amplification, invasion, angiogenesis, and metastasis (reviewed in Refs. 4–7). As a result, hypoxia and subsequent genetic interactions may lead to overexpression of HIF and may potentially increase patient mortality.


   Rodent Models of Prostate Cancer
Top
 Abstract
 Introduction
 Rodent Models of Prostate...
The LW Rat Model...
 Discussion
 References
 
There is great need for a model of refractory cancer that could provide leads to mechanisms aimed at prevention and therapy. Current murine models of prostate cancer include: (i) genetically engineered mice, and (ii) five strains of rats: Wistar Unilever; Fischer F344; Noble; ACI; and Lobund-Wistar (LW). A consensus report on 22 genetically engineered mice models expressed cautious optimism that useful systems would be developed, but they need further development (8). However, the transgene adenocarcinoma mouse prostate (TRAMP) transgenic mouse is an excellent model that spontaneously develops metastasizing prostate cancer that is prevented by genistein (9). Rat models were assessed at the First International Workshop on Animal Models of Prostate Cancer (10): the Wistar Unilever, F344, and Noble rat strains are of limited use because they do not develop HRPC spontaneously; HRPCs are induced in them by extensive and intensive manipulation of chemical carcinogens and prolonged exposures to high doses of testosterone (T) and/or of estrogens. Most of the tumors were of microscopic size, rarely metastatic, and did not progress to the refractory disease described in Table 4Go. The ACI (AXC) rat strain develops cancer spontaneously in the ventral lobe, a site that is absent in man.


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  		Table 4. Homology of Spontaneous Hormone-Refractory Prostate Cancer in LW Rats and Patients
 

   The LW Rat Model of Prostate Cancer
Top
 Abstract
 Introduction
 Rodent Models of Prostate...
 The LW Rat Model...
Discussion
 References
 
The LW rat was derived from a long-term breeding colony of germfree inbred Wistar strain rats fed a natural ingredient diet, L485 (Teklad, Madison, WI; Ref. 11) ad libitum. It was noted, initially in the 37th generation, that occasional aged rats had developed large metastasizing adenocarcinomas in the prostatic complex (12). Large primary HRPCs had developed expanding foci of necrotic cells, especially in the center of the tumors. Metastatic tumors were observed in the lungs and/or in the peritoneal cavity, where the tumor cells attached to and invaded visceral organs. The rats were conventionalized (removed from the germfree isolator) at the 57th generation and maintained pathogen-free thereafter, in isolated environmentally controlled rooms. The incidence of spontaneous metastatic HRPC increased in aged conventionalized rats from approximately 10% to approximately 30%. Transplants of tumor cells and of skin from LW rats were rejected by rats of five inbred rat strains (Wistar, Fischer, Sprague-Dawley, Copenhagen, and Noble strains; unpublished data), suggesting that underlying genetic change(s) had occurred in the LW rat. We do not know why the LW rat appeared in the colony of germfree Wistar rats, although genetic drift is a likely explanation.

The LW Rat Model of Spontaneous PC—Premalignant Stage I.
Our historical record shows that PCs developed spontaneously, with metastatic spread from large advanced-stage tumors in 155/516 (30%) LW rats by average age 22 months (Table 1Go). Spontaneous PCs in LW rats share developmental characteristics with PCs in aging patients (Table 2Go). The LW rat is inherently predisposed to develop spontaneous metastasizing PC by endogenous mechanisms through two stages (Table 3Go). The initial site of tumorigenesis was reported in the seminal vesicle (13) and subsequently reported in the anterior lobe of the prostate (14–16). Some histologic sections demonstrated a primitive branching duct system in the dorsolateral lobes, surrounded by aggregates of large tumor cells with mitotic figures. Increased numbers of cells, many in glandular formation, join with other aggregates to produce the large tumor that we associate with refractory cancer. This suggests that T-dependent cells are activated in the seminal vesicles, in the anterior prostate, and, likely, in the dorsolateral lobes. In the premalignant clinically not apparent stage, luminal cells in the seminal vesicle developed microscopic T-dependent foci of hyperplastic, dysplastic, and neoplastic cells—the likely precursors of prostate cancer (17). The activated luminal cells penetrated the basement membrane into a preformed matrix (Fig. 1Go), where they multiplied as sheets of large cells with prominent nuclei and assembled to form glandular structures. The driving oncogenic force is associated with high endogenous production of mitogenic T (18, 19), reaching sustained or transient levels in excess of 3000 pg/ ml serum. Rats of the five inbred strains noted above that rarely develop PC spontaneously manifested endogenous T levels no higher than 1500 pg/ml of serum (data not published).


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  		Table 1. Development of Prostate Cancer in LW Ratsa
 

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  		Table 2. Homology of Spontaneous Prostate Cancer in LW Rats and Patients
 

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  		Table 3. Progression of Spontaneous Prostate Cancer in LW Ratsa
 


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  		Figure 1. Spontaneous premalignant Stage I prostate tumor (T), developed from testosterone-activated luminal cells in seminal vesicles (V). Hematoxylin and eosin (H&E) stain; magnification: x40.

