Cadherins are regulated by Ep-CAM via phosphaditylinositol-3 kinase

Winter, Manon J.; Cirulli, Vincenzo; Bruijn, Inge H. Briaire-de; Litvinov, Sergey V.

doi:10.1007/s11010-007-9420-y

Cited by 30 publications

(33 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Consistent with this hypothesis, although the exact function of Ep-CAM is still unknown, recent insights have revealed a more versatile role for Ep-CAM that is not limited only to cell adhesion but includes diverse processes such as signaling, cell migration, proliferation, and differentiation. 16,17 Taken all together, these observations suggest that targeting the high expression of Ep-CAM, as found in our study, on the surface of chemotherapy-resistant ovarian tumors, may be a novel, potentially effective option to attack residual/resistant disease after standard adjuvant chemotherapy. This hypothesis may be now easily tested because fully human antiYEp-CAM antibody (MT201, adecatumumab) has been developed and characterized 11 and are currently being tested in phase 2 clinical trials in breast and prostate cancer patients.…”

Section: Discussionsupporting

confidence: 66%

Overexpression of Epithelial Cell Adhesion Molecule in Primary, Metastatic, and Recurrent/Chemotherapy-Resistant Epithelial Ovarian Cancer

Bellone

Siegel

Cocco

et al. 2009

International Journal of Gynecological Cancer

View full text Add to dashboard Cite

To evaluate the potential of epithelial cell adhesion molecule (Ep-CAM/TROP-1)-specific immunotherapy against epithelial ovarian carcinomas (EOCs), we have analyzed the expression of Ep-CAM at RNA and protein level in patients harboring primary, metastatic, and chemotherapy-resistant/recurrent EOC. Epithelial cell adhesion molecule expression was evaluated by real-time polymerase chain reaction and immunohistochemistry in 168 fresh-frozen biopsies and paraffin-embedded tissues. In addition, Ep-CAM surface expression was evaluated by flow cytometry in several freshly established ovarian carcinoma cell lines derived from patients harboring tumors resistant to chemotherapy in vivo as well as in vitro. Epithelial cell adhesion molecule transcript was found significantly overexpressed in primary, metastatic, and recurrent EOC when compared with normal human ovarian surface epithelium cell lines and fresh-frozen normal ovarian tissue (P < 0.001). Similarly, by immunohistochemistry, Ep-CAM protein expression was found significantly higher in primary, metastatic, and recurrent EOC when compared with normal ovarian tissues. Of interest, metastatic/recurrent tumors were found to express significantly higher levels of Ep-CAM protein when compared with primary ovarian carcinomas (P < 0.001). Finally, a high surface expression of Ep-CAM was found in 100% (5/5) of the chemotherapy-resistant ovarian carcinoma cell lines studied by flow cytometry. These results demonstrate high Ep-CAM overexpression in ovarian carcinoma, especially in metastatic and recurrent/chemotherapy-resistant ovarian disease. The lack of Ep-CAM expression on the chelomic epithelium in the peritoneal cavity, combined with the recent development of fully human monoclonal antibodies against this surface molecule, suggest Ep-CAM as a promising target for antibody-mediated therapies in ovarian carcinoma patients harboring tumors refractory to standard treatment modalities.

show abstract

Section: Discussionsupporting

confidence: 66%

Overexpression of Epithelial Cell Adhesion Molecule in Primary, Metastatic, and Recurrent/Chemotherapy-Resistant Epithelial Ovarian Cancer

Bellone

Siegel

Cocco

et al. 2009

International Journal of Gynecological Cancer

View full text Add to dashboard Cite

show abstract

“…Presumably, these cells loose expression under artificial in vitro conditions and loss of normal tissue polarity, since in vivo both basal/progenitor as well as differentiated luminal cells are strongly positive for immunoreactive EpCAM. Moreover, cell-cell adhesions in our HMECs are primarily mediated by E-cadherin, which has been described to be a counter player of EpCAM [10,18,31]. Typically, HMEC cultures age under mitotic stress and induce p16 INK4A and/or p53 [32,33].…”

