scholarly journals Epithelial-mesenchymal interconversions in ovarian cancer: the levels and functions of E-cadherin in intraabdominal dissemination

2020 ◽  
Vol 14 (1) ◽  
Author(s):  
Ricardo J. Roque ◽  
Margarida Figueiredo Dias ◽  
Filipa Costa Sousa
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cells ◽  
Abdominal Cavity ◽  
Growth Factor Receptor ◽  
Expression Variability ◽  
Epithelial Growth Factor ◽  
Multicellular Aggregates ◽  
Dynamic Expression ◽  
Response To Chemotherapy ◽  
E Cadherin

The metastatic process of ovarian cancer (OC) is almost exclusively defined by direct shedding of tumor cells into the abdominal cavity, followed by clustering into multicellular aggregates and posterior peritoneal anchorage. This process relies on dynamic intercellular interactions which are modified by epithelial-mesenchymal interconversions and, therefore, E-cadherin expression variability. Although widely accepted as a tumor suppressor in many types of cancer, E-cadherin is currently known to have a dynamic expression and a much more complex role in OC. First, high E-cadherin expression is considered a sign of metaplasia in the normal ovarian epithelium, due to its association with epithelial growth factor receptor (EGFR) mediated cell proliferation. Subsequently, it is the decreased expression of E-cadherin that allows the acquisition of a more invasive phenotype, leading to the spread of primary tumor cells into the peritoneal fluid. This downregulation seems to depend on complex regulatory mechanisms, from molecular proteolysis to microenvironment interference and epigenetic regulation. E-cadherin cleavage and its resulting fragments appear to be essential to the process of dissemination and even to the formation of multicellular aggregates. Paradoxically, the maintenance of some E-cadherin expression seems to promote intercellular adhesion, resistance, and survival while decreasing cancer response to chemotherapy. Multiple studies have shown that reversing epithelial-mesenchymal transaction (EMT) and increasing E-cadherin expression prevents OC intraperitoneal dissemination, but findings that simultaneously correlate E-cadherin downregulation to higher chemotherapy sensitivity should not be ignored. Nevertheless, EMT and E-cadherin seem to have a potential interest as therapeutic targets in novel approaches to OC treatment.

Stem-like tumor cells and proinflammatory cytokines in the ascitic fluid of ovarian cancer patients

2021 ◽  
Vol 66 (5) ◽  
pp. 297-303
Author(s):  
S. O. Gening ◽  
T. V. Abakumova ◽  
I. I. Antoneeva ◽  
A. A. Rizvanov ◽  
T. P. Gening ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Blood Serum ◽  
Tumor Cells ◽  
Ascitic Fluid ◽  
Early Stage ◽  
Abdominal Cavity ◽  
Disease Stage ◽  
Cell Populations ◽  
Benign Ovarian Tumors ◽  
Number Of Cells

Ovarian cancer (OC) is able to develop implantation metastases in the abdominal cavity. Ascites is potentially useful for evaluating cancer features. The aim of the study was to assess the content of stem-like tumor cells and inflammatory mediators in ascites of OC. The prospective study included 11 patients with primary OC having ascites, 8 patients with benign ovarian tumors having ascites and 22 healthy women. In ascitic fluid obtained by laparocentesis, the populations of tumor stem-like cells were determined on a Cytoflex S` flow cytometer (Beckman Coulter, USA) and CytExpert Software using monoclonal antibodies to CD45, CD44 and CD133. The cytokine profiles of ascitic fluid and blood serum (IL-1β, IL-18, IL-4, IL-10 and VEGF) were assessed by ELISA. Stem-like cells were found in all samples. 5 cell populations were evaluated. The number of cells expressing both markers: CD44 + and CD133+, was the lowest. The highest, about 32%, was the number of CD44+ cells. The number of cells CD45-CD44+CD133- in ascites strongly positively correlated with the content of IL-10 in ascites, and the numbers of CD45-CD133+ and CD45-CD44-CD133+ - with the level of VEGF in blood serum. No correlations were found between the numbers of stem-like cells and the disease stage or the level of CA125 in blood. The combination of IL-4 and IL-10 in ascites had the greatest significance in predicting the disease stage. These results suggest a relationship between the levels of VEGF, IL-10, and cancer stem cells in the OC ascites. Stem-like cells in OC ascites are heterogeneous and are present even at an early stage of the disease. It seems promising to study cell populations and cytokine profile of ascites together, to assess the biomarker potential of their combination.

