Cell cycle arrest or survival signaling through αv integrins, activation of PKC and ERK1/2 lead to anoikis resistance of ovarian cancer spheroids

Carduner, Ludovic; Picot, Cědric R.; Leroy-Dudal, Johanne; Blay, Lyvia; Kellouche, Sabrina; Carreiras, Franck

doi:10.1016/j.yexcr.2013.11.011

Cited by 78 publications

(66 citation statements)

References 44 publications

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“…Interestingly, Src and ERK activation was also seen in SFCs compared with NSFCs. Consistent with these data, it has been reported that several mediators of CDCP1 signaling, including integrin β1, 37 Akt 38 and ERK, 39 also mediate formation of ovarian cancer cell spheroids. We confirmed the importance of elevated CDCP1 by showing that a functionblocking anti-CDCP1 antibody that we have previously used to inhibit vascular metastasis 18 caused a marked reduction in the ability of SFCs to form i.p.…”

Section: Resultssupporting

confidence: 75%

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

Harrington

et al. 2015

Oncogene

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Hematogenous metastases are rarely present at diagnosis of ovarian clear cell carcinoma (OCC). Instead dissemination of these tumors is characteristically via direct extension of the primary tumor into nearby organs and the spread of exfoliated tumor cells throughout the peritoneum, initially via the peritoneal fluid, and later via ascites that accumulates as a result of disruption of the lymphatic system. The molecular mechanisms orchestrating these processes are uncertain. In particular, the signaling pathways used by malignant cells to survive the stresses of anchorage-free growth in peritoneal fluid and ascites, and to colonize remote sites, are poorly defined. We demonstrate that the transmembrane glycoprotein CUB-domain-containing protein 1 (CDCP1) has important and inhibitable roles in these processes. In vitro assays indicate that CDCP1 mediates formation and survival of OCC spheroids, as well as cell migration and chemoresistance. Disruption of CDCP1 via silencing and antibody-mediated inhibition markedly reduce the ability of TOV21G OCC cells to form intraperitoneal tumors and induce accumulation of ascites in mice. Mechanistically our data suggest that CDCP1 effects are mediated via a novel mechanism of protein kinase B (Akt) activation. Immunohistochemical analysis also suggested that CDCP1 is functionally important in OCC, with its expression elevated in 90% of 198 OCC tumors and increased CDCP1 expression correlating with poor patient disease-free and overall survival. This analysis also showed that CDCP1 is largely restricted to the surface of malignant cells where it is accessible to therapeutic antibodies. Importantly, antibody-mediated blockade of CDCP1 in vivo significantly increased the anti-tumor efficacy of carboplatin, the chemotherapy most commonly used to treat OCC. In summary, our data indicate that CDCP1 is important in the progression of OCC and that targeting pathways mediated by this protein may be useful for the management of OCC, potentially in combination with chemotherapies and agents targeting the Akt pathway.

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Section: Resultssupporting

confidence: 75%

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

Harrington

et al. 2015

Oncogene

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“…HGS-OvCa dissemination involves the acquisition of the phenotypes that allow carcinoma cells to: (a) exfoliate from fimbriae into the peritoneal cavity, (b) cope with the proapoptotic stress induced by detachment from the basement membrane (anoikis) during transit through the fluids of the peritoneal cavity (14–16), and (c) attach to and clear the superficial layer of the mesothelium that encloses the organs in the peritoneal cavity (17–22). Although TP53 mutations are a hallmark of HGS-OvCa (9, 11, 23), the role that mutant p53 variants play in the acquisition of these phenotypes is currently not known.…”

