Altered expression of transforming growth factor-beta 1 in cervical neoplasia as an early biomarker in carcinogenesis of the uterine cervix.

Abstract

Transforming growth factor-beta 1 (TGF-beta 1) is a potent growth inhibitor of epithelial cell growth, but can also stimulate stromal cell growth. Loss of responsiveness to TGF-beta 1 or loss of TGF-beta 1 itself may be important in the progression of cervical intraepithelial neoplasia (CIN) to invasive cervical carcinoma. METHODS. To examine the expression of TGF-beta in early stages of malignant transformation of the uterine cervix, paraffin embedded tissue samples from 11 patients with normal cervical epithelium, 15 with CIN I-III, 12 with microinvasive, and 18 with invasive squamous cell carcinoma were examined using an immunohistochemical technique. Tissues were immunostained with polyclonal antibodies that react with intracellular and extracellular forms of TGF-beta 1. Percent positive staining for the intracellular form of TGF-beta 1 was 100% for normal epithelium, 73.3% for CIN, and 44.1% for invasive carcinomas, (P = 0.002). Percent positive staining for the extracellular form of TGF-beta 1 was 63.6% for stroma underlying normal epithelium, 60% for stroma associated with CIN, and 94.1% for stroma surrounding invasive cancer (P = 0.007). Decreased expression of intracellular TGF-beta 1 in neoplastic epithelium and increased expression of extracellular TGF-beta 1 in stroma associated with invasive cervical carcinoma suggest that an early event in the neoplastic transformation of cervical epithelia] cells may involve the loss of TGF-beta 1. Tumor progression may be indirectly promoted by TGF-beta 1 secreted into or produced by supporting stromal elements.