 
The clinical manifestations of PC can be enhanced or suppressed by exogenous agents. For example, tumor development was promoted by high dietary fat (19), by subcutaneous slow-release implants of exogenous T-propionate (20, 21), by exogenous dihydrotestosterone (DHT) propionate (22); and suppressed by caloric restriction (23), by T-deprivation resulting from early castration, by subcutaneous implants of exogenous estradiol, by implants of nonesterified DHT (24), and by dietary soy protein isolate with isoflavones (SPII; Refs. 18, 19, 25). The oncogenic driving force of T on PC development (and spontaneous development of liver tumors in rats older than 30 months) was moderated by dietary restriction (26). Up to age 12 months, progression of most tumors to the refractory Stage II was reversed by changing the diet from L485 to the SPII diet (19). Diet L485 contains soy meal, which did not reduce levels of T, although the amount of isoflavones in soy meal exceeded those in the SPII diet.

Spontaneous Refractory HRPC—Stage II.
Without intervention by T-deprivation before age 12 months, premalignant Stage I tumors progressed spontaneously to refractory Stage II tumors. At age 18–20 months, small tumors (approximately 0.5-cm diameter) were palpable in the caudal area of the pelvic region of the abdomen as hard structures with rough surfaces. The tumors grew to approximately 3-cm diameters within the following 2 months (Fig. 2Go). The large tumors were solid and scirrhotic when incised, rapidly growing, irreversible, and metastatic, with numerous glandular structures (Fig. 3Go). As the tumors increased in size, they developed three morphological zones after exposure to the pimonidazole reagent: (i) expanding foci of cellular necrosis in the center of the tumor; (ii) tumor cells adjacent to the necrotic foci demonstrated positive staining for hypoxia; and (iii) normoxic cells in the periphery of the tumors that were replicating and appeared morphologically normal (Fig. 4Go). During progression, tumor stromas changed from sparse to prominent dense connective tissue; monolayered luminal cells in glands changed to multilayered large tumor cells with prominent nuclei and occasional mitotic figures; and glandular structures appeared in various rigid shapes, with reduced secretions. Tumor cells spread from the primary tumor through lymphatic channels, with occasional swollen lumbar, hepatic, and axillary lymph nodes, to the lungs, where they developed as discrete, expanding, solid subpleural invasive tumors. Tumor cells also penetrated the prostate capsule into the peritoneal cavity, where they developed as pearl-like tumors that attached to peritoneal membranes and invaded visceral organs. The Stage II refractory PCs did not respond to T deprivation. Spontaneous metastasis of tumor cells to skeletal bone was not observed. Obstruction of urine flow by large dorsolateral tumors resulted in urine retention and hydronephrosis.



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  		Figure 2. Advanced Stage II HRPC (T) in a 22-month-old LW rat.

 


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  		Figure 3. Photomicrograph of advanced Stage II spontaneous refractory prostate cancer. Note the necrotic, anoxic area (A) and normoxic tumor (N). Stained with hematoxylin and eosin (H&E); magnification: x250.

 


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  		Figure 4. Photomicrograph of spontaneous refractory prostate cancer. Note three zones: anoxic, necrotic zone (A); hypoxic zone (B); and normoxic zone (C). Stained with pimonidazole hypoxyprobe; magnification: x250.

 
Table 4Go lists characteristics associated with refractory cancer in LW rats and in human patients (4–7), including stromal hyperplasia; intratumor hypoxia, as determined by staining with the pimonidazole reagent; expression of HIF-1a; presence of the tumor-promoting gene EZH2, as determined by gene microarray (presence in LW rat prostate tumors communicated by A. Martin); expression of urokinase plasminogen activator (27); expression of tissue procoagulant factor (28); expression of vascular endothelial growth factor, as determined by immunohistochemistry; and the presence of hepatocyte growth factor/scatter factor tyrosine kinase Met receptor (presence in the transplantable PAIII rat tumor communicated by G. van de Woude; Ref. 29).

Chemically Induced Refractory HRPC in LW Rats.
Metastasizing autochthonous HRPCs were induced in LW rats after a single intravenous inoculation of methylnitrosourea (MNU), with or without subsequent subcutaneous implants of T-propionate (TP) in slow-release silastic capsules, each at intervals of 2 months (Table 1Go). Methylnitrosourea-induced tumors developed in approximately 30% of rats at approximately 12 months after MNU exposure. Among rats treated with MNU plus 2–3 implants of TP, approximately 80% (variable with the number of implants) developed PCs by approximately 8 months after MNU inoculation. Development Stages I and II occurred with shorter latency periods. Reversal of tumorigenesis could be initiated by changing diets from L485 to SPII at 6 months after MNU inoculation; and at 4 months after MNU plus TP inoculations (30). The induced tumors and lung metastases were morphologically similar to the spontaneous refractory HRPCs; and the tumors demonstrated the three morphological zones (including the hypoxia zone stained by the pimonidazole reagent) and most of the characteristics of the refractory disease noted in Table 4Go.

