transforming-growth-factor-alpha and Cystadenoma

The biologic significance of epidermal growth factor (EGF)-related proteins and EGF receptor (EGFR) in the development and progression of human ovarian carcinoma was studied in 7 ovarian cystadenomas, 6 mucinous tumors of low malignant potential (LMP), and 25 invasive adenocarcinomas by immunohistochemistry. Results were correlated with clinicopathologic features. We also examined immunoreactivity in five serous adenocarcinomas both before and after cisplatin chemotherapy. Amphiregulin (AR) expression was observed only in mucinous tumors (4 of 8 cystadenomas, 2 of 6 tumors of LMP, and 6 of 10 cystadenocarcinomas), but was not detected in the serous tumors or clear cell adenocarcinomas. EGF, cripto, and EGFR expression was significantly higher in mucinous cystadenocarcinomas than in mucinous cystadenomas or mucinous tumors of LMP. Three of five specimens obtained at a second operation after chemotherapy had more intense or diffuse immunostaining for transforming growth factor alpha (TGF-alpha) than the initial specimens did. Coexpression of more than two of the EGF-related proteins or EGFR significantly correlated with increased surgical stage in serous and clear cell carcinoma. AR expression seems to correlate with mucinous differentiation rather than with advanced stages of ovarian tumors. Our results indicate that expression of some EGF-related proteins is greater in certain subtypes of ovarian carcinomas than in their benign counterparts and that coexpression of these proteins is associated with advanced stage in serous and clear cell carcinoma. Increased TGF-alpha expression may also be related to ovarian tumor resistance to cisplatin chemotherapy.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; Biomarkers, Tumor; Cystadenoma; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Middle Aged; Ovarian Neoplasms; Transforming Growth Factor alpha

Although transforming growth factor (TGF) alpha and epidermal growth factor (EGF) receptor (EGFR) autocrine mechanism is widely demonstrated in many kinds of cancers, its biological significances still remain circumstantial. We critically assessed the significance of this mechanism on the growth of an ovarian cancer cell line. Northern blot analysis in polyadenylated RNA isolated from cells by using 32P-labeled pre-TGF alpha, EGRF, and prepro-EGF complementary DNAs as probes revealed that pre-TGF alpha and EGFR but not prepro-EGF gene transcripts were expressed in the cell. TGF alpha and EGFR but not EGF proteins were observed by immunocytochemical stainings, using monoclonal antibodies against human TGF alpha, EGFR, and EGF, respectively. This cell line possessed a class of high affinity EGF receptor by 125I-EGF binding studies; Kd being 2.9 x 10(-10) M and Bmax to be 7.7 x 10(4) sites/cell. As much as 1.12 +/- 0.14 ng (SD; n = 3)/10(7) cells/24 h of TGF alpha was secreted in the conditioned media. These results suggested the expression of a TGF alpha/EGFR autocrine mechanism in this cell line. We, therefore, assessed the biological significance of this mechanism on the growth of this cell line in serum-free monolayer cell cultures. Although 0.1, 1.0, and 10 nM concentrations of TGF alpha did not show significant growth promotion, monoclonal antibodies against TGF alpha and EGFR but not EGF significantly inhibited cell growth. All these data suggested the biological importance of a TGF alpha/EGFR autocrine mechanism on the growth of this cell line in vitro.

Topics: Antibodies, Monoclonal; Antigens, Tumor-Associated, Carbohydrate; Biomarkers, Tumor; Blotting, Northern; Cell Division; Cell Line; Culture Media, Serum-Free; Cystadenoma; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Kinetics; Ovarian Neoplasms; Poly A; Protein Precursors; RNA; RNA, Messenger; Transforming Growth Factor alpha; Transforming Growth Factor beta

We have elucidated the importance of a transforming growth factor (TGF) alpha and epidermal growth factor receptor autocrine mechanism on the growth of a human ovarian serous cystadenocarcinoma-derived cell line (SHIN-3) in vitro. In this study, we studied the biological significance of this autocrine mechanism in vivo using female athymic nude (nu/nu) mice. We measured the mouse plasma epidermal growth factor and TGF alpha levels by radioimmunoassay and enzyme-linked immunosorbent assay, respectively. Plasma epidermal growth factor concentrations were remarkably decreased by sialoadenectomy (Sx): 410 +/- 65 (SE) pg/ml (n = 10) in intact animals; and undetectable in Sx mice (n = 5). Plasma TGF alpha levels were 90 and 40 pg/ml in intact and in Sx animals, respectively. Ten million SHIN-3 cells inoculated into nu/nu mice formed tumors in 100% of mice, and tumors grew progressively. Implantabilities and tumor growth rates of inoculated cells were not affected by Sx and even by Sx and anti-mouse epidermal growth factor antibody treatment. However, anti-TGF alpha monoclonal antibody (mAb) administered to SHIN-3 cell-inoculated Sx animals drastically reduced the tumor growth. Although 10(7) SHIN-3 cells formed tumors in this group, tumor growth was significantly inhibited by 10 micrograms of anti-TGF alpha mAb given 3 times a week, and growth inhibitions were more by 20 micrograms of anti-TGF alpha mAb. Moreover, as aggressive tumor growth as that in Sx animals was resumed by the cessation of anti-TGF alpha mAb treatments. All these data suggested the biological importance of a TGF alpha/epidermal growth factor receptor autocrine mechanism on the growth of this cell line in vivo.

Topics: Animals; Antibodies, Monoclonal; Cell Division; Cell Line; Cystadenoma; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor; ErbB Receptors; Female; Humans; Kinetics; Mice; Mice, Nude; Neoplasm Transplantation; Ovarian Neoplasms; Radioimmunoassay; Transforming Growth Factor alpha; Transplantation, Heterologous