OVX1 radioimmunoassay results are dependent on the method of sample collection and storage.
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Antigens, Tumor-Associated, Carbohydrate↗
Biomedical subjects
R C Bast
Publications and source records attributed to R C Bast.
Decreased Src tyrosine kinase activity inhibits malignant human ovarian cancer tumor growth in a nude mouse model.
The Src protein tyrosine kinase is overexpressed and activated in a number of human cancers, including some human ovarian cancers. To determine whether Src activity plays a role in ovarian tumor growth, stable derivatives of the SKOv-3 human ovarian cancer cell line that exhibited reduced Src tyrosine kinase activity were generated by transfection with an antisense c-src construct. Comparison of these cell lines with parental SKOv-3 cells and stable sense c-src vector-transfected control lines revealed no phenotypic alterations in anchorage-dependent proliferation, adherence, density saturation, or wound migration. However, reduction in Src activity was associated with altered cellular morphology, dramatically reduced anchorage-independent growth, and, when assessed for tumor development in a xenograft nude mouse model, diminished tumor growth. Furthermore, reduction of Src activity in the antisense c-src cell lines was associated with reduced vascular endothelial growth factor mRNA expression in vitro, and tumors derived from these cell lines displayed a phenotype indicative of abortive microvessel vascularization. These results strongly suggest that Src is involved in critical oncogenic pathways that modulate tumor growth from this ovarian cell line. Furthermore, this evidence suggests that as in other tumor systems, Src activity is required for vascular endothelial growth factor induction and angiogenic development.
Animals↗
Should therapy of ovarian cancer patients be individualized based on underlying genetic defects?
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Female↗
The outcome of heregulin-induced activation of ovarian cancer cells depends on the relative levels of HER-2 and HER-3 expression.
Members of the epidermal growth factor receptor family of tyrosine kinases, including epidermal growth factor receptor, c-erbB-2 (HER-2), c-erbB-3 (HER-3), and c-erbB-4 (HER-4), can be coexpressed at different levels in nonhematopoietic tissues. Amplification and overexpression of HER-2 is found in approximately one-third of cancers that arise in the breast and ovary. In our previous studies, heregulin (HRG) and anti-HER-2 antibodies inhibited proliferation, increased invasiveness, and enhanced tyrosine autophosphorylation of SKBr3 breast cancer cells that overexpressed HER-2. In the present report, the effects of HRG and anti-HER-2 antibody have been compared in six ovarian cancer cell lines. HRG inhibited anchorage-independent growth of SKOv3 cells that overexpressed HER-2 (10(5) receptors/cell) but stimulated the growth of OVCA420, OVCA429, OVCA432, OVCA433, and OVCAR-3 cells that expressed lower levels of the receptor (10(4) receptors/cell). Thus, cell lines with a high level of HER-2 relative to HER-3 or HER-4 were growth inhibited, whereas cell lines with lower levels of HER-2 were growth stimulated by HRG. Stimulation or inhibition of clonogenic growth did not correlate with endogenous expression of HRG or with the impact of exogenous HRG on phosphorylation of HER-2, HER-3, or HER-4. Anti-HER-2 antibodies inhibited the growth of SKOv3 cells but failed to affect the growth of the other cell lines. In OVCAR-3 cells that had been transfected with HER-2 cDNA to increase expression to 10(5) receptors/cell, HRG inhibited rather than stimulated growth. Conversely, when HER-2 expression by SKOv3 cells was downregulated by transfection of the viral E1A gene, HRG stimulated rather than inhibited growth. To evaluate the relative importance of HER-3 and HER-4, NIH 3T3 cells were cotransfected with HER-2 and HER-3 or with HER-2 and HER-4. HRG inhibited the growth of cells with a high ratio of HER-2:HER-3, whereas HRG stimulated the growth of cells with low levels of the two receptors. In cells that express only HER-2 and HER-4, HRG stimulated the growth of cells that expressed HER-4 independent of HER-2 levels. Anti-HER-2 antibodies inhibited the growth of transfectants with high levels of HER-2 expression independent of HER-3 or HER-4 expression. In ovarian cancer cells that express all three receptors, the relative levels of HER-2 and HER-3 appear to determine the response to HRG. Taken together, these studies support the concept that the level of HER-2 expression can modulate response to HRG, determining whether the response is stimulatory or inhibitory. In contrast, agonistic antibodies that bind to HER-2 alone inhibit anchorage-independent growth but fail to mimic HRG's ability to stimulate growth of cells with low HER-2: HER-3 ratios.