Occasional rats, representing many strains, including the LW rat, develop local carcinomas in the external ear canal (Zymbal’s tumor) in response to MNU inoculation (31).

The PAIII Transplantable Prostate Cancer Cell Line.
The PAIII cell line was derived from a germfree LW rat with spontaneous advanced Stage II HRPC. The cells were propagated in vitro, cloned, and inoculated subcutaneously into LW rats at 2 months of age. Local and metastatic lung tumors developed (32). The PAIII cells have been transplanted for many passages in LW rats with no change in pattern of disease (33), and the cell line is stored frozen at liquid nitrogen temperature. When PAIII cells were transplanted subcutaneously in the flank, approximately 99% of the rats developed large metastasizing subcutaneous adenocarcinomas within 40 days. The tumors demonstrated the three histological zones related to the intratumor oxygen gradient when stained with the pimonidazole reagent. The PAIII cells spread spontaneously from the subcutaneous primary tumor through ipsilateral lymphatic channels, resulting in numerous coalescing metastatic tumors in the lungs. The refractory PAIII cells produced subcutaneous and metastatic lung tumors in intact male and female LW rats and in castrated LW rats, but not in other rat strains (Table 3Go). Tumors arising from PAIII cells did not respond to the T-deprivation procedures noted above. We studied the in vivo interaction of tumor cells on skeletal bone. The PAIII cells were deposited on the surface of skeletal bone, with disruption of the periosteum. There were numerous osteoclasts at the interface of the PAIII tumor and bone. The PAIII cells invaded the bone, causing osteolytic and adjacent osteoblastic changes, which were prevented by subcutaneous inoculations of dichloromethylene diphosphonate. However, this drug had no effect on established osteoblastic lesions. The PAIII cells did not pass through the intact periosteum (34–36).


   Discussion
Top
 Abstract
 Introduction
 Rodent Models of Prostate...
 The LW Rat Model...
 Discussion
References
 
The goal of cancer prevention must focus on the refractory disease, the terminal stage that develops in many organ-related solid cancers. Hormone-refractory prostate cancer is a good example of that disease. Most of the autochthonous prostate tumors induced by intensive doses of chemical and hormone agents in Fischer (37) and in Wistar Unilever (38) rats produced premalignant tumors that did not progress to the refractory stage of tumorigenesis (Table 4Go); therefore, these models would be inappropriate for studies on prevention and therapy of refractory cancer.

The versatility of the four experimental protocols provided in the LW model system (Table 1Go) has attracted many investigators who represent a wide range of disciplines in basic and applied subjects. Some of their published reports include: siRNA (39); tumor biology (15, 40–43); antiangiogenesis (22); electron microscopy (44); genomic linkages (45); metastasis (46–49); therapy (50–55); immunization (56, 57); tumor prevention (58–60); caloric restriction (61); bone cancer (62–65); androgen receptor (66); procoagulant activity (28); and the EGF growth promoter (67).

Development of prostate cancers was associated with stromal changes (called stromal tumors) in cancers in the breast and prostate (68). Subsequently, this lesion was associated with stromal-epithelial interchanges in a variety of cancers that were associated with the hepatocyte growth factor/scatter factor tyrosine kinase Met receptor, causing rapid tumor growth and metastasis (69). The Met receptor is expressed by PAIII cells and manifests the related stromal hyperplasia noted above. Is it possible that inhibition of tyrosine kinase by genistein will inhibit development of the Met receptor?

This is the first documented model of HRPC that will enable studies on prevention and therapy. The relationship of hormone-refractory cancer may be related mechanistically to refractory disease associated with chemical- and radiation-treated cancers. Supporting this notion is our finding that the premalignant stage of induced PC was significantly prevented in LW rats by dietary 4-hydroxyphenylretinamide (4-HPR; Ref. 70), and feeding the same 4-HPR to male LW rats did not significantly inhibit the growth and spread of the hormone-refractory PAIII cells (71).

In summary, a growing body of evidence shows that the LW rat is a unique animal model for studies aimed at prevention and therapy of HRPC.


   Acknowledgments
 
We thank P. H. Luckert, W. Wolter, L. Sun, B. A. Teah, E. Zelmer, D.L. Snyder, and V. Schroederfor their personal commitment to this research program. We thank the staff of the Freimann Life Science Center for animal care.


   Footnotes
 
Supported in part by funds from the National Institutes of Health grants CA 17559 and RR 00294, the Coleman Foundation of Chicago, the Retirement Research Foundation of Chicago, the Scully Trust, the United States Soyboard, and the University of Notre Dame.

Received for publication December 10, 2004. Accepted for publication May 6, 2005.


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 Rodent Models of Prostate...
 The LW Rat Model...
 Discussion
 References
 

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