scholarly journals Lysophosphatidic Acid Disrupts Junctional Integrity and Epithelial Cohesion in Ovarian Cancer Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Yueying Liu ◽  
Rebecca Burkhalter ◽  
Jaime Symowicz ◽  
Kim Chaffin ◽  
Shawn Ellerbroek ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Lysophosphatidic Acid ◽  
Time Dependent ◽  
Ovarian Cancer Cells ◽  
Ectodomain Shedding ◽  
Lpa Receptor ◽  
Multicellular Aggregates ◽  
Cancer Dissemination ◽  
E Cadherin

Ovarian cancer metastasizes via exfoliation of free-floating cells and multicellular aggregates from the primary tumor to the peritoneal cavity. A key event in EOC metastasis is disruption of cell-cell contacts via modulation of intercellular junctional components including cadherins. Ascites is rich in lysophosphatidic acid (LPA), a bioactive lipid that may promote early events in ovarian cancer dissemination. The objective of this paper was to assess the effect of LPA on E-cadherin junctional integrity. We report a loss of junctional E-cadherin in OVCAR3, OVCA429, and OVCA433 cells exposed to LPA. LPA-induced loss of E-cadherin was concentration and time dependent. LPA increased MMP-9 expression and promoted MMP-9-catalyzed E-cadherin ectodomain shedding. Blocking LPA receptor signaling inhibited MMP-9 expression and restored junctional E-cadherin staining. LPA-treated cells demonstrated a significant decrease in epithelial cohesion. Together these data support a model wherein LPA induces MMP-9 expression and MMP-9-catalyzed E-cadherin ectodomain shedding, resulting in loss of E-cadherin junctional integrity and epithelial cohesion, facilitating metastatic dissemination of ovarian cancer cells.

Role of CD70 in pathogenesis of ovarian cancer cell metastasis

2018 ◽  
Vol 6 (4) ◽  
pp. 315-322
Author(s):  
Jack L. Pincheira ◽  
Maria Wiseman
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Abdominal Cavity ◽  
Activated T Cells ◽  
Cancer Society ◽  
Tissue Samples

American Cancer Society identifying ovarian carcinoma as the gynecologic malignancy with the highest case-to-fatality. Ovarian carcinoma metastasizes either by direct extension from the ovarian/fallopian tumor to neighboring organs (bladder/colon) or when cancer cells detach from the primary tumor. Exfoliated tumor cells are transported throughout the peritoneum by physiological peritoneal fluid and disseminate within the abdominal cavity. Extensive seeding of the peritoneal cavity by tumor cells is often associated with ascites, particularly in advanced, high-grade serous carcinomas. CD70 (encoded by the TNFSF7 gene) is a co-stimulatory factor present on B-cells, activated T-cells, and dendritic cells. CD70 is over expressed in tumor cells of various solid cancers including ovarian carcinoma, recently reported the role of CD70 expression as a predictive marker of resistance to chemotherapy in ovarian cancers. We evaluated the expression of CD70 level in the pathogenesis of metastasis ovarian cancer cell. Seventy five tissue samples from metastatic ovarian carcinoma were evaluated by quantitative real-time PCR for CD70 and statistical analyses were performed using the Mann-Whitney test. Further, humanized anti-CD70 antibodies were investigated in xenograft mice models of ovarian cancer. Increasing expression of CD70 level was associated with increased risks for disease progression (HR = 1.04; 95% CI, 1.03 to 1.14) and death (HR = 1.13; 95% CI, 1.09 to 1.2). expression of CD70 was associated with a worse PFS and OS compared with non- expression of CD70 carcinomas. Furthermore, humanized anti-CD70 antibodies have shown significant antitumor activity in preclinical xenograft models of ovarian cancer cell.