Antibodies, Monoclonal↗
Lysophosphatidic acid induces urokinase secretion by ovarian cancer cells.
Lysophosphatidic acid (LPA) is present at high concentrations in ascites from ovarian cancer patients and has potent mitogenic properties in vitro. Urokinase plasminogen activator (uPA), a critical component of the metastatic cascade, is also found at high concentrations in ovarian ascites and ovarian cancers, and the levels of uPA correlate inversely with prognosis. Because LPA stimulates the invasion of both hepatoma and lung cell lines, we investigated whether LPA could induce uPA secretion by ovarian epithelial cells and whether this process was associated with malignant transformation of ovarian epithelial cells. As indicated by zymography and Western blotting, physiologically relevant concentrations of LPA equivalent to those present in ovarian cancer ascites stimulated uPA secretion in the ovarian cancer cell lines OVCAR-3, SKOV-3, OVCA 429, OVCA 432, and OVCA 433, but not from established normal ovarian epithelial (NOE) cells as indicated by normal epithelial cell lines NOE 033 and NOE 035 or from SV40 large T antigen-immortalized normal epithelial cell lines IOSE 29 and IOSE 80. 18:1 LPA, but not 18:0 LPA, 16:0 LPA, or lysophosphatidylcholine, induced uPA secretion, concordant with previous studies of LPA receptor selectivity. Expression of the edg-2 LPA receptor was not consistently different between normal epithelial cell lines and ovarian cancer cell lines. In contrast, expression of the edg-4 LPA receptor was markedly increased in ovarian cancer cell lines as compared with NOE cell lines, raising the possibility that the edg-4 LPA receptor contributes to the ability of ovarian cancer cells but not NOE cells to produce uPA in response to LPA. LPA induced a consistent increase in uPA promoter activity and mRNA levels, suggesting that increased uPA production is, at least in part, transcriptional. Malignant transformation may alter LPA-induced cell activation by altering the pattern of LPA receptors present and may possibly lead to more aggressive behavior by up-regulating LPA-mediated uPA secretion and stimulating extracellular stromal breakdown and invasion.
Breast Neoplasms↗
Prognostic significance of p53 expression in advanced-stage ovarian serous borderline tumors.
The purpose of this study was to investigate the frequency of p53 overexpression in the primary ovarian tumors of patients with stages II and III serous borderline tumors (SBTs) and to determine the relationship between p53 overexpression and risk of progression/recurrence and survival. Of 112 patients with stages II-IV SBTs, paraffin-embedded tissue from the primary ovarian tumor was available in 68 cases. Immunohistochemical staining for p53 was performed. Clinical information was abstracted from the medical records. The major end points selected for analysis were time to progression/relapse, disease-free survival, overall survival, and cause-specific survival. Univariate and multivariate regression analyses were also performed. The median patient age was 37 years (range, 17-67 years). Twenty-two patients had stage II disease, and 46 had stage III disease. The mean follow-up time was 105 months. Nineteen patients (28%) had either disease progression (1 patient) or relapse (18 patients). Eleven patients died: 10 patients died of their tumor, and 1 patient died of other causes. Thirteen cases (19%) had positive immunostaining for p53. Overexpression of p53 was significantly associated with an increased probability of progression/recurrence (P = 0.005) and a decreased overall survival (P = 0.012). After adjusting for age, International Federation of Gynecology and Obstetrics (FIGO) stage, the presence of residual tumor, and the presence of invasive implants, patients whose tumors overexpressed p53 had a 4-fold increased risk of progression/ recurrence. Similarly, women whose tumor overexpressed p53 had an approximately 6-fold increased risk of death. p53 overexpression in the ovarian tumors of patients with stage II and III SBTs is significantly associated with increased probability of relapse and decreased overall survival. This information should provide better prognostic data to patients and their families and allow us to select patients who might benefit from postoperative treatment.
