CD44 and β1 Integrin Mediate Ovarian Carcinoma Cell Adhesion to Peritoneal Mesothelial Cells

Lessan, Khashayar; Aguiar, Dean J.; Oegema, Theodore R.; Siebenson, Lisa; Skubitz, Amy P.N.

doi:10.1016/s0002-9440(10)65406-5

Cited by 205 publications

(177 citation statements)

References 30 publications

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“…Contrary to these findings, in human mesothelial cells we have demonstrated that tumourmesothelial adhesion is required for the induction of apoptosis, which cannot be reproduced by the substitution of tumourconditioned media. This is supported by other in vitro work that has implicated cell adhesion molecules, such as CD44 and the b1 integrins, in tumour-mesothelial invasion, (Schlaeppi et al, 1997;Lessen et al, 1999;Strobel and Cannistra, 1999). The requirement for cell -cell contact to initiate the invasive process supports the role of cell membrane bound ligands, such as FasL, as the mediators of mesothelial apoptosis.…”

Section: Discussionsupporting

confidence: 55%

“…It is well documented that tumour cells adhere rapidly to the mesothelium both in vivo and in vitro, and a role for the cell adhesion molecule CD44 and the integrins b1, a2, a3 and a5 in mesothelial invasion has been postulated (Kiyasu et al, 1981;Schlaeppi et al, 1997;Lessen et al, 1999;Strobel and Cannistra, 1999). In these studies, tumour adhesion appeared to precede dissagregation of the mesothelial monolayer, and could be partially blocked by pretreatment with anti-CD44 and anti-b1 antibodies.…”

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confidence: 91%

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Tumour-induced apoptosis in human mesothelial cells: a mechanism of peritoneal invasion by Fas Ligand/Fas interaction

et al. 2004

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Gastrointestinal carcinomas frequently disseminate within the abdominal cavity to form secondary peritoneal metastases. Invasion of the peritoneal mesothelium is fundamental to this process, yet the underlying invasive mechanisms remain unclear. Preliminary in vitro work suggested that tumour cells can induce mesothelial apoptosis, representing a novel mechanism of peritoneal invasion. We examined the role of tumour cell-induced mesothelial apoptosis and explored the role of the death ligand/receptor system, Fas Ligand/Fas, as mediators of the apoptotic process. Cultured human mesothelial cells were used to establish in vitro co-culture models with the SW480 colonic cancer cell line. Tumour-induced mesothelial apoptosis was confirmed by phase-contrast microscopy and apoptotic detection assays. Human mesothelial cells and SW480 tumour cells constitutively expressed Fas and Fas Ligand mRNA and protein as determined by RT -PCR and confocal fluorescent microscopy. Stimulation of human mesothelial cells with anti-Fas monoclonal antibody or crosslinked soluble Fas Ligand-induced apoptosis, confirming the functional status of the Fas receptor. Pretreatment of SW480 cells with a blocking recombinant anti-Fas Ligand monoclonal antibody significantly reduced mesothelial apoptosis, indicating that tumour-induced mesothelial apoptosis may, in part, be mediated via a Fas-dependent mechanism. This represents a novel mechanism of mesothelial invasion and offers several new targets for therapeutic intervention.

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Section: Discussionsupporting

confidence: 55%

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confidence: 91%

Tumour-induced apoptosis in human mesothelial cells: a mechanism of peritoneal invasion by Fas Ligand/Fas interaction

et al. 2004

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“…Modulation of cell-cell and cell-matrix adhesion are key events in ovarian cancer metastasis, as intraperitoneal adhesion of malignant cells and multicellular aggregates combined with localized integrin-mediated invasion of the collagen-rich submesothelial matrix are necessary to anchor secondary lesions (5,40). Intraperitoneal ovarian cancer metastasis is mediated by adhesion via integrins ␣2␤1 and ␣3␤1 to peritoneal mesothelial cells displaying surface expression of collagen and the exposed interstitial (types I and III) collagen-rich submesothelial matrix, and antibodies directed against these integrins block collagen binding (41)(42)(43)(44)(45)(46)(47). Integrin engagement by a multivalent matrix ligand results in receptor aggregation, functionally coupling the extracellular environment to specific signal transduction pathways that modulate distinct cellular responses, including gene transcription, cell migration, and survival (48).…”