Metabolic Markers and HSP60 in Chemonaive Serous Solid Ovarian Cancer Versus Ascites

2014 ◽  
Vol 24 (8) ◽  
pp. 1389-1394 ◽  
Author(s):  
Elisabet Hjerpe ◽  
Suzanne Egyhazi Brage ◽  
Marianne Frostvik Stolt ◽  
Hemming Johansson ◽  
Maria Shoshan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Mrna Expression ◽  
Tumor Cells ◽  
Solid Tumor ◽  
Messenger Rna ◽  
Abdominal Cavity ◽  
Advanced Ovarian Cancer ◽  
Tumor Type ◽  
Heat Shock Protein 60 ◽  
Metabolic Markers

ObjectiveMetabolic pathway alterations in cancer are thought to be dependent upon tumor type–specific oncogenic activation and local nutrient and oxygen supply during disease progression. In serous ovarian cancer, the typical peritoneal spread of disease is caused by shedding of tumor cells into the abdominal cavity, often along with ascites formation. Not much is known about the metabolic features of these detached serous tumor cells. In this study, we investigate the messenger RNA (mRNA) expression of GAPDH (glycolytic glyceraldehyde 3-phosphate dehydrogenase) and PKM2 (pyruvate kinase isoform M2), ATP5B (mitochondrial β-F1-ATPase), and heat shock protein 60 in matched serous solid tumor and corresponding ascites.Materials/MethodsFresh samples from solid tumor and corresponding ascites were prospectively collected from 40 patients undergoing primary surgery for suspected advanced ovarian cancer. Of these, 25 met the study eligibility criteria, that is, stage IIC to IV disease of the serous (24) or endometrioid (1) subtype with solid and ascites specimens containing 50% or more tumor cells and with good quality and quantity mRNA yield. All but 2 patients (92%) had type II disease. GAPDH, PKM2, ATP5B, and HSP60 mRNA expressions were assessed by real-time polymerase chain reaction. For each marker, the mRNA expression in solid tumor was pairwise compared with the corresponding expression in ascites using the Wilcoxon matched pairs signed rank sum test.ResultsIn contrast to our hypothesis, the mRNA expression of analyzed metabolic markers and HSP60 did not significantly differ between matched solid tumor and malignant ascites.ConclusionsOur results indicate that further expression changes in genes related to glycolysis or oxidative phosphorylation are not a prerequisite for serous cancer cell survival after detachment.

scholarly journals Epithelial growth factor receptor status in primary and recurrent ovarian cancer

2006 ◽  
Vol 19 (4) ◽  
pp. 607-610 ◽  
Author(s):  
Sylvia Stadlmann ◽  
Uwe Gueth ◽  
Ulrich Reiser ◽  
Pierre-Andre Diener ◽  
Alain Gustave Zeimet ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Recurrent Ovarian Cancer ◽  
Epithelial Growth Factor Receptor ◽  
Receptor Status ◽  
Epithelial Growth Factor ◽  
Epithelial Growth

The Plasticity of Circulating Tumor Cells in Ovarian Cancer During Platinum-containing Chemotherapy

2021 ◽  
Vol 21 ◽  
Author(s):  
Gening Snezhanna O. ◽  
Dolgova Dinara R. ◽  
Abakumova Tatyana V. ◽  
Antoneeva Inna I. ◽  
Gening Tatyana P.
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Principal Component ◽  
Progression Free Survival ◽  
Metastatic Potential ◽  
Disease Stage ◽  
Molecular Characteristics ◽  
Ercc1 Expression ◽  
E Cadherin

Background: Circulating tumor cells (CTCs) are a potential source of metastases and relapses. The data on the ovarian cancer (OC) CTCs molecular characteristics are limited. Objective: Two CTCs subpopulations (EpCAM+CK18+E-cadherin+; EpCAM+CK18+Vimentin+) were enriched using immunomagnetic separation before treatment and after 3 cycles of platinum-containing CT. Expression of mRNA was assessed using RT-qPCR. Results: The study included 31 I-IV stage OC patients. During CT, TGFβ levels increased in both fractions (p=0.054) compared with the initial levels. ERCC1 expression in E-cadherin+ CTCs was higher during neoadjuvant than adjuvant CT (p=0.004). CXCL2 level in E-cadherin+ CTCs increased (p=0.038) during neoadjuvant CT compared with the initial. TGF-β expression in vimentin+ CTCs during CT was negatively correlated to disease stage (p=0.003). Principal component analysis before CT revealed a component combining VEGFA, TGFβ, CXCL2, and a component with ERCC1 and VEGFA; during CT, component 1 contained ERCC1 and VEGFA, component 2 - TGFβ and CXCL2 in both fractions. Increased ERCC1 expression in E-cadherin+ CTCs during CT was associated with decreased progression-free survival (PFS) (HR 1.11 (95% CI 1.03-1.21, p=0.009) in multivariate analysis. Conclusion: EpCAM+ OC CTCs are phenotypically heterogeneous, which may reflect variability in their metastatic potential. CT changes the molecular characteristics of CTCs. Expression of TGFβ in EpCAM+ CTCs increases during CT. High ERCC1 expression in EpCAM+CK18+E-cadherin+ CTCs during CT is associated with decreased PFS in OC.