Adolescent↗
Overexpression of edg-2/vzg-1 induces apoptosis and anoikis in ovarian cancer cells in a lysophosphatidic acid-independent manner.
Lysophosphatidic acid (LPA) is one of the major growth factors in ascites from ovarian cancer patients and appears to play an important role in proliferation, survival, and invasion of ovarian cancer cells. Recently, several groups have shown that Edg-2, which belongs to the G-protein coupled receptor family, is a functional LPA receptor. Northern blot analysis showed that most ovarian cancer cell lines express Edg-2. Edg-2 expression was especially high in the cisplatin-resistant and slowly proliferating 2780cp cell line and was almost absent from the cisplatin-sensitive and rapidly proliferating A2780 cell line. We thus assessed whether Edg-2 could contribute to changes in cell viability, cell proliferation, or cisplatin resistance. Stable overexpression of Edg-2 in A2780 cells induced an exogenous LPA-independent decrease in proliferation but did not alter cisplatin sensitivity. The LPA-independent decrease in growth rate induced by overexpression of Edg-2 could be explained, at least in part, by Edg-2-induced apoptosis rather than by effects on cell cycle progression. In agreement with the results in stably transfected A2780 cells, transient expression of Edg-2 in Jurkat T cells also induced apoptosis. When cells were separated from the extracellular matrix, they underwent a specialized form of apoptosis called anoikis, which is particularly important in survival of cells in the circulation during metastasis. A2780 cells engineered to overexpress Edg-2 were particularly sensitive to anoikis. These observations suggest that Edg-2 may be a negative regulator for ovarian epithelial cell growth and metastasis.
Animals↗
Activation of the ras-mitogen-activated protein kinase pathway and phosphorylation of ets-2 at position threonine 72 in human ovarian cancer cell lines.
The activation status of the ras pathway was studied in eight ovarian tumor cell lines. Three biochemical parameters indicative of ras activation were tested: (a) the ratio of the ras-GTP:ras-GDP complex; (b) the activity of mitogen-activated protein kinases p42/p44; and (c) ets-2 phosphorylation at position threonine 72, a mitogen-activated protein kinase phosphorylation site in vivo. Four of the ovarian tumor cell lines had an activated ras pathway by these three parameters, whereas only one of these contained a mutated ras gene. In addition, ras/ets-2 responsive genes such as the urokinase plasminogen activator (uPA) were activated in these four cell lines. Transient transfection assays indicated that the compound ets-AP1 oncogene responsive enhancer present in the uPA gene was the target of ras signaling in ovarian tumor cells and that the combination of activated ras and ets-2 could superactivate the uPA enhancer element. Coexpression of the dominant-negative ras-Asn17 cDNA gene abrogated activity of this uPA element in ovarian tumor cells. These data indicate that ets-2 is a nuclear target of ras action in ovarian tumor cell lines and that ras signaling pathways may be activated in ovarian cancer by mechanisms independent of direct genetic damage to ras genes.
Antineoplastic Agents↗
Expression of p16 induces transcriptional downregulation of the RB gene.
The RB and p16(INK4A) tumor suppressor genes function in the same pathway of cell cycle control. Previous evidence indicates that the p16(INK4A) gene is transcriptionally repressed by the RB gene product, pRB. In this study using human ovarian cancer cell lines, we found that RB protein and mRNA were expressed at higher levels in cell lines lacking p16 than in those with normal p16. Since this suggests a potential role of p16 in regulating the cellular level of pRB, we studied the effect of wild-type p16(INK4A) on expression of the RB gene. Introduction of p16(INK4A), carried by an adenovirus vector, into p16-negative cell lines dramatically decreased expression of RB protein and mRNA. Nuclei run-off assays demonstrated that p16 expression induced transcriptional downregulation of the RB gene. These results indicate that expression of RB is inversely regulated by p16. The findings reveal a new dimension of pRB-p16 interaction and should have implications for p16(INK4A)-mediated gene therapy.
Adenoviridae↗
Suppression of diacylglycerol levels by antibodies reactive with the c-erbB-2 (HER-2/neu) gene product p185c-erbB-2 in breast and ovarian cancer cell lines.
