Commentary

Lobund-Wistar Rat Model of Prostate Cancerin Man

Morris Pollard*

Lobund Laboratory, University of Notre Dame, Notre Dame, Indiana

Twenty-five years ago, in the course of monitoringa small colony of germ-free (GF) Wistar rats, I ob-served tumors in the pelvic region among aged rats ofthe 36th and later the 57th generation. They were pros-tatic adenocarcinomas which had metastasized to thelungs [1]. We have no explanation for this develop-ment, because the Wistar strain from which they werederived was free of such spontaneous neoplasms. Per-haps the change was the result of ‘‘genetic drift,’’ be-cause transplants of their tumors and skin were re-jected by all rat strains other than the GF strain fromwhich the tissues had been derived. The 57th genera-tion of rats was conventionalized and propagatedthereafter to the present 15th generation of rats whichwe designated the ‘‘Lobund-Wistar’’ (L-W) strain [2].

Based on investigations presented below, the char-acteristics of L-W rats are unique. This is the onlyknown rat strain that is inherently predisposed tospontaneous metastasizing hormone-influenced ad-enocarcinomas in the prostate (dorsolateral and ante-rior lobes and the seminal vesicles). Thus, we call themP-SV tumors [3–7]. Similar original sites of inducedP-SV tumors have been reported in F344 [8] and inWistar [9] rats. By its clinical manifestations and re-sponses to modifying agents, the L-W rat is a model ofprostate cancer in man.

Large P-SV tumors (2–4 cm in diameter) (Fig. 1)developed spontaneously in 66 of 244 (27%) conven-tional L-W rats in, on average, 26 months [10,11]. Tu-mors (∼0.5 cm in diameter) were detectable earlier bypalpation at, on average, age 20 months. In contrast,spontaneous P-SV tumors were not observed in 1,000Fisher (F344) rats at age 2 years [12], nor in Sprague-Dawley, Wistar, and ACI rats [13]. Spontaneous pros-tate cancers developed in 0.54% of Nb rats [14], andthe transplantable Dunning tumor was derived fromone Copenhagen rat [15].

In vivo tumorigenesis has been investigated in L-Wrats on three operational levels: 1) spontaneous and (2)

induced tumors which relate to autochthonous pros-tate cancer in man, and 3) metastasizing transplantedtumors, exemplified by prostate adenocarcinoma-III(PA-III) [16], which was derived from a spontaneoustumor in an aged GF L-W rat.

The autochthonous (spontaneous and induced P-SV tumors) were palpable as discrete, hard masses inthe pelvic region, with rough surfaces. The tumorswere cirrhotic when incised, and moderately differen-tiated adenocarcinomas in a prominent stroma of con-nective tissue. Myelocytes were observed in the tu-mors, especially in areas of necrosis. Originally, thetumors were thought to originate in the dorsolaterallobes that expanded into adjacent areas [1], but exami-nations of tumor-bearing rats earlier in latency periodlocated their origins in the seminal vesicles and in thedorsolateral and anterior lobes [3–7].

P-SV tumors, similar in morphology to the sponta-neous tumors, were induced in L-W rats by 1) one IVinoculation of methylnitrosourea (MNU), in 29/135(21.5%) rats in, on average, 12 months, or by 2) a seriesof slow-release SC implants of testosterone propionatein 14–27% rats in 14 months, or by 3) a combination ofthe two methods, resulting in P-SV tumors in 167 of185 (90%) rats in, on average, 10.5 months; also, thetumors were detected by earlier palpation in 155 of177 (88%) rats in, on average, 8.5 months after inocu-lation of MNU [17,18] (Pollard, unpublished obser-vations). The majority of rats with large tumors haddeveloped discrete metastatic tumors in the lungsand/or in the peritoneal cavity, but not in skeletalbone; however, rats with earlier detected small tumorswere free of metastatic tumors. The time-frames of the

Contract grant sponsor: Coleman Foundation; Contract grant spon-sor: Scully Trust; Contract grant sponsor: University of Notre Dame.*Correspondence to: Morris Pollard, Lobund Laboratory, Universityof Notre Dame, Notre Dame, IN 46556.Received 19 March 1998; Accepted 7 April 1998

The Prostate 37:1–4 (1998)

© 1998 Wiley-Liss, Inc.

tumorigenesis process were related to the shorter lifespan of rats compared to the much longer life span ofman.