Section: Introductionmentioning

confidence: 99%

Mutant p53 regulates ovarian cancer transformed phenotypes through autocrine matrix deposition

et al. 2016

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High-grade serous ovarian carcinoma (HGS-OvCa) harbors p53 mutations and can originate from the epithelial cell compartment of the fallopian tube fimbriae. From this site, neoplastic cells detach, survive in the peritoneal cavity, and form cellular clusters that intercalate into the mesothelium to form ovarian and peritoneal masses. To examine the contribution of mutant p53 to phenotypic alterations associated with HGS-OvCA, we developed live-cell microscopy assays that recapitulate these early events in cultured fallopian tube nonciliated epithelial (FNE) cells. Expression of stabilizing mutant variants of p53, but not depletion of endogenous wild-type p53, in FNE cells promoted survival and cell-cell aggregation under conditions of cell detachment, leading to the formation of cell clusters with mesothelium-intercalation capacity. Mutant p53R175H-induced phenotypes were dependent on fibronectin production, α5β1 fibronectin receptor engagement, and TWIST1 expression. These results indicate that FNE cells expressing stabilizing p53 mutants acquire anchorage independence and subsequent mesothelial intercalation capacity through a mechanism involving mesenchymal transition and matrix production. These findings provide important new insights into activities of mutant p53 in the cells of origin of HGS-OvCa.

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“…Recent studies reported that cell cycle arrest in G1 or G1/S phase may be linked to resistance to anoikis [40,41]. Flow cytometry analyzes demonstrated that AV-38/398 triggers a marked increase in the G2/M fraction and a parallel decrease in G0/G1 and S phase cells.…”

Section: Discussionmentioning

confidence: 98%

A Novel Small-Molecule Integrin Antagonist Inhibits Cells Adhesion Followed By Anoikis in Endothelial Cells - A Comparative Analysis with Cilengitide

Christenheit¹

2016

Glob J Cancer Ther

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Background: Despite the crucial role of integrin receptors in cancer pathogenesis and massive efforts towards establishing clinically relevant drugs, to the present no effective integrin antagonist for the treatment of malignant diseases has been introduced into the clinic.Context and purpose of the study: The purpose of the study was to examine the cellular effects and molecular mechanisms of a novel anti-integrin compound designated AV-398/38 and to compare it with cilengitide, one of the most advanced and best characterized αVβ3/αVβ5 integrin antagonists. AV-398/38 is a small molecule integrin antagonist that is currently in an early phase of pre-clinical evaluation. It was identified by virtual screening of chemical databases with the aim to detect novel integrin αVβ3 antagonist-like candidates. Based on preliminary in vitro data, the compound was recognized as a potential anti-neoplastic drug candidate, displaying high specificity and binding affinity in the nanomolar range towards the αVβ3 receptor, as well as showing potentially favorable drug-like properties.Results: Our studies revealed that its anti-neoplastic properties are most likely mediated by inhibition of integrin-mediated cell attachment to the extracellular matrix resulting in anoikis in a TP53 independent manner. Additionally, we observed inhibition of integrin-linked pathways involved in cell proliferation, survival and migration such as FAK, Akt, and MAPK as well as direct inhibitory effects on cell migration. We compared the effects of the compound with cilengitide, which is one of the bestcharacterized αVβ3 antagonists available. Main findings:The main finding was the observation, that AV-398/38 is capable of inducing cell death via induction of anoikis in a TP53 independent manner. Conclusions:Integrin αVβ3/αVβ5 inhibition leads to apoptotic cell death most likely triggered by a loss of adherence. Brief summary and potential implications:Our data indicate that compound AV-398/38 or structurally similar molecules may be promising candidates for preclinical development.

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Cell cycle arrest or survival signaling through αv integrins, activation of PKC and ERK1/2 lead to anoikis resistance of ovarian cancer spheroids

Cited by 78 publications

References 44 publications

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

Elevated CDCP1 predicts poor patient outcome and mediates ovarian clear cell carcinoma by promoting tumor spheroid formation, cell migration and chemoresistance

Mutant p53 regulates ovarian cancer transformed phenotypes through autocrine matrix deposition

A Novel Small-Molecule Integrin Antagonist Inhibits Cells Adhesion Followed By Anoikis in Endothelial Cells - A Comparative Analysis with Cilengitide

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