Role of CD70 in pathogenesis of ovarian cancer cell metastasis

2020 ◽  
Vol 8 (2) ◽  
pp. 101-111
Author(s):  
Jack L. Pincheira ◽  
Maria Wiseman
Keyword(s):  
Ovarian Cancer ◽  
Ovarian Carcinoma ◽  
Tumor Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Abdominal Cavity ◽  
Activated T Cells ◽  
Cancer Society ◽  
Tissue Samples

Abstract American Cancer Society identifying ovarian carcinoma as the gynecologic malignancy with the highest case-to-fatality. Ovarian carcinoma metastasizes either by direct extension from the ovarian/fallopian tumor to neighboring organs (bladder/colon) or when cancer cells detach from the primary tumor. Exfoliated tumor cells are transported throughout the peritoneum by physiological peritoneal fluid and disseminate within the abdominal cavity. Extensive seeding of the peritoneal cavity by tumor cells is often associated with ascites, particularly in advanced, high-grade serous carcinomas. CD70 (encoded by the TNFSF7 gene) is a co-stimulatory factor present on B-cells, activated T-cells, and dendritic cells. CD70 is over expressed in tumor cells of various solid cancers including ovarian carcinoma, recently reported the role of CD70 expression as a predictive marker of resistance to chemotherapy in ovarian cancers. We evaluated the expression of CD70 level in the pathogenesis of metastasis ovarian cancer cell. Seventy five tissue samples from metastatic ovarian carcinoma were evaluated by quantitative real-time PCR for CD70 and statistical analyses were performed using the Mann-Whitney test. Further, humanized anti-CD70 antibodies were investigated in xenograft mice models of ovarian cancer. Increasing expression of CD70 level was associated with increased risks for disease progression (HR = 1.04; 95% CI, 1.03 to 1.14) and death (HR = 1.13; 95% CI, 1.09 to 1.2). expression of CD70 was associated with a worse PFS and OS compared with non- expression of CD70 carcinomas. Furthermore, humanized anti-CD70 antibodies have shown significant antitumor activity in preclinical xenograft models of ovarian cancer cell.

scholarly journals Formation of E-Cadherin-Mediated Cell-Cell Adhesion Activates Akt and Mitogen Activated Protein Kinase via Phosphatidylinositol 3 Kinase and Ligand-Independent Activation of Epidermal Growth Factor Receptor in Ovarian Cancer Cells

2005 ◽  
Vol 19 (10) ◽  
pp. 2564-2578 ◽  
Author(s):  
Pradeep Reddy ◽  
Lian Liu ◽  
Chong Ren ◽  
Peter Lindgren ◽  
Karin Boman ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Cell Adhesion ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Ovarian Cancer Cells ◽  
Phosphatidylinositol 3 Kinase ◽  
Epithelial Cancers ◽  
Epidermal Growth ◽  
E Cadherin

Abstract E-cadherin is a well characterized adhesion molecule that plays a major role in epithelial cell adhesion. Based on findings that expression of E-cadherin is frequently lost in human epithelial cancers, it has been implicated as a tumor suppressor in carcinogenesis of most human epithelial cancers. However, in ovarian cancer development, our data from the current study showed that E-cadherin expression is uniquely elevated in 86.5% of benign, borderline, and malignant ovarian carcinomas irrespective of the degree of differentiation, whereas normal ovarian samples do not express E-cadherin. Thus, we hypothesize that E-cadherin may play a distinct role in the development of ovarian epithelial cancers. Using an E-cadherin-expressing ovarian cancer cell line OVCAR-3, we have demonstrated for the first time that the establishment of E-cadherin mediated cell-cell adhesions leads to the activation of Akt and MAPK. Akt activation is mediated through the activation of phosphatidylinositol 3 kinase, and both Akt and MAPK activation are mediated by an E-cadherin adhesion-induced ligand-independent activation of epidermal growth factor receptor. We have also demonstrated that suppression of E-cadherin function leads to retarded cell proliferation and reduced viability. We therefore suggest that the concurrent formation of E-cadherin adhesion and activation of downstream proliferation signals may enhance the proliferation and survival of ovarian cancer cells. Our data partly explain why E-cadherin is always expressed during ovarian tumor development and progression.

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