Seven of 10 murine monoclonal antibodies reactive with the extracellular domain of p185c-erbB-2 inhibited the anchorage independent growth of the SKBr3 breast cancer cell line that overexpressed p185c-erbB-2. Significant inhibition (56-72%) of diacylglycerol (DAG) levels (P < 0.0001) was observed with the 10 antibodies that inhibited SKBr3 growth (RC1, NB3, RC6, PB3, 741F8, DB5, ID5), whereas the 3 antibodies (TA1, 520C9, 454C11) that failed to inhibit SKBr3 growth also failed to affect DAG levels. Thus, DAG levels correlated with antibody-mediated growth regulation for each of the 10 monoclonal reagents. Antibody-induced inhibition of anchorage-independent growth of SKBr3 could be reversed by incubation with phorbol myristate acetate. The ID5 antibody inhibited growth of the SKBr3, SKOv3, and OVCA 432 tumor cell lines, but not of OVCA 420, OVCA 429, and OVCA 433. DAG levels were significantly decreased after ID5 treatment of the SKBr3 and SKOv3 cell lines, but not the OVCA 420, OVCA 429, and OVCA 433 lines. In the 432 line, there was a decrease which did not reach significance. Consequently, changes in DAG levels correlated with growth regulation in 5 of 6 breast and ovarian carcinoma cell lines tested with a trend toward correlation in the sixth. Decreases in DAG may be one mediator of the growth regulatory signals produced by anti-p185c-erbB-2 antibodies.
Antibodies, Monoclonal↗
A phase I study of a daily x3 schedule of intravenous vinorelbine for refractory epithelial ovarian cancer.
PURPOSE: To determine the toxicity and activity of intravenous vinorelbine given daily for 3 consecutive days every 3 weeks in patients with platinum-resistant epithelial ovarian cancer. PATIENTS AND METHODS: Between September 1994 and October 1995, 23 women with refractory epithelial ovarian cancer were entered onto this phase I study. All patients had measurable disease and platinum-resistant tumor, and prior therapy was limited to a maximum of two prior regimens. Nineteen (83%) were assessable for toxicity and 20 (87%) were assessable for response. Vinorelbine was administered intravenously daily for 3 consecutive days; this was repeated every 21 days. The starting dose was 20 mg/m2 daily x3, with dose escalation by 5 mg/m2 daily x3. Dose-limiting toxicity (DLT) was defined as grade 4 granulocytopenia for >3 days, grade 4 thrombocytopenia, neutropenic fever, or grade 3 or greater nonhematologic toxicity. The maximal tolerated dose (MTD) was defined as the highest dose level at which <50% of patients developed a DLT. Once the MTD of vinorelbine without granulocyte colony-stimulating factor (filgrastim) support was defined, dosing was begun at the MTD level and administration of 5 microg/kg filgrastim was initiated on day 4 and continued until WBC counts reached >10,000/microL. Clinical response, progression-free survival, and survival were also determined. RESULTS: Nineteen patients evaluable for toxicity received a total of 135 cycles of vinorelbine. The major DLT was neutropenia. The MTD of vinorelbine without filgrastim support was established as 20 mg/m2 daily x3. The MTD of vinorelbine with filgrastim support was established as 25 mg/m2 daily x3. Of 20 patients evaluable for response, 2 patients (10%) had a complete response and 4 (20%) had a partial response, for an overall response rate of 30%. CONCLUSION: These results warrant further study of vinorelbine in patients with platinum-resistant epithelial ovarian cancer. However, further study of the daily x3 schedule may not be warranted because of failure to achieve higher weekly dose intensity and because of nonhematologic toxicity in the form of intense bone pain.
Adult↗
Physiologic and pathologic drug resistance in ovarian carcinoma--a hypothesis based on a clonal progression model.