Four sequential stages of tumorigenesis were noted:1) premalignant intraluminal cellular hyperplasia, de-scribed as prostate epithelial neoplasm (PIN) byBostwick [19]; 2) androgen-independent cancer cellsthat penetrated the ductal and acinar walls into anextensive stroma, which 3) switched spontaneously tothe androgen-independent stage; and 4) metastaticspread of tumor cells to the target sites noted above.

Early stages of spontaneous and induced tumorswere prevented by dietary restriction [20] and by SC-implanted nonesterified dihydrotestosterone (DHT)[21] (Table I). Early stages of induced tumors in L-Wrats were prevented by estradiol cypionate [22], cas-tration [22], DHT [22,23], angiostatic linomide [23],and tamoxifen [24]. These same agents were inactivein rats that had developed palpable tumors prior totreatment [22,25]. In rats that were fed soy proteinisolates, with high isoflavone content, from an earlyage, the onset of P-SV tumors was delayed [26]. Meta-static spread of cells from induced autochthonous tu-mors was suppressed by IV inoculation of viable BCGorganisms, but direct penetration of cells through thegland capsule into the peritoneal cavity was not inhib-ited [27].

As noted above, following an early SC implant ofnonesterified 5a dihydrotestosterone (DHT) (5a [an-drostan-17b-ol-3-one]), the development of spontane-ous and induced P-SV tumors was suppressed [21–23],but DHT had no tumor-inhibitory effect in rats if itwas administered after they had developed palpabletumors [21,22]. The tumor-inhibitory effect of DHTwas confirmed in Fisher rats [8,28]. DHT propionate[23] and benzoate [11] did not interfere with develop-ment of tumors. DHT implants caused suppression oftestosterone production and of spermatogenesis. In

the absence of the substrate, testosterone, DHT wasnot produced through the action of 5a reductase. Thiseffect was interpreted as feedback inhibition of thehypothalamic-pituitary-testicular axis. Implants ofDHT did not produce overt adverse effects, and theblocked physiological functions noted above were re-versible by removal of the implant of DHT. Since thetumor-suppressive effects of DHT were not complete,it is likely that some of the early androgen-dependenttumors had already switched to androgen-independent status prior to onset of DHT treatment.Early onset of DHT treatment did interfere with de-velopment of MNU/TP-induced tumors [11]. Earlypublications described very high concentrations ofDHT in the seminal vesicles of rats, which may ex-plain seminal vesicles as an early development site ofP-SV tumors [29,30]. That early tumors were andro-gen-dependent, and not an independent line of cells, issupported by the absence of tumors in rats and in menwho were castrated at early ages [22,31]. It was im-pressive that rats with large, actively growing tumorswere negative for detectable testosterone in theirblood: their tumors had developed androgen-independent status.

Since no model is a perfect replica of the counter-part disease that it serves, how does the P-SV tumorsystem in L-W rats equate with the counterpart pros-tate cancer in man? The inherent susceptibility tospontaneous disease, i.e., its natural history, is the bestmodel, remote from the more aggressive induced neo-plasm, and more remote from the transplanted tumorswhich are fundamentally artifacts. However, both au-tochthonous tumor systems will reveal importantmessages: What genetic ‘‘lesion’’ explains susceptibil-ity? What initiates the spontaneous disease, and whythe switch from androgen-dependent to -independentdisease? Is the change attributed to the age-relateddecline of circulating testosterone? Is the suppressionof testosterone in the testicle also related to its produc-tion in the adrenal gland? Is spontaneous metastasis topredetermined target sites an inherent characteristic ofthe tumor cell? Intervention of gene-regulated mecha-nisms in P-SV tumorigenesis has been implementedby epigenetic and environmental factors, which mustbe further addressed. How can inherent ethnic differ-ences in endogenous mechanisms, such as levels of 5areductase, be modified to control the production ofDHT? Finally, to what extent are aberrant physiologi-cal mechanisms responsible for cancer development;and possibly are they the mechanism(s) by which theycan be controlled?