Section: Discussionmentioning

confidence: 99%

EpCAM overexpression prolongs proliferative capacity of primary human breast epithelial cells and supports hyperplastic growth

et al. 2013

View full text Add to dashboard Cite

IntroductionThe Epithelial Cell Adhesion Molecule (EpCAM) has been shown to be strongly expressed in human breast cancer and cancer stem cells and its overexpression has been supposed to support tumor progression and metastasis. However, effects of EpCAM overexpression on normal breast epithelial cells have never been studied before. Therefore, we analyzed effects of transient adenoviral overexpression of EpCAM on proliferation, migration and differentiation of primary human mammary epithelial cells (HMECs).MethodsHMECs were transfected by an adenoviral system for transient overexpression of EpCAM. Thereafter, changes in cell proliferation and migration were studied using a real time measurement system. Target gene expression was evaluated by transcriptome analysis in proliferating and polarized HMEC cultures. A Chicken Chorioallantoic Membrane (CAM) xenograft model was used to study effects on in vivo growth of HMECs.ResultsEpCAM overexpression in HMECs did not significantly alter gene expression profile of proliferating or growth arrested cells. Proliferating HMECs displayed predominantly glycosylated EpCAM isoforms and were inhibited in cell proliferation and migration by upregulation of p27KIP1 and p53. HMECs with overexpression of EpCAM showed a down regulation of E-cadherin. Moreover, cells were more resistant to TGF-β1 induced growth arrest and maintained longer capacities to proliferate in vitro. EpCAM overexpressing HMECs xenografts in chicken embryos showed hyperplastic growth, lack of lumen formation and increased infiltrates of the chicken leukocytes.ConclusionsEpCAM revealed oncogenic features in normal human breast cells by inducing resistance to TGF-β1-mediated growth arrest and supporting a cell phenotype with longer proliferative capacities in vitro. EpCAM overexpression resulted in hyperplastic growth in vivo. Thus, we suggest that EpCAM acts as a prosurvival factor counteracting terminal differentiation processes in normal mammary glands.

show abstract

“…In a murine fibroblast model, Winter et al [126] subsequently demonstrated that this may occur by disruption of the link between a-catenin and F-actin, probably by EpCAM's disruption of the actin cytoskeleton or possibly via p120. In later work, on human breast epithelial cells, Winter et al [127] demonstrated that EpCAM cross-signalling with N-cadherin resulted in the abrogation of cadherin adhesion complexes, mediated by PI(3)K. In breast cancer cell lines, Martowicz et al [128] showed that epithelial cells need EpCAM to promote growth and invasion, yet mesenchymal tumour cells are independent of EpCAM for invasion and progression; Martowicz et al [129] also demonstrated that overexpression of EpCAM in human mammary epithelial cells led to a more proliferative phenotype and downregulation of E-cadherin. There is likely considerable plasticity in these pathways [110], with cells reverting to a less aggressive state by mesenchymal-to-epithelial transition (MET) or by the reversal of the CSC phenotype, and most likely influenced by the tumour microenvironment [23].…”

Section: Cadherins and Epcammentioning

confidence: 99%

Cell adhesion and urothelial bladder cancer: the role of cadherin switching and related phenomena

Bryan

2015

Phil. Trans. R. Soc. B

View full text Add to dashboard Cite

Cadherins are mediators of cell-cell adhesion in epithelial tissues. E-cadherin is a known tumour suppressor and plays a central role in suppressing the invasive phenotype of cancer cells. However, the abnormal expression of N-and P-cadherin ('cadherin switching', CS) has been shown to promote a more invasive and m alignant phenotype of cancer, with P-cadherin possibly acting as a key mediator of invasion and metastasis in bladder cancer. Cadherins are also implicated in numerous signalling events related to embryonic development, tissue morphogenesis and homeostasis. It is these wide ranging effects and the serious implications of CS that make the cadherin cell adhesion molecules and their related pathways strong candidate targets for the inhibition of cancer progression, including bladder cancer. This review focuses on CS in the context of bladder cancer and in particular the switch to P-cadherin expression, and discusses other related molecules and phenomena, including EpCAM and the development of the cancer stem cell phenotype.

show abstract

Cadherins are regulated by Ep-CAM via phosphaditylinositol-3 kinase

Cited by 30 publications

References 26 publications

Overexpression of Epithelial Cell Adhesion Molecule in Primary, Metastatic, and Recurrent/Chemotherapy-Resistant Epithelial Ovarian Cancer

Overexpression of Epithelial Cell Adhesion Molecule in Primary, Metastatic, and Recurrent/Chemotherapy-Resistant Epithelial Ovarian Cancer

EpCAM overexpression prolongs proliferative capacity of primary human breast epithelial cells and supports hyperplastic growth

Cell adhesion and urothelial bladder cancer: the role of cadherin switching and related phenomena

Contact Info

Product

Resources

About