Conventional models for successful chemotherapy suggest that early-stage ovarian cancer should be more responsive to cytotoxic drugs than advanced disease, that multiple drugs will prove more efficacious than single agents and that more intensive chemotherapy will prove superior to conventional doses. The purpose of numerous clinical studies has been to test these predictions and the results often fall short of the expectations. In trials to date, adjuvant chemotherapy for high-risk, early-stage ovarian cancer has provided only a modest, equivocal increase in disease-free survival. Combination chemotherapy produces higher response rates but this has not consistently resulted in prolonged survival. Dose intensification with high-dose chemotherapy increases rate of response further, but most responses are of short duration. The objective of this review is to integrate clinical and molecular biological observations into a novel model of drug resistance. We hypothesize that drug sensitivity is an acquired characteristic of neoplastic cells, and that there are two broad cellular forms of resistance to cytotoxic drugs. 'Physiological drug resistance' is a cellular state when drug sensitivity of cancer cells is similar to that of the corresponding normal tissue. This form of drug resistance can precede the acquisition of drug sensitivity and may be predominant in the early stages of neoplastic progression. A distinct, 'pathological drug resistance' can reappear later during tumor progression or during chemotherapy as a result of increased detoxification, upregulation of repair pathways or defective apoptosis. Tumors are formed of heterogeneous cell populations and in terms of drug sensitivity three distinct cell types may be present: drug-sensitive, physiologically drug-resistant and pathologically drug-resistant. Clinical response to chemotherapy is determined by the relative contribution of these different cell populations to the total cellular mass. Depending on the predominant type of surviving population, distinct patterns of clinical failure may develop that require different treatment strategies for optimal management. For chemosensitive cells that survived insufficient chemotherapy, consolidation with further, perhaps, high-dose chemotherapy is a rational option. For pathologically drug-resistant cells, pharmacological manipulation of drug resistance, and signaling pathways in combination with chemotherapy could be exploited. For physiologically drug-resistant cells, non-chemotherapy-based, 'chemopreventive' strategies to arrest tumor progression may prove beneficial.
Apoptosis↗
Coexpression of the HER-2 gene product, p185HER-2, and epidermal growth factor receptor, p170EGF-R, on epithelial ovarian cancers and normal tissues.
Monoclonal antibodies (MAbs) and immunoconjugates reactive with different antigens expressed by neoplastic cells can inhibit tumor growth. Use of these agents in combination with one another or with chemotherapy can exert additive or synergistic cytotoxicity against tumor cells. An augmented therapeutic activity with favorable therapeutic index might be attained when coexpression is observed on tumor cells, but not in normal tissues. In this study frozen sections of 19 ovarian cancers (2 stage I, 10 stage III, 2 stage IV, and 5 recurrent), as well as 29 normal tissues, were evaluated by immunohistochemistry using 11 distinct MAbs against HER-2/p185 and 2 antibodies against EGF-R/p170 to assess coexpression of these receptors. HER-2/p185 expression was detected in 5 to 100% of ovarian cancers and 0 to 50% of normal ovarian epithelia, depending on the antibody used. EGF-R/p170 expression was detected in approximately 70% of cancers and 40% of normal ovaries by both antibodies. Coexpression of p185 and p170 was observed in 47-68% of ovarian cancers and 9-18% of normal ovarian epithelial specimens depending upon the combination of antibodies used. Staining of 273 specimens from 29 normal tissues indicated that coexpression of HER-2 and EGF-R is rare. Normal tissues that coexpressed both receptors in > or =50% of the cases included cervix, endometrium, esophagus, skin, and prostate. These data confirm that HER-2 and EGF-R are more frequently expressed in advanced ovarian cancers than in normal ovarian epithelium and a significant fraction of these tumors coexpress both HER-2 and EGF-R.
Antibodies, Monoclonal↗
SCC antigen. Summary remarks.
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Antigens, Neoplasm↗
CA 125 in ovarian cancer: advances and controversy.
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CA-125 Antigen↗
Cell surface density of p185(c-erbB-2) determines susceptibility to anti-p185(c-erbB-2)-ricin A chain (RTA) immunotoxin therapy alone and in combination with anti-p170(EGFR)-RTA in ovarian cancer cells.
