431 



PHYSIOLOGY OF GONADS 



the epithelium occurred in the RIII strain 

 but no malignant proliferation of metaplas- 

 tic cells followed. It was noted that the 

 epithelial changes which occurred with 

 raethylcholanthrene treatment were "almost 

 identical" with the secjuence of changes fol- 

 lowing prolonged estrogen administration in 

 Strong A mice (Horning, 1947). 



Horning (1949, 1952) studied the effects 

 of castration, diethylstilbestrol, and testos- 

 terone propionate on growth rates of pros- 

 tatic tumors transplanted as grafts. Tumors 

 were induced in ventral prostate, dorsal 

 prostate, and coagulating gland tissue of 

 Strong A mice by wrapping pieces of epi- 

 thelium around crystals of methylcholan- 

 threne and transplanting the grafts su!)cu- 

 taneously into 75 intact males. Of the 54 

 tumors which developed, 42 were adenocar- 

 cinomas or secreting glandular carcinomas, 

 10 were squamous cell carcinomas, and 2, 

 spindle cell sarcomas. Neoplastic develop- 

 ment began, apparently, in epithelium in 

 a nonsecretory phase, and hyperplastic 

 changes followed the sequence of mitosis, 

 abnormal cell division, and pyknosis ac- 

 companied by an increase in fibromuscular 

 tissue. Three distinct types of epithelial pro- 

 liferation then occurred; one, with tongue- 

 like groups of early malignant cells, gave 

 rise to secretory glandular carcinomas; the 

 second, from acinar ejMthelium, and the 

 third, from duct epithelium, developed into 

 squamous cell carcinomas with keratiniza- 

 tion and formation of keratin pearls. Some 

 grafts had foci of the first and third type 

 and the evidence suggested that the tumors 

 subsequently became squamous cell carci- 

 nomas. Both tumor types were transplanta- 

 ble and were cari'icd through many serial 

 transi)lantations without losing their histo- 

 logic characteristics. 



In an effort to study effects of testicular 

 androgen on growth, transplants of an ade- 

 nocarcinoma were made into intact and cas- 

 trated males. The tumors grew rapidly and 

 progressively in intact mice but regressed 

 in castrates. Testosterone propionate ad- 

 ministration to castrated males bearing re- 

 gressed tumors resulted in a resumption of 

 tumor growth in some cases. Gonadectomy 

 of the host had little effect on the growth of 

 transplanted s(|uamous cell carcinomas. An- 



drogen-dependence of secreting glandular 

 carcinomas was suggested. 



When stilbestrol pellets were implanted 

 into one flank of intact males and a glandu- 

 lar carcinoma into the opposite flank, the 

 effects varied from slight to pronounced re- 

 tardation of the tumor but complete re- 

 gression did not occur. The squamous cell 

 carcinomas were insensitive to stilbestrol. 



Additional experiments (Horning, 1952) 

 involved transplanting pieces of prostatic 

 epithelium impregnated with methylcholan- 

 threne alone, or with the carcinogen com- 

 bined with stilbestrol or testosterone pro- 

 pionate into intact males (groups of 35 

 for each treatment). The carcinogen alone 

 induced 8 adenocarcinomas and 5 squamous 

 cell carcinomas; carcinogen and stilbestrol, 

 23 squamous cell carcinomas and 3 sar- 

 comas; carcinogen and testosterone pro- 

 pionate, 2 squamous cell carcinomas and 1 

 sarcoma. The increased tumor incidence 

 with estradiol was interpreted as an in- 

 hibitory action of the estrogen on secretory 

 epithelial cells, making them more suscepti- 

 ble to methylcholanthrenc. 



Brandes and Bourne (1954) made homo- 

 grafts of pieces of ventral and anterior pros- 

 tate (coagulating gland) impregnated with 

 methylcholanthrenc into intact males of the 

 Strong A strain, and studied histochemical 

 changes. The grafts underwent squamous 

 metaplasia and the processes of epithelial 

 proliferation, stratification, and keratiniza- 

 tion were completed within 10 days in some 

 cases. Histochemical changes from the nor- 

 mal i)attern (Table 6.8) occurred concur- 

 rently. Alkaline phosphatase activity dis- 

 appeared early; acid phosphatase activity 

 became weak in nuclei and cytoplasm but 

 keratohyalin granules were strongly reac- 

 tive; PAS-positive reactions were gradually 

 lost in luminal secretion and intracyto- 

 plasmic granules but retained in the base- 

 ment membrane. In some grafts there was 

 transformation into squamous cell carcino- 

 mas and when this happened phosjihatase 

 activity was lost but the basement mem- 

 branes were still PAS-positive. 



Lasnitzki (1951, 1954, 1955a. b, 1958) 

 grew ventral jirostate glands from C3H and 

 Strong A mice in culture by the watch-glass 

 t('chnif|ue and added methylcholanthrenc to 

 the medium. Hyperplasia and squamous 

 metaplasia resulted in glands ex]ilanted 



