The epithelial ovarian carcinomas, which make up more than 85% of human ovarian cancer, arise in the ovarian surface epithelium (OSE). The etiology and early events in the progression of these carcinomas are among the least understood of all major human malignancies because there are no appropriate animal models, and because methods to culture OSE have become available only recently. The objective of this article is to review the cellular and molecular mechanisms that underlie the control of normal and neoplastic OSE cell growth, differentiation, and expression of indicators of neoplastic progression. We begin with a brief discussion of the development of OSE, from embryonic to the adult. The pathological and genetic changes of OSE during neoplastic progression are next summarized. The histological characteristics of OSE cells in culture are also described. Finally, the potential involvement of hormones, growth factors, and cytokines is discussed in terms of their contribution to our understanding of the physiology of normal OSE and ovarian cancer development.

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Ovarian surface epithelium: biology, endocrinology, and pathology.

Treatment of solid tumors despite improved techniques in detection, surgery, radiation therapy, and chemotherapy remains difficult. Therefore, strategies to improve efficacy in accord with safety are needed. Many epithelial cancers have been found to overexpress the receptor to epidermal growth fact

Epidermal growth factor receptor biology (IMC-C225)

The epidermal growth factor receptor (EGFR), a growth factor receptor involved in the regulation of cellular differentiation and proliferation, is highly expressed by many tumor cells. In light of a relationship between overexpression of EGFR and clinically aggressive malignant disease, EGFR has emerged as a promising target for cancer therapy. In recent years, several molecular strategies have been explored to modulate either the EGFR itself, or the downstream signal beyond the cell surface receptor. One of the most promising current strategies involves the use of anti-EGFR monoclonal antibodies (mAbs), either alone or in combination with conventional cytotoxic modalities such as chemotherapy or radiotherapy. This review focuses primarily on recent progress in the development of anti-EGFR mAbs, and examines their potential in the treatment of cancer.

Epidermal growth factor receptor inhibition in cancer therapy: biology, rationale and preliminary clinical results.

https://www.glowm.com/pdf/Book-OvarianCancerBasicSci-CC-BY-Ch02.pdf

Inflammation and ovarian cancer.

The Wilms' tumor gene WT1 plays multiple roles in the development of the genitourinary organs and Wilms' tumors. The aims of this study were to immunohistochemically evaluate WT1 expression in normal female genital tissues and in epithelial ovarian tumors and to look for correlations between WT1 expression and histologic subtypes and cell proliferation in epithelial ovarian tumors. In normal female genital organs, WT1 expression was recognized in ovarian surface epithelium, the lining of inclusion cysts, and tubal epithelium, but not in the cervical or endometrial epithelium. In epithelial ovarian tumors, serous tumors generally revealed a high WT1 expression. Among adenocarcinomas, serous carcinoma revealed a significantly higher WT1 expression than the other histologic subtypes. There were no significant correlations between the WT1 labeling index and the Ki-67 labeling index, and no significant difference in survival between those showing high and low WT1 expression among the malignant cases. These results suggest that WT1 expression may be related to cell differentiation, and that the histologic subtypes of epithelial ovarian carcinomas may differ considerably in their biological characteristics.

Immunohistochemical detection of the Wilms' tumor gene (WT1) in epithelial ovarian tumors

BACKGROUND: As in the case of other epithelial neoplasms, most ovarian cancers arise from single clones of cells that have undergone multiple genetic alterations. A comparison of normal and malignant ovarian epithelium has identified several differences in growth regulation by peptide growth factors, protooncogenes, and tumor suppressor genes. METHODS: Recent articles and abstracts have been reviewed. RESULTS: The malignant ovarian epithelial phenotype has been associated with (1) autocrine growth stimulation by transforming growth factor-alpha, (2) loss of autocrine growth inhibition by transforming growth factor-beta, (3) mutation or amplification of ras in 2-12% of cases, (4) amplification of myc in 23% of specimens, (5) expression of fms in 56% of cases with potential autocrine stimulation by macrophage colony stimulating factor, (6) paracrine stimulation by macrophage products including interleukin-1, interleukin-6 and tumor necrosis factor, (7) overexpression of c-erbB-2 (HER-2/neu) in 30% of cases, and (8) mutation with consequent overexpression of p53 in 50% of advanced ovarian cancers. A poor clinical prognosis is associated with expression or overexpression of the epidermal growth factor receptor, fms, and HER-2/neu. Antibodies against the extracellular domain of the HER-2/neu gene product p185 inhibit the growth of tumor cells that overexpress HER-2/neu and are associated with marked decreases in diacylglycerol levels. The intracellular kinase domain is required for growth inhibition. Antibodies that inhibit growth stimulate phosphorylation of intracellular substrates. Ricin A chain monoclonal antibody conjugates that react with p185 also inhibit the growth of tumor cells that overexpress p185. The intracellular kinase region is not required for immunotoxin-mediated killing. Coexpression of HER-2/neu and the epidermal growth factor receptor has been observed in 65% of epithelial ovarian cancers and in a limited number of normal tissue from a fraction of donors. CONCLUSIONS: Multiple alterations in growth factors, protooncogenes and growth factors have been detected in different epithelial ovarian cancers. Inappropriate signalling from receptor tyrosine kinases may be particularly important for ovarian oncogenesis. Drugs that affect tyrosine kinase and phosphatase activity deserve attention as potential therapeutic agents for ovarian cancer. The extracellular domains of the HER-2/neu gene product p185 and the epidermal growth factor receptor may provide useful targets for serotherapy.

https://acsjournals.onlinelibrary.wiley.com/doi/pdf/10.1002/cncr.2820710426

Ian Jacobs

Papers

Cell growth regulation in epithelial ovarian cancer