Telomerase activity in benign and malignant epithelial ovarian tumors.

BACKGROUND: Ovarian epithelial tumors include benign lesions lacking invasive and metastatic abilities (cystadenomas) in addition to malignant lesions (carcinomas). An intermediate category, called tumors of low malignant potential (LMP), is also recognized. The merit of this classification is being challenged because the clinical behavior of LMP tumors appears closer to that of cystadenomas than to that of carcinomas. PURPOSE: To verify our hypothesis that the expression of the enzyme telomerase distinguishes these two categories of ovarian epithelial tumors, we examined and compared such expression in ovarian cystadenomas and carcinomas. By examining the expression of telomerase in LMP tumors, we then sought to determine if these tumors were more closely related to cystadenomas or to carcinomas with regard to telomerase expression. METHODS: We examined a total of 64 consecutive ovarian tumors subdivided into 20 carcinomas, 17 LMP tumors, and 27 cystadenomas. We subsequently discarded three of the 27 cystadenomas because of the presence of admixed normal ovarian stroma in those specimens. Tumor subtyping was done without knowledge of the telomerase results, and telomerase assays were likewise interpreted without knowledge of tumor types. Telomerase activity was determined by use of the TRAP (i.e., telomeric repeat amplification protocol) assay. Differences between the proportions of tumors expressing this enzyme in each subgroup were evaluated by use of Fisher's exact test (two-sided). RESULTS: Telomerase activity was detected in all 20 carcinomas and in all 17 LMP tumors examined. In contrast, it was not detected in 19 of the 24 cystadenomas. These differences between rates of telomerase expression in either carcinomas or LMP tumors and those in cystadenomas were statistically significant (P<.0001). All five of the telomerase-positive cystadenomas belonged to a variant called papillary cystadenomas, whereas none of the telomerase-negative cystadenomas belonged to this variant (P<.0001). CONCLUSIONS AND IMPLICATIONS: The presence of telomerase expression in ovarian LMP tumors supports the merit of continuing to separate these tumors from cystadenomas, in spite of their apparent benign clinical course. The finding of telomerase expression in papillary cystadenomas suggests that such tumors may be mechanistically related to LMP tumors and should perhaps be reclassified as variants of LMP tumors. Lack of telomerase expression in ovarian cystadenomas raises questions about the alleged immortality of these tumors because expression of this enzyme is thought to be essential for continuous growth in adult tumors.

Growth regulation of the human papillary thyroid cancer cell line by protein tyrosine kinase and cAMP-dependent protein kinase.

We established a cell line (hPTC) from the tissue of papillary thyroid cancer surgically excised from a 27-year-old female patient. Synthesis of cAMP by the hPTC cells was stimulated by TSH. This cell line has continued to divide as a monolayer in a tissue culture for three years. We assessed growth regulation of the hPTC cells by protein tyrosine kinase and cAMP-dependent protein kinase by measuring the DNA content of the hPTC cells in 24-well plates with 3,5-diaminobenzoic acid after incubation in various growth factors. Basic fibroblast growth factor (FGF), epidermal growth factor (EGF), and insulin-like growth factor-1 (IGF-1), all of which bind to their respective receptors with tyrosine kinase activity, stimulated DNA synthesis in the hPTC cells. Neutralizing antibodies to basic FGF and EGF suppressed the growth stimulation by basic FGF and EGF, respectively. Genistein, a specific protein tyrosine kinase inhibitor, inhibited proliferation of the hPTC cells. On the other hand, thyrotropin, dibutyryl cAMP (dBC) and forskolin inhibited proliferation. KT5720, a specific cAMP-dependent protein kinase inhibitor, restored the growth of the hPTC cells even in the presence of dBC. This study shows that stimulation of the protein tyrosine kinase activity by basic FGF, EGF, and IGF-1 promoted DNA replication by the human thyroid cancer cell line. However, activation of the cAMP-dependent protein kinase inhibited proliferation of this cell line.