Approximately 30% of ovarian and breast cancers overexpress p185(c-erbB-2) with as many as 10(6) receptors/cell. Normal cells have as few as 10(4) receptors/cell. We have examined the susceptibility of SKOv3 human ovarian cancer cells to anti-c-erbB2 antibodies and immunotoxins as a function of c-erbB-2 density on the cell surface. A panel of SKOv3 clones that expressed different densities of p185(c-erbB-2) receptor were generated through transfection with the c-erbB-2 gene. A significant correlation was found between p185(c-erbB-2) density and susceptibility to killing by anti-p185(c-erbB-2)-ricin A chain (anti-p185(c-erbB-2)-RTA) immunotoxins. With 10(5) copies/cell of p185(c-erbB-2), <10% of clonogenic ovarian cancer cells could be eliminated, whereas in clones that expressed 10(6) copies/cell of p185(c-erbB-2), 99.9% of clonogenic tumor cells were killed. In cell lines that overexpressed p185(c-erbB-2) and also expressed p170(EGFR), anti-p185(cerbB-2)-RTA and anti-p170(EGFR)-RTA immunotoxins exerted synergistic cytotoxicity. Treatment with the two immunotoxins could eliminate 99.99% of clonogenic cells. Importantly, tumor cells that had survived first treatment with anti-p185(c-erbB2)-RTA alone still retained sensitivity to repeat treatment with the same immunotoxin and also proved susceptible to the synergistic cytotoxicity of anti-p185(cerbB-2)-RTA in combination with anti-p170(EGFR)-RTA. Growth characteristics of the clones expressing various levels of p185(c-erbB-2) were also studied. No correlation was found between p185(c-erbB-2) expression levels and the rate of anchorage-dependent growth, anchorage-independent growth, or in vivo growth in nude mice.
Animals↗
Reexpression of the retinoblastoma protein in tumor cells induces senescence and telomerase inhibition.
Normal human diploid cells senesce in vitro and in vivo after a limited number of cell divisions. This process known as cellular senescence is an underlying cause of aging and a critical barrier for development of human cancers. We demonstrate here that reexpression of functional pRB alone in RB/p53-defective tumor cells via a modified tetracycline-regulated gene expression system resulted in a stable growth arrest at the G0/G1 phase of the cell cycle, preventing tumor cells from entering S phase in response to a variety of mitogenic stimuli. These cells displayed multiple morphological changes consistent with cellular senescence and expressed a senescence-associated beta-galactosidase biomarker. Further studies indicated that telomerase activity, which was assumably essential for an extended proliferative life-span of neoplastic cells, was abrogated or repressed in the tumor cell lines after induction of pRB (but not p53) expression. Strikingly, when returned to an non-permissive medium for pRB expression, the pRB-induced senescent tumor cells resumed DNA synthesis, attempted to divide but most died in the process, a phenomenon similar to postsenescent crisis of SV40 T-antigen-transformed human diploid fibroblasts in late passage. These observations provide direct evidence that overexpression of pRB alone in RB/p53-defective tumor cells is sufficient to reverse their immortality and cause a phenotype that is, by all generally accepted criteria, indistinguishable from replicative senescence. The results suggest that pRB may play a causal role in the intrinsic cellular senescence program.
Cellular Senescence↗
Lysophosphatidylcholine stimulates activator protein 1 and the c-Jun N-terminal kinase activity.
Lysophosphatidylcholine (lyso-PC), a natural lipid generated through the action of phospholipase A2 on membrane phosphatidylcholine, has been implicated in atherogenesis and the inflammatory process. In vitro studies have established a role for lyso-PC in modulation of gene expression and other cellular responses including differentiation and proliferation. There is also evidence that lyso-PC may act as an intracellular second messenger transducing signals elicited from membrane-associated receptors. The mechanisms behind the diverse activities of lyso-PC are poorly understood. We report, in this study, that treatment of cultured cells with exogenous lyso-PC, at nontoxic concentrations, potently induced activator protein-1 (AP-1) DNA binding and transcriptional activity independent of well known AP-1 activators, protein kinase C or mitogen-activated protein kinases ERK1 and ERK2. Lyso-PC also activated the c-Jun N-terminal kinase (JNK/SAPK), a recently characterized member of the mitogen-activated protein kinase family, known to activate AP-1. The stimulated JNK and AP-1 activities probably mediate or contribute to some bioactive effects of lyso-PC.
Animals↗