834 



THE CARCINOGENIC STIMULUS 



also occur spontaneously, but only occasionally in inbred mice (Gardner, 1943b). 

 Natural and synthetic estrogens have both been effective tumorigenic agents 

 (Gardner, 1943a; Bonser, 1942). 



TESTICULAR TUMORS FOLLOWING ESTROGEN 



Fig. 25. Development of mouse testicular (inter- 

 stitial) cell tumors following administration of 

 estrogenic hormone. The induced tumors may 

 grow only in estrogen-treated mice of the same 

 inbred strain, indicative of estrogen-dependence. 



PITUITARY GLAND 



(I) ESTROGEN 

 EXOGENOUS, 



(2) HYPERSECRETION 

 OF ICSH 



(3) INTERSTITIAL 

 CELL NEOPLASM* 



TRANSPLANTS INTO 



ESTROGEN-TREATED 



HOSTS 



RESPONSE DETERMINED 



BY GENETIC 



CONSTITUTION 



That the mechanism of induction involves the pituitary gland is suggested by 

 the following experiments. As in the case of ovarian tumors, testicular tumors have 

 developed in testes transplanted to the spleens (Fig. 26) of castrated animals 

 (Biskind and Biskind, 1945; Twombly et al., 1949; Jones, 1955). The degree of 

 success is less, however, than with ovarian grafts. Heterologous sera with large 

 amounts of antigonadotrophin may inhibit the induction of testicular tumors by 

 estrogenic hormone (Ely, 1953). 



The administration of exogenous estrogen probably induces excessive secretion 

 by the pituitary gland of a tumor-producing gonadotrophin (Fig. 25) ; response 

 of the testicular target tissue is determined genetically (Fig. 26) (Trentin and 

 Gardner, 1957). Tumor induction initiated by the injection of estrogen may be 

 completed by gonadotrophin although injection of exogenous gonadotrophin 

 produces only interstitial cell hyperplasia (Pfeiffer and Hooker, 1943). 



Fig. 26. Sequences of events in testicular 

 tumorigenesis when testis is grafted to the 

 spleen. 



TESTICULAR TUMORIGENESIS FOLLOWING 

 TRANSPLANTATION TO SPLEEN 



PITUITARY GLAND 



(2) LOW BLOOD 

 LEVEL OF- 

 ANOROGENIC 

 HORMONE 



(I) ANDROGEN SECRETED 

 BY GRAFT INACTIVATED 

 BY LIVER 



(3) HYPERSECRETION 



OF GONADOTROPE 



TO INDUCE 



NTERSTITIAL 



CELL TUMOR 



(4) TESTICULAR 

 TRANSPLANT 

 ^BECOMES NEOPLASTIC) 

 (SECRETES ANDROGEN) 



Transplantation of induced testicular tumors can be effected usually only by 

 estrogenizing histoconapatible recipients (Bonser, 1942; Gardner, 1945). Ander- 

 vonl etal., (1957) have demonstrated that removal of the pellet of tumor-inducing 

 estrogenic hormone is followed by progressive (independent) tumor growth in 

 some cases, regression in others, and resumption of growth with a second hormonal 

 stimulus. A similar mechanism of tumorigenesis may be involved in the induction 



