Reduced EGFR expression in ovarian carcinoma cells decreased their adhesion to laminin-1, expression of the alpha(6)-integrin subunit (a well-characterized laminin-1 receptor), and MMP-9 activity. These data support the hypothesis that EGFR overexpression in ovarian cancer cells results in multiple phenotypic changes that enhance the invasive phenotype.

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Over‐expression of epidermal growth factor receptor (EGFR) in ovarian cancer has been well documented. Human NIH:OVCAR‐8 ovarian carcinoma cells were transfected with an expression vector containing the anti‐sense orientation of truncated human EGFR cDNA. EGFR anti‐sense over‐expression resulted in decreased EGFR protein and mRNA expression, cell proliferation and tumor formation in nude mice. In accordance with the reduced levels of EGFR in EGFR anti‐sense–expressing cells, tyrosine phosphorylation of EGFR was decreased compared to untransfected parental cells treated with EGF. In EGFR anti‐sense–transfected cells, expression of erbB‐3, but not erbB‐2, was increased. In addition, basal and heregulin‐β1–stimulated tyrosine phosphorylation of erbB‐3 was higher in EGFR anti‐sense vector–transfected cells. A morphological alteration in EGFR anti‐sense gene–expressing cells was correlated with a decrease in the expression of E‐cadherin, α‐catenin and, to a lesser extent, β‐catenin. Changes in the expression of these proteins were associated with a reduction in complex formation among E‐cadherin, β‐catenin and α‐catenin and between β‐catenin and EGFR in EGFR anti‐sense–expressing cells compared to sense‐transfected control cells. These results demonstrate that EGFR expression in ovarian carcinoma cells regulates expression of cell adhesion proteins that may enhance cell growth and invasiveness. Int. J. Cancer 88:566–574, 2000. © 2000 Wiley‐Liss, Inc.

Since identifying a transmissible agent responsible for tumorigenesis in chickens, the v-Src oncogene, significant progress has been made in determining the functions of its cellular homologue. c-Src is the product of the SRC gene and has been found both over-expressed and highly activated in a number of human cancers. In fact the relationship between c-Src activation and cancer progression is significant. Furthermore c-Src may play a role in the acquisition of the invasive and metastatic phenotype. In this review we will summarize some of the latest evidence for the role of c-Src in tumorigenesis and particularly in human tumor progression. In this review, specifically, we will address growth signals, adhesion, migration, invasion, angiogenesis and functional genomics.

Expression of the RIa subunit of cAMP-dependent protein kinase type I is increased in human cancers in which an autocrine pathway for epidermal growth factorrelated growth factors is activated. We have investigated the e ect of sequence-speci®c inhibition of RIa gene expression on ovarian cancer cell growth. We report that RIa antisense treatment results in a reduction in RIa expression and protein kinase A type I, and inhibition of cell growth. The growth inhibition was accompanied by changes in cell morphology and appearance of apoptotic nuclei. In addition, EGF receptor, c-erbB-2 and c-erbB-3 levels were reduced, and the basal and EGF-stimulated mitogen-activated protein kinase activities were reduced. Protein kinase A type I and EGF receptor levels were also reduced in cells overexpressing EGF receptor antisense cDNA. These results suggest that the antisense depletion of RIa leads to blockade of both the serinethreonine kinase and the tyrosine kinase signaling pathways resulting in arrest of ovarian cancer cell growth.

Enhanced expression of the RIa subunit of cAMP-dependent protein kinase type I (PKA-I) has been shown during carcinogenesis, in human cancer cell lines and in primary tumors. We demonstrate that the sequence-specific inhibition of RIa gene expression by antisense oligonucleotides results in the differentiation of leukemia cells and growth arrest of cancer cells of epithelial origin and tumors in mice. The loss of RI by the antisense results in rapid increase in the half-life of the competitor molecule, RII protein, via its stabilization in a holoenzyme complex (PKA-II) that insures depletion of PKA-I and sustained inhibition of tumor growth. RI antisense, which restrains tumor cell growth by turning on the signals for blockade of tumor cell survival, namely blockade of the tyrosine kinase signaling, cell cycle deregulation and apoptosis, provides a single gene-targeting approach to treatment of cancer.

We assessed the relationship between the parathyroid hormone-related protein (PTHrP) and the development of humoral hypercalcemia of malignancy (i.e., hypercalcemia due to the production by solid tumors of hypercalcemic factors) by assaying tumor extracts from hypercalcemic and normocalcemic patients with cancer for immunoreactive PTHrP contents. Immunoreactive PTHrP was demonstrated in extracts of 21 of 22 tumor tissues obtained from 22 patients with humoral hypercalcemia of malignancy. Immunoreactive PTHrP was rarely seen in tumor tissue extracts obtained from 34 normocalcemic patients with cancer and two hypercalcemic patients with cancer with severe bone metastases. Gel filtration studies of tumor extracts revealed a molecular-size heterogeneity of immunoreactive PTHrP. These radioimmunoassay data indicate a close relationship between detection of PTHrP in tumor tissues and the development of humoral hypercalcemia of malignancy.

Coexpression of epidermal growth factor receptor (EGFR) and cerbB-2 in 47-68% of ovarian cancer cells indicate their strong association with tumor formation. We examined the effects of simultaneous antisenseor immunosuppression of EGFR and c-erbB-2 expression on the invasive phenotype, aneuploidy, and genotype of cultured human ovarian carcinoma cells (NIH:OVCAR-8). We report here that suppression of both EGFR and c-erbB-2 results in regression of aneuploidy and genomic imbalances in NIH:OVCAR-8 cells, restores a more normal phenotype, and results in a more normal gene expression profile. Combined with cytogenetic analysis, our data demonstrate that the regression of aneuploidy is due to the selective apoptosis of double antisense transfected cells with highly abnormal karyotype.