Structural changes and alteration in expression of TGF-beta 1 and its receptors in prostatic intraepithelial neoplasia (PIN) in the ventral prostate of noble rats

BACKGROUND. Prostatic intraepithelial neoplasia (PIN) is the most likely pr e-cancereous lesion and represents the major target for chemoprevention of prostate cancer. The multifunctional role of TGF-beta1, together with its r eceptors, in normal prostate and development of prostatic neoplasia remains controversial and requires further investigation. METHODS. Ventral prostates were removed from Noble rats treated with a comb ination of testosterone (T) and estradiol (E-2) for various periods of time , and processed for ultrastructural examination and histopathological gradi ng. To evaluate the role of TGF-beta1 and TGF beta receptor types I and II in normal prostate and high-grade PIN development, expression pattern of TG F-beta1 and TGF beta -RI and TGF beta -RII were studied on prostate samples with PIN lesions. RESULTS. Pathologically, low-grade PIN (LGPIN) and high-grade PIN (HGPIN) w ere observed in ducts or alveoli after three and five months of T + E-2 tre atment, respectively. EM study revealed that HGPIN cells were characterized by a reduction in abundance of secretory apparatus and the nucleus with hi ghly irregular and undulated membrane and often with inclusion bodies altho ugh the basal lamina remained largely normal. This was associated with a hi gh level of expression of TGF-beta1 in stromal tissue subjacent to foci of HGPIN. No definite positive reactivity of TGF-beta1 was identified in gland ular epithelial cells of HGPIN. These results implicated that the major sit e for the TGF-beta1 production remained to be restricted to stromal compart ment at the stage of HGPIN, and a paracrine regulation of TGF-beta1 might b e involved in the development of HGPIN. Positive staining for the TGF beta -RI was found in the cytoplasm of luminal epithelial cells of normal ventra l prostate. The intense positive reactivity for TGF beta -RI was also ident ified in prostates with HGPIN lesions. Similar expression pattern of TGF be ta -RII was also observed. CONCLUSIONS. Based on the EM study, we concluded that HGPIN in ventral pros tate was accompanied with alterations in nuclear morphology together with a change in secretory activity. The over expression of TGF beta -RI and RII in HGPIN cells as well as TGF-betaZ in stromal tissue subjacent to HGPIN im plicated a growth-stimulating role instead of inhibiting role of this pepti de growth factor during the early stage of prostatic neoplasia. (C) 2000 Wi ley-Liss, Inc.