Structural changes and alteration in expression of TGF-β1 and its receptors in prostatic intraepithelial neoplasia (PIN) in the ventral prostate of noble rats

Abstract

BACKGROUND. Prostatic intraepithelial neoplasia (PIN) is the most likely pre-cancereous lesion and represents the major target for chemoprevention of prostate cancer. The multifunctional role of TGF-β1, together with its receptors, 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 combination of testosterone (T) and estradiol (E2) for various periods of time, and processed for ultrastructural examination and histopathological grading. To evaluate the role of TGF-β1 and TGFβ receptor types I and II in normal prostate and high-grade PIN development, expression pattern of TGF-β1 and TGFβ-RI and TGFβ-RII were studied on prostate samples with PIN lesions. RESULTS. Pathologically, low-grade PIN (LGPIN) and high-grade PIN (HGPIN) were observed in ducts or alveoli after three and five months of T + E2 treatment, respectively. EM study revealed that HGPIN cells were characterized by a reduction in abundance of secretory apparatus and the nucleus with highly irregular and undulated membrane and often with inclusion bodies although the basal lamina remained largely normal. This was associated with a high level of expression of TGF-β1 in stromal tissue subjacent to foci of HGPIN. No definite positive reactivity of TGF-β1 was identified in glandular epithelial ceils of HGPIN. These results implicated that the major site for the TGF-β1 production remained to be restricted to stromal compartment at the stage of HGPIN, and a paracrine regulation of TGF-β1 might be involved in the development of HGPIN. Positive staining for the TGFβ-RI was found in the cytoplasm of luminal epithelial ceils of normal ventral prostate. The intense positive reactivity for TGFβ-RI was also identified in prostates with HGPIN lesions. Similar expression pattern of TGFβ-RII was also observed. CONCLUSIONS. Based on the EM study, we concluded that HGPIN in ventral prostate was accompanied with alterations in nuclear morphology together with a change in secretory activity. The over expression of TGFβ-RI and RII in HGPIN cells as well as TGF-β1 in stromal tissue subjacent to HGPIN implicated a growth-stimulating role instead of inhibiting role of this peptide growth factor during the early stage of prostatic neoplasia. (C) 2000 Wiley-Liss, Inc.