High TGFbeta1, estrogen receptor, and aromatase gene expression in a large cell calcifying sertoli cell tumor (LCCSCT): implications for the mechanism of oncogenesis.
Large cell calcifying Sertoli cell tumors (LCCSCT) are associated with Carney complex and Peutz-Jeghers syndrome. The mechanisms linking these 2 genetic defects to the genesis of this tumor are obscure. Studies of CYP19 (aromatase) and transforming growth factor (TGF)-beta1 messenger RNA (mRNA) abundance, estrogen receptor (ER), TGFbeta1, and TGFbeta type II receptor (R) immunochemistry were carried out in the testis of a patient with this tumor to gain information on possible mechanisms of cell tumor development. Testicular tissue of a prepubertal patient, collected at gonadectomy, was separated into 2 macroscopically distinct fractions: tumoral nodules (Tu) and extratumoral, normal-looking testicular tissue (ExTu). The patient was a 9.5-year-old boy with a 5-year history of bilateral gynecomastia (Tanner stage 4), no pubic hair, incipient genital development, and bilateral testicular nodules. Multiple pigmented lesions of the skin were present. Bilateral mammectomy and gonadectomy was performed. RNA was extracted from Tu and ExTu for semiquantitative reverse transcriptase-polymerase chain reaction of CYP19 and TGFbeta1. Protein expression of ER, TGFbeta1, and TGFbeta type II R in Tu and ExTu was detected by immunohistochemistry. Cell proliferation was estimated by Ki-67 antigen immunochemistry and apoptosis using a modified TUNEL assay. Mean expression of aromatase and TGFbeta1 mRNAs in Tu was 6- and 2.3-fold higher than in ExTu, respectively (P<0.05). Tumoral cells exhibited ER staining with a predominant extranuclear localization. Positive staining of Sertoli cells in Tu was higher than in ExTu. TGFbeta1 immunostaining of the interstitial cells in Tu was higher than in ExTu. TGFbeta type II R immunostaining was detected in most Sertoli and interstitial cells, but intensity in ExTu was lower than in Tu. No significant difference was detected in the proliferation index, but in Tu, the percentage of Sertoli cells in apoptosis (1.4%) was significantly lower (P<0.01) than in ExTu (14.0%). The following hypothesis is proposed. The congenital gene defects of Carney complex or of Peutz-Jeghers syndrome might trigger a cascade of intracellular events that leads to overexpression of aromatase in Sertoli cells, favoring the development of a LCCSCT. At some point in the evolution of the disease, a mutational event might induce a higher expression of the ER. Also, TGFbeta1 protein expression is increased in neighboring cells. In this environment, TGFbeta1 might switch from tumor suppressor to oncogenic factor and, along with estrogen-ER complexes, might favor tumor progression by inhibiting apoptosis.
Saraco
Nora
N
Laboratorio de Investigación, Hospital de Pediatria Garrahan, Buenos Aires, Argentina.
Berensztein
Esperanza
E
Sciara
Mariela
M
de Davila
Maria T G
MT
Ciaccio
Marta
M
Ferrari
Patricia
P
Belgorosky
Alicia
A
Rivarola
Marco A
MA
D017209:Apoptosis; D001141:Aromatase / Q000235:genetics / Q000378:metabolism*; D002114:Calcinosis; D002648:Child; D015870:Gene Expression; D006177:Gynecomastia / Q000601:surgery; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008954:Models, Biological; D009919:Orchiectomy; D012333:RNA, Messenger / Q000032:analysis; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism*; D012707:Sertoli Cell Tumor / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D013736:Testicular Neoplasms / Q000201:enzymology / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*
D012333:RNA, Messenger; D011960:Receptors, Estrogen; D016212:Transforming Growth Factor beta; D001141:Aromatase