While investigators may be reluctant to invest time,effort, and funds in this slow-developing spontaneoustumor, is it more productive to apply those resourcesto transplanted tumors which often reveal data of lim-

Fig. 1. Spontaneous prostatic-seminal vesicle cancer in Lobund-Wistar rat, age 20 months. Tumor weight 25.5 g, metastatic toperitoneal cavity.

2 Pollard

ited relevance to the autochthonous disease? Two de-cisive sequential events must be addressed: 1) the de-velopment of androgen-dependent tumors, which in-evitably progress to 2) androgen-independent tumorswhich, in man, also constitute the lethal terminationpoint. Lacking effective cytotoxic agents and with the

failure of androgen-ablative procedures in advancedstage tumors, the prospective plans of experimentaloncologists should focus on 1) decisively preventingthe development of androgen-dependent stages of P-SV tumors, without adverse effects on the host; and 2)therapeutic inhibition of mitogenic tumor-promotingfactors in advanced tumor stages. Exemplary of thelatter are studies on insulin-like growth factors [33]and on decorin, a small chondroitin sulfate proteogly-can [34]. I am confident that the autochthonous P-SVtumor systems described here will contribute substan-tially to our knowledge of prostate cancer.

ACKNOWLEDGMENTS

I have learned much from this experimental ven-ture, especially from the interest and advice of fellowinvestigators with whom I shared animals and proce-dures, and from others who confirmed some of myunexpected observations. I thank them all, and espe-cially Phyllis Luckert for 30 years of devoted commit-ment to this continuing challenge from its fortuitousbeginning.

REFERENCES

1. Pollard M: Spontaneous prostate adenocarcinomas in agedgermfree Wistar rats. J Natl Cancer Inst 1973;511:1235–1241.

2. Pollard M, Luckert PH: Transplantable metastasizing prostateadenocarcinomas in rats. J Natl Cancer Inst 1975;54:643–649.

TABLE I. Comparison of Effects of Agents and Procedures onAutochthonous P-SV Tumors in Lobund-Wistar Rats*

Prevention Therapy Reference

Spontaneous tumorsDiet restriction + − 20Dihydrotestosterone + − 21

Induced tumorsDiet restriction + − Unpublished dataDihydrotestosterone + − 22,23Estradiol + − 22Castration + − 22Linomide + − 23,25Tamoxifen + − 24Hypophysectomy + ND Unpublished dataSoy isoflavones +a − 26BCG-IV inoculation +a − 27

*Rats were examined for spontaneous tumors until age 24 and 26 months. Rats,examined for effects of agents and procedures on development of induced P-SVtumors, were monitored for 14 months after inoculation of MNU.aWhile IV-inoculated BCG was inactive against the primary tumor, metastasiswas suppressed to the lungs, but direct passage of tumor cells into the perito-neal cavity was not suppressed. Isoflavones delayed onset of P-SV tumorgrowth.

TABLE II. Comparison of Autochthonous P-SV Tumorsin L-W Rats and Prostate Cancer in Man*

In L-W ratsa Manifestation In man [35]

+ Familial ++ Age-related ++ Spontaneous ++ Testosterone promotion ++ Premalignant PIN ++ Adenocarcinoma ++ Androgen-dependent ++ Androgen-independent ++ Metastatic +− Therapy −Early prevention by+ Castration ++ Anti-androgens ++ Dietary modulation +

*Except for initial sites in prostate-seminal vesicle in L-W ratsand posterior lobe in man, and no metastatic spread of P-SVtumors to bone.aThis information is derived from a number of our pertinentpublications, some of which are in the list of references reportedhere.

L-W Rat Model of Prostate Cancer 3

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