Cadherins as Modulators of Cellular Phenotype

Wheelock, Margaret J.; Johnson, Keith R.

doi:10.1146/annurev.cellbio.19.011102.111135

Cited by 596 publications

(499 citation statements)

References 160 publications

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“…E-cadherin, a homotypic cell-cell adhesion molecule ubiquitously expressed on epithelial cells, is considered an active suppressor of invasion and growth in normal epithelial cells. [35][36][37][38] Alterations in cell surface expression of cadherins correlate with cancer progression and molecular pathogenesis: in the majority of epithelial cancers membrane expression of E-cadherin is lost. These changes are mediated by mutational inactivation of E-cadherin or b-catenin genes, by transcriptional repression or by proteolysis of the extracellular cadherin domain.…”

Section: Discussionmentioning

confidence: 99%

“…E-cadherin is downregulated in various cancers and its loss can lead to increased expression of MMP9 and cellular invasion. 35,36 Integrin-b4 is another membrane protein involved in cellcell adhesion, with key roles in assembly and adhesive functions of the hemidesmosome. Both are adhesionrelated transmembrane proteins, whose expression is regulated by MDA-7.…”

Section: Overexpressionmentioning

confidence: 99%

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Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

et al. 2006

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The melanoma differentiation-associated gene-7 (mda-7) is a member of the interleukin-10 cytokine family and a novel tumor suppressor gene. Adenoviral-mediated mda-7 (Ad-mda7) gene transfer has tumor-specific growth inhibitory and proapoptotic effects in a broad spectrum of cancer cells. In breast cancer cells, adenoviral-induced mda-7 expression triggers antiproliferative effects by downregulation of survival signals, such as Bcl-2 and Akt. The anti-human epidermal growth factor receptor-2 (Her-2) monoclonal antibody, Trastuzumab (Herceptin), increases the sensitivity of Her-2/neu-overexpressing breast cancer cells to chemotherapeutic agents and radiotherapy. In this study, we evaluate the effects of treatment with Ad-mda7 and Herceptin combination therapy in a panel of Her-2/neu-overexpressing cell lines, and in established tumors in nude mice. Compared to individual treatments, the combination of Ad-mda7 and Herceptin elicits supra-additive antitumor activity in Her-2/neuoverexpressing tumor cell lines: increased cell death, cell cycle block and apoptosis. The Ad-mda7 and Herceptin interaction was shown to be synergistic by isobologram analysis. Ad-mda7 does not alter cell surface Her-2/neu levels, but the combination of Ad-mda7 þ Herceptin results in increased expression of cell surface E-cadherin with concomitant translocation of b-catenin from the nucleus to the cell membrane. In vivo, the combination of Ad-mda7 and Herceptin showed significantly increased antitumor activity (Po0.003) against Her-2/neu-overexpressing tumors. These data suggest that the combination of Ad-mda7 with Herceptin may be a novel therapy for breast cancer patients whose tumors overexpress Her-2/neu. The observed synergistic effect may improve treatment options for otherwise poorly responsive, Her-2-positive, breast cancer patients. Cancer Gene Therapy (2006) 13, 958-968.

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Section: Discussionmentioning

confidence: 99%

Section: Overexpressionmentioning

confidence: 99%

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

et al. 2006

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“…In striking contrast to other epithelia, normal OSE epithelial integrity is maintained primarily by N-cadherin [ Fig. 2,16 In other tumors, N-cadherin enhances motility even when co-expressed with E-cadherin [48,50], but the potential role of N-cadherin expression in ovarian cancer is unclear at this time.…”

