Epidermal growth factor receptor expression in normal and malignant endometrium

Epidermal growth factor receptor expression in fresh-frozen uterine tissues was studied with the use of monoclonal antibody 528, which recognizes an epitope on the external domain of the epidermal growth factor receptor. Immunohistochemically detectable epidermal growth factor receptor was seen in all uterine cell types in 19 of 20 normal uteri. Staining of endometrial glands and endometrial stromal cells was consistently greater than that of myometrium, and no variation in intensity or distribution of staining was seen during the menstrual cycle. Immunohistochemically detectable epidermal growth factor receptor was found less frequently in endometrial adenocarcinomas than in normal endometrium (p less than 0.01). Thirteen of 40 endometrial adenocarcinomas (32.5%) did not express detectable receptor. Epidermal growth factor receptor expression did not correlate with histologic grade, depth of myometrial invasion, estrogen-progesterone receptor status, the presence of extrauterine metastases, or the development of recurrent disease.     

Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. II. Relationship between receptor expression and response to epidermal growth factor

Previously we have shown that epidermal growth factor acts as a mitogen for some, but not all, ovarian cancer cells in culture. In this study we examined the effect of epidermal growth factor on proliferation of normal human ovarian epithelial cells in monolayer culture. We found that epidermal growth factor stimulated twofold to fourfold increases in proliferation in epithelial cells from each of five normal ovaries (p less than 0.01). In addition, Scatchard analysis of binding of epidermal growth factor tagged with iodine 125 indicated the presence of high-affinity receptors in all of the ovarian epithelial cells and ovarian cancer cell lines. The number and affinity of receptors was similar in the normal epithelium and cancer cell lines, and there was no relationship between epidermal growth factor receptor number and responsiveness to epidermal growth factor. We conclude that human ovarian epithelial cells normally express epidermal growth factor receptors and that epidermal growth factor acts as a mitogen for these cells. Although the mitogenic response to epidermal growth factor often is attenuated in ovarian cancer cell lines, loss of responsiveness to epidermal growth factor does not appear to be due to decreased receptor expression.     

Epidermal growth factor receptor expression in the normal and inflamed cervix uteri: a comparison with estrogen receptor expression

The expression of epidermal growth factor receptor (EGFR) was studied in the normal and inflamed cervix uteri, and the results were compared with estrogen receptor (ER) expression. The study was performed on fresh frozen specimens from 18 cases by means of immunohistochemistry, with application of EGFR1 antibody and an ER-ICA kit (Abbott, Wiesbaden, F.R.G.). The EGFR was expressed by the basal and parabasal layers of ectocervical and metaplastic epithelium and by reserve cells. No cyclic fluctuations in EGFR expression were noted. The glandular epithelium did not express EGFR. Some glands stained positive in the region of the basement membrane. Staining was not diminished in inflammatory foci, in contrast to ER expression, which was trace or absent. This was observed in both normal and dysplastic squamous epithelium. It may be assumed that the change of the normal relationship between ERs and EGFRs influences the process of proliferation and maturation of the squamous epithelium and may play a role in its disturbances.     

Epidermal growth factor receptor expression in normal endometrium and endometriosis: an immunohistochemical study.

OBJECTIVE: To study epidermal growth factor (EGF) receptor expression in endometrium throughout the menstrual cycle and to compare EGF-receptor expression in endometrium from patients with endometriosis with receptor expression in synchronously sampled endometriosis and in endometrium from healthy women. DESIGN: An immunohistochemical study of receptor expression using murine monoclonal antibodies and timed endometrial and endometriotic biopsies. SUBJECTS: 25 healthy women and 27 patients with a diagnosis of endometriosis. RESULTS: Positive staining for EGF receptors was observed in 24 of 25 samples from normal women and in 26 of 27 endometrial samples from patients with endometriosis. In neither group was there any variation in the intensity of staining throughout the menstrual cycle and both glands and stroma were stained. EGF-receptor expression was observed in the glands of 15 out of 17 endometriotic lesions and in 12 of these biopsies positive staining was also present within endometriotic stroma. CONCLUSION: This study shows no difference in the intensity of staining of EGF receptors in endometrium throughout the menstrual cycle or between the glands of normal endometrium and those of endometriosis.     

Epidermal growth factor binding and receptor distribution in term human placenta

Human placenta has a large number of epidermal growth factor (EGF) receptors when measured either by [125I]iodoEGF binding or by protein yield after purification. To localize EGF receptors in situ in normal human term placenta, two different light microscopic methods were used. To detect unoccupied, accessible EGF binding sites on the extracellular surface of placental cells in intact blocks of tissue, samples were incubated with [125I]iodoEGF, sectioned and autoradiography performed. To detect the total pool of intracellular and extracellular EGF receptors, placental tissue was sectioned, treated with detergent, and then anti-EGF receptor antibody was localized by immunohistoperoxidase techniques. Both [125I]iodoEGF and anti-EGF receptor antibody methods showed that EGF receptors were primarily present on syncytiotrophoblast cells of placental villi. Smooth muscle cells of placental blood vessels also contained EGF receptors. Neither connective tissue cells within the core of terminal chorionic villi nor endothelium of fetal blood vessels had detectable [125I]iodoEGF binding or immunoreactive EGF receptors. Since the quantity of placental smooth muscle cells is only a small fraction compared to trophoblast cells, we conclude that syncytiotrophoblast cells are primarily responsible for the high levels of EGF receptors found in extracts prepared from human term placenta.     

Epidermal growth factor receptor and human epidermal growth factor receptor 2 gene polymorphisms in endometrial cancer in a Japanese population

Endometrial cancer is associated with both EGFR and HER2 receptor activation. The EGFR and HER2 genes could be disease susceptibility candidate genes for this cancer. This study was conducted to investigate a possible association between EGFR and HER2 gene polymorphisms and endometrial cancer and the influence of these polymorphisms on the clinical outcome of endometrial cancer patients in a Japanese population. The authors compare the genotype distributions and allele frequencies of the EGFR +2073 A/T and HER2 +655 A/G polymorphisms in 116 endometrial cancer patients and 213 controls using polymerase chain reaction-restriction fragment length polymorphism (RFLP) analysis. RFLP results were confirmed by direct DNA sequencing. Of the 116 patients, 76 (65.5%) could be followed up. Disease-free survival estimates were computed using the Kaplan-Meier method, and differences between survival periods were assessed using the log-rank test. No significant differences were observed in either genotype distributions or allele frequencies in the EGFR +2073 A/T and HER2 +655 A/G polymorphisms between endometrial cancer patients and controls. The stratification by histological types and staging failed to identify significant differences between endometrial cancer patients and controls. No statistical differences were noted between these polymorphisms and disease-free survival (Kaplan-Meier log-rank test P = .55 and .66, for the EGFR +2073 A/T and HER2 +655 A/G, respectively). These results suggest that the EGFR +2073 A/T and HER2 +655 A/G polymorphisms are not associated with endometrial cancer in a Japanese population. These conclusions are based on relatively small numbers and will require verification from additional independent studies.     

Epidermal growth factor receptor expression and the presence of human papillomavirus in cervical squamous intraepithelial lesions.

To determine the relationship between the expression of epidermal growth factor receptor (EGFR) and the presence or type of human papillomavirus (HPV) in cervical squamous intraepithelial lesions (SIL), paired colposcopically directed cervical biopsies were obtained from 88 patients referred for abnormal Papanicolaou smears. One biopsy was formalin-fixed and processed for conventional light microscopy, and the other was immediately frozen. A portion of the frozen tissue was used for Southern blot HPV DNA hybridization and a portion for immunohistochemical studies for EGFR using a monoclonal antibody. Forty-seven cases were SIL and 41 were normal. In 41 (87%) of the cases of SIL and in eight (20%) of the normal cases, HPV DNA was detected. Of the SIL cases, HPV 16 was the most frequently detected type, being present in 12 (25%), followed by 10 (21%) types 31 or 35, nine (19%) types 52 or 56, five (11%) uncharacterized types, three (6%) type 18, and two (4%) multiple types. Regardless of histology, EGFR was detected in all cases. In normal cases, EGFR expression was detected in the basal cells only and in SIL in abnormal proliferating parabasal cells such that it correlated with the grade of SIL. When stratified by grade of SIL, no differential expression of EGFR was seen in cases where HPV was detected; in contrast, in cases where no HPV was detected, no differential expression was seen between cases of different HPV type. Thus, EGFR is expressed by all proliferating squamous epithelial cells and as such correlates with the grade of SIL.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epidermal growth factor receptor in normal ovaries and benign ovarian tumours.

Epidermal growth factor receptor (EGFR) was assayed in 52 women who had normal ovaries removed at hysterectomy and in 30 women with benign ovarian tumours. The histology of each ovary was recorded. A single point screen was performed on all samples and in positive cases a full Scatchard analysis. EGFR was present in 8 of 52 normal ovaries (15.4%) and 3 contained the high-affinity component while 5 had the low affinity component. In the benign ovarian tumour group 4 of 30 tumours (13.3%) had receptor present, one was high affinity and 3 were low affinity in type. We can conclude that EGFR is detectable only at low frequency in normal and benign ovarian tumours.     

Epidermal growth factor receptor status in four carcinoma of the cervix cell lines

We have evaluated aspects of the EGF receptor content of four human cell lines derived from patients with previously untreated carcinoma of the cervix. Scatchard analysis revealed that three of the lines possessed approximately 2×10⁵ low-affinity and 2×10⁴ high-affinity receptors, whereas the fourth line had approximately 9×10⁴ low-affinity receptors and 9×10³ high-affinity receptors. Immunocytochemical staining using the monoclonal antibody EGFR1 showed wide intra- and inter-line variation in staining intensity. Flow cytometric analysis of EGFR1 demonstrated a fivefold difference in staining intensity between lines. Thirteen cloned derivatives of one of the lines exhibited a 200% variation in EGFR1 staining intensity. There were no differences in radiosensitivity in four of the cloned lines with different EGF receptor levels. Southern blotting analysis did not reveal any rearrangement or amplication of the EGF receptor gene. These three different methods for determining receptor content produced variations in the ranking of receptor number across the four cell lines. These studies with cervix carcinoma cell lines demonstrate the presence of varied levels of EGF receptors according to the methodology used. This may reflect differences in biological characteristics of the cell lines evaluated.     

Epidermal growth factor receptor expression in normal ovarian epithelium and ovarian cancer. I. Correlation of receptor expression with prognostic factors in patients with ovarian cancer

Previous studies in breast and bladder cancer have suggested that epidermal growth factor receptor is expressed by only a proportion of cancers and is associated with poor clinical outcome. We used a monoclonal antibody specifically reactive with the extracellular domain of the epidermal growth factor receptor to localize this receptor immunohistochemically in frozen sections of normal ovary and epithelial ovarian cancer. Normal ovarian epithelium was found to express epidermal growth factor receptor in all cases. Among 87 ovarian cancers, however, 23% did not express immunohistochemically detectable receptor. Epidermal growth factor receptor expression was not related to histologic grade or stage, but was associated with poor survival (p less than 0.05). The median length of survival of patients with tumors that did not express epidermal growth factor receptor was 40 months compared with 26 months in patients with tumors that did express epidermal growth factor receptor. As in breast and bladder cancer, expression of epidermal growth factor receptor in ovarian cancer appears to be a poor prognostic factor.     

Immunohistochemical studies on epidermal growth factor receptor (EGF-R) in gynecological malignant tumor

The expression of Epidermal Growth Factor Receptor (EGF-R) in gynecological malignant tumors was investigated immunohistochemically. 1) With respect to the expression of EGF-R in the uterine cervix, it was seen in 20.0% with benign lesion. In cases of dysplasia, it was expressed in 62.5% of the cases with mild dysplasia, 81.8% with moderate dysplasia and 53.3% with severe dysplasia. In cases of CIS, it was seen in 46.7% and in cases of invasive cancer, it was seen in 22.2%. By hystological type, the expression rates were 27.3% for keratinized squamous cell carcinoma and 33.3% for large cell non-keratinized squamous cell carcinoma. No expression was seen in three cases of small cell non-keratinized squamous cell carcinoma or four cases of adenocarcinoma. In cases of benign lesions, EGF-R was localized in the cell walls of the basal layer, but in cases with dysplasia, it was found in the cell walls and also in the cytoplasm in all layers of the epithelium. 2) The expression rate in endometrial carcinoma was 14.3% and all of these cases were well-differentiated adenocarcinoma. There was no reverse correlation with estrogen receptors. 3) The expression rate for advanced malignant ovarian tumors was 31.4% and there was no clear correlation with the histological type. The prognosis tended to be better in cases expressing EGF-R than in those not. These results indicated that EGF-R appears to be related to the degree of advance of cervical dysplasia, but it was clear that the frequency of expression of EGF-R decreased when the cancer became invasive. In cases of malignant ovarian tumors, the expression of EGF-R tended to be related to the prognosis.     

Epidermal growth factor receptor signaling enhanced by long-term medroxyprogesterone acetate treatment in endometrial carcinoma

OBJECTIVE: Progestin is an effective endocrine treatment for patients with atypical hyperplasia or with endometrial carcinoma that is estrogen receptor (ER) positive and progesterone receptor (PR) positive. However, long-term progestin treatment may lead to resistance. We have studied the progestin resistance phenotype that frequently develops in endometrial carcinoma. METHODS: Ishikawa endometrial carcinoma cells were cultured for a long period (10 months) in the presence of the synthetic progestin medroxyprogesterone acetate (MPA), thereby generating a subline refractory to the growth-suppressive effects of MPA. RESULTS: The MPA-resistant subline showed growth stimulation rather than inhibition after MPA treatment. Immunocytochemical analysis showed reduced ER alpha and PR-B expression and increased ER beta expression in this subline compared with parental Ishikawa cells. Progestin-resistant Ishikawa cells also showed increased expression of transforming growth factor alpha (TGFalpha), the epidermal growth factor receptor (EGFR), and EGFR tyrosine kinase (EGFR-TK); MPA treatment further stimulated the expression of TGFalpha in these cells. Additionally, progestin-resistant Ishikawa cells were highly sensitive to growth stimulation by TGFalpha and to growth inhibition by the EGFR-TK-specific inhibitor AG1478, and they showed increased dependence on TGFalpha-EGFR signaling. CONCLUSIONS: Our results suggest that prolonged treatment of endometrial carcinoma cells with MPA induces resistance to the growth-suppressive effects of MPA and enhances cancer cell proliferation. The downregulation of ER alpha and PR-B, the upregulation of ER beta, and highly activated TGF-EGFR signaling are thus likely to contribute to progestin resistance in endometrial carcinoma. Therefore, an EGFR-TK-specific inhibitor might be useful in the treatment of progestin-resistant endometrial carcinoma.     

Epidermal growth factor and necrotizing enterocolitis

As the number of extremely low-birth-weight infants increases,necrotizing enterocolitis remains a critical eminent problem. Supplementation of enteral feeds with biologically active substances normally present in breast milk, such as epidermal growth factor, seems to be a logical and safe way to reduce the incidence of intestinal inflammation and necrotizing enterocolitis. Continuing basic research and clinical studies are essential before epidermal growth factor can be introduced as an efficient therapeutic approach in the treatment of neonatal necrotizing enterocolitis.     

Increased glycodelin levels in gynecological malignancies

Abstract. Horowitz IR , Cho C, Song M, Flowers LC, Santanam N, Parthasarathy S, Ramachandran S. Increased glycodelin levels in gynecological malignancies.
Glycodelin, an immunosuppressive protein with contraceptive properties, is synthesized by a variety of tissues and cell types. The ability of reproductive tissues to synthesize glycodelin is of major interest in pregnancy and disease conditions. We studied glycodelin levels in subjects with malignant gynecological tumors and in control subjects. Using a polyclonal glycodelin antibody against the synthetic glycodelin peptide sequence, an enzyme-linked immunosorbent assay (ELISA) was devised to measure plasma glycodelin levels. The assay detected as much as 5 ng/ml of glycodelin. There was a significant increase in plasma glycodelin levels in endometrial > ovarian > cervical cancer subjects when compared to those of controls. Strong expression of mRNA and protein were found in the ovarian and endometrial tumor tissues. Given glycodelin's immunosuppressive abilities, increased level of glycodelin may facilitate tumor growth in gynecological malignancies.     

Safe fertility-preserving management in gynecological malignancies

Objective To provide a review in the available literature about the safe fertility-preserving management in gynecological malignancies, focusing on the selection criteria of the patients, treatment options and follow-up. Design Literature survey. Results The incidence of cancer in women who still want to get pregnant is increasing significantly. An early detection in gynecological malignancies allows less aggressive approaches to cure such disorders. A more conservative management, which preserves fertility, is considered safe and an option for those who have not completed their child-bearing. Conclusions Selected patients with cervical, endometrial and ovarian cancer may be candidates to a safe fertility-preserving management. A careful stage and follow-up of the patients is essential to achieve success with this practice.     

胎盘表皮生长因子受体的表达改变与胎儿宫内生长迟缓的关系研究

目的　研究胎儿宫内生长迟缓 (IUGR)患者胎盘表皮生长因子受体 (EGFR)的表达与正常妊娠及巨大儿胎盘之间是否有差异 ,并分析其变化与胎盘绒毛发育是否有关。方法　取足月分娩胎盘组织标本 6 3例 ,于分娩后立即置于 4%中性甲醛缓冲液固定。用免疫组织化学SP法进行胎盘EGFR检测。同时对末梢绒毛血管大小、面积及绒毛面密度等进行分析测量。结果　IUGR组胎盘EGFR的表达较正常对照组和巨大儿组明显增加 (P <0 0 1) ,IUGR胎盘末梢绒毛血管数及血管占绒毛横面积比均明显减少 (P均 <0 0 5 ;P均 <0 0 0 1) ;而巨大儿组与对照组比较无显著性差异。三组胎盘绒毛面密度无显著性差异 (P >0 0 5 )。结论　IUGR儿胎盘EGFR表达增加与其胎盘绒毛发育不良有关 ,EGFR在胎儿胎盘的生长发育及IUGR的发生中起重要调节作用。     

Clinical applications of immunohistochemistry in gynecological malignancies

Over the past two decades, immunohistochemical techniques have improved to such a degree that it is now a common adjuvant test to the traditional hematoxylin and eosin-stained histologic sections. It is used in most realms of surgical pathology and can often aid in final diagnosis and, in some cases, prognosis. However, immunohistochemistry (IHC) is not always helpful and many pitfalls to its use exist. Understanding the basics of IHC, its utility and difficulties will aid clinicians in better understanding how diagnoses are rendered. This study reviews the general principles of IHC and demonstrates its utility with several commonly encountered problematic areas in gynecological pathology.     

妇科肿瘤标志物的一些相关问题

肿瘤标志物是肿瘤组织本身存在和分泌的或机体对肿瘤反应而产生的一类物质,它反映了肿瘤的存在和生长情况。肿瘤标志物的研究已有100多年的历史,只是从20世纪下半叶才受到广泛重视,其定义范畴也从肿瘤相关抗原拓展到包括糖类、蛋白质、激素、酶及同工酶、多胺、病毒性肿瘤相关物质和癌基因产物等。肿瘤标志物人绒毛膜促性腺激素（hCG）、甲胎蛋白（AFP）、CA125、癌胚抗原（CEA）等的发现,在妇科肿瘤的辅助诊断、鉴别诊断、疗效观察、复发监测以及预后评价中发挥了重要作用。这些年来,妇科肿瘤标志物的研究取得了长足的进步。