Section: Discussionmentioning

confidence: 99%

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Burkhalter

Symowicz

Hudson

et al. 2011

Journal of Biological Chemistry

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Reversible modulation of integrin-regulated cell-matrix adhesion and epithelial (E)-cadherin-mediated cell-cell adhesion plays a critical role in the establishment of ovarian cancer metastases. In contrast to most epithelial cell-derived tumors that down-regulate E-cadherin expression during progression, acquisition of E-cadherin expression accompanies malignant transformation of the ovarian surface epithelium and is maintained in peritoneal metastases. Metastatic epithelial ovarian cancer cells are disseminated intraperitoneally and preferentially adhere via integrins to interstitial collagens in the peritoneal cavity. This study was undertaken to determine whether integrin engagement influences E-cadherin and ␤-catenin localization and function. The data demonstrate that multivalent integrin engagement results in increased internalization of E-cadherin, inhibition of GSK-3␤, elevated levels of nuclear ␤-catenin, increased ␤-catenin-regulated promoter activation, and transcriptional activation of Wnt/␤-catenin target genes. Blocking ␤-catenin transcriptional control with inhibitor of ␤-catenin and Tcf-4 reduces cellular invasion, suggesting a key role for ␤-catenin nuclear signaling in EOC invasion and metastasis. These studies support a model wherein cell-matrix engagement regulates the functional integrity of cell-cell contacts, leading to increased ␤-catenin nuclear signaling and enhanced cellular invasive activity. Furthermore, these results provide a mechanism for activation of Wnt/␤-catenin signaling in the absence of activating mutations in this pathway.Epithelial (E) 3 -cadherin is a single-span transmembrane glycoprotein that mediates calcium-dependent cell-cell adhesion via interaction with the extracellular domains of cadherins on the surface of neighboring cells (1, 2). Key functions of E-cadherin include the regulation of cell polarity and the maintenance of epithelial organization (3). Although most normal epithelia express high levels of E-cadherin, this cadherin is absent in the mesenchymally derived normal ovarian surface epithelium, which expresses neural (N)-cadherin. In most carcinomas, E-cadherin expression is down-regulated or lost, facilitating cellular dispersal, invasion, and metastasis (4). However, a unique feature of EOC is that E-cadherin becomes more abundant in primary differentiated carcinomas, with all histotypes displaying strong immunoreactivity (reviewed in Refs. 5, 6). There is less clarity regarding relative E-cadherin levels during ovarian tumor progression and metastasis. Although complete loss of E-cadherin is uncommon, reduced staining is often detected in late stage tumors and in ascites-derived tumor cells (7-9), and negative E-cadherin is predictive of poor overall survival (10, 11).␤-Catenin is found predominantly in association with the E-cadherin cytoplasmic domain at cell-cell junctions (12). In the absence of cell-cell contact and Wnt signaling, cytosolic ␤-catenin forms a complex with adenomatous poliosis coli, Axin/conductin, casein kinases 1␣ and 1⑀, and glyc...

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“…In ovarian carcinoma, integrins have been shown to mediate the organisation of extracellular matrix (ECM) (Carreiras et al, 1999a), adhesion to ECM components (Lessan et al, 1999) and cell motility (Carreiras et al, 1999b). The b1 family of integrins and CD44 has been shown to mediate interactions between ovarian carcinoma cells and the mesothelial cells that line the abdominal organs (Lessan et al, 1999). CD44 binds the ECM glycosaminoglycan hyaluronan with high affinity (Casey and Skubitz, 2000) and affects cell adhesion (Lessan et al, 1999), migration (Casey and Skubitz, 2000) and tumour growth (Strobel et al, 1997) in ovarian carcinoma cells.…”

mentioning

confidence: 99%

“…The b1 family of integrins and CD44 has been shown to mediate interactions between ovarian carcinoma cells and the mesothelial cells that line the abdominal organs (Lessan et al, 1999). CD44 binds the ECM glycosaminoglycan hyaluronan with high affinity (Casey and Skubitz, 2000) and affects cell adhesion (Lessan et al, 1999), migration (Casey and Skubitz, 2000) and tumour growth (Strobel et al, 1997) in ovarian carcinoma cells.…”

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confidence: 99%

Ascites induces modulation of α6β1 integrin and urokinase plasminogen activator receptor expression and associated functions in ovarian carcinoma

et al. 2005

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Interactions between cancer cells and the surrounding medium are not fully understood. In this study, we demonstrate that ascites induces selective changes in the expression of integrins and urokinase plasminogen activator/urokinase plasminogen activator receptor (uPA/uPAR) in ovarian cancer cells. We hypothesise that this change of integrin and uPA/uPAR expression triggers signalling pathways responsible for modulating phenotype-dependent functional changes in ovarian cancer cells. Human ovarian surface epithelial (HOSE) cell lines and epithelial ovarian cancer cell lines were treated with ascites for 48 h. Ascites induced upregulation of a6 integrin, without any change in the expression of av, b1 and b4 integrin subunits. Out of the four ovarian cancer cell lines studied, ascites induced enhancement in the expression of uPA/uPAR in the more invasive OVCA 433 and HEY cell lines without any change in the noninvasive OVHS1 and moderately invasive PEO.36 cell lines. On the other hand, no change in the expression of a6 integrin or uPAR, in response to ascites, was observed in HOSE cells. In response to ascites, enhancement in proliferation and in adhesion was observed in all four ovarian cancer cell lines studied. In contrast, no significant increase in proliferation or adhesion by ascites was observed in HOSE cells. Ascites-induced expression of uPA/uPAR correlated with the increased invasiveness of HEY and OVCA 433 cell lines but was not seen in OVHS1, PEO.36 and HOSE cell lines. Upregulation of a6 integrin and uPA/uPAR correlated with the activation of Ras and downstream Erk pathways. Ascites-induced activation of Ras and downstream Erk can be inhibited by using inhibitory antibodies against a6 and b1 integrin and uPAR, consistent with the inhibition of proliferation, adhesion and invasive functions of ovarian cancer cell lines. Based on these findings, we conclude that ascites can induce selective upregulation of integrin and uPA/uPAR in ovarian cancer cells and these changes may modulate the functions of ovarian carcinomas.

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CD44 and β1 Integrin Mediate Ovarian Carcinoma Cell Adhesion to Peritoneal Mesothelial Cells

Cited by 205 publications

References 30 publications

Tumour-induced apoptosis in human mesothelial cells: a mechanism of peritoneal invasion by Fas Ligand/Fas interaction

Tumour-induced apoptosis in human mesothelial cells: a mechanism of peritoneal invasion by Fas Ligand/Fas interaction

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Ascites induces modulation of α6β1 integrin and urokinase plasminogen activator receptor expression and associated functions in ovarian carcinoma

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