Section: B Cadherin Expression In Eocmentioning

confidence: 99%

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Hudson

Zeineldin

Stack

2008

Clin Exp Metastasis

163

172

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The mesodermally derived normal ovarian surface epithelium (OSE) displays both epithelial and mesenchymal characteristics and exhibits remarkable phenotypic plasticity during post-ovulatory repair. The majority of epithelial ovarian carcinomas (EOC) are derived from the OSE and represent the most lethal of all gynecological malignancies, as most patients (~70%) present at diagnosis with disseminated intra-abdominal metastasis. The predominant pattern of EOC metastasis involves pelvic dissemination rather than lymphatic or hematologic spread, distinguishing EOC from other solid tumors. Acquisition of the metastatic phenotype involves a complex series of interrelated cellular events leading to dissociation (shedding) and dispersal of malignant cells. A key event in this process is disruption of cell-cell contacts via modulation of intercellular junctional components. In contrast to most carcinomas that downregulate E-cadherin expression during tumor progression, an unique feature of primary well-differentiated ovarian cancers is a gain of epithelial features, characterized by an increase in expression of E-cadherin. Subsequent reacquisition of mesenchymal features is observed in more advanced tumors with concomitant loss of E-cadherin expression and/ or function during progression to metastasis. The functional consequences of this remarkable phenotypic plasticity are not fully understood, but may play a role in modulation of cell survival in suspension (ascites), chemoresistance, and intraperitoneal anchoring of metastatic lesions. Keywords ovarian cancer; epithelium; cadherin; keratin; vimentin; epithelial-mesenchymal transition; plasticity Ovarian Cancer-OverviewTumors arising from the ovarian epithelium account for ~90% of ovarian malignancies and epithelial ovarian carcinoma (EOC) is the leading cause of death from gynecologic malignancy, resulting in approximately 15,280 deaths in the United States alone in 2006 [1]. These distressing statistics are largely due to the low detection rate of disease confined to the ovary (stage 1) when 5-year survival is >90%. Approximately 75% of women are initially diagnosed with disseminated intra-abdominal disease (stage III-IV) and have a 5-year survival of <20%.Ovarian tumors are pathologically heterogeneous with four major histotypes: serous, endometroid, clear cell and mucinous. These classifications are histogenetically based on The early steps of EOC metastasis involve shedding of the cells from the primary tumor to form free floating cells or multi-cellular aggregates (MCAs) in ascites [ Fig. 1]. Cell-cell and cell-matrix adhesion molecules mediate interaction of metastasizing tumor cells with mesothelial cells lining the inner surface of the peritoneal cavity and the sub-mesothelial extracellular matrix (ECM). Localized proteolytic degradation of sub-mesothelial ECM components facilitates migration of tumor cells and anchoring of secondary lesions on adjacent pelvic organs, and at later stages, metastasis to distant organs [9,10]. However, the majority of wo...

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“…The cadherins are transmembrane glycoproteins responsible for calciumdependent homophilic cell-to-cell adhesion (Thiery et al, 1988;Yagi and Takeichi, 2000;Wheelock and Johnson, 2003). The cadherins constitute a large superfamily that includes the classic cadherins, desmosomal cadherins, protocadherins, and atypical cadherins.…”

Section: Introductionmentioning

confidence: 99%

Zebrafish protocadherin 10 is involved in paraxial mesoderm development and somitogenesis

Murakami

Hijikata

Matsukawa

et al. 2005

Developmental Dynamics

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Here, we present the first report of the molecular cloning of zebrafish protocadherin 10 (Pcdh10, OLprotocadherin) and describe its functional analyses in the development of segmental plate. Epitope-tagged Pcdh10 expressed in embryos was localized on cell peripheries of adjacent cells. In situ hybridization showed that pcdh10 was expressed in the paraxial mesoderm (PAM) and developing somites, and in the pineal body, the diencephalon, and the vicinity of otocysts. Expression in PAM increased in the last few presumptive somites, reached the maximum level in the latest segmenting somites, and decreased thereafter during somite maturation. These expression patterns suggested that Pcdh10 is involved in development of PAM and somites. This was confirmed by morpholino knockdown and dominant-negative inhibition of Pcdh10 in embryos, which disturbed movements of PAM cells and somite segmentation. Comparative studies showed that pcdh10 expression lasted up to approximately three times longer in maturing somites than that of paraxial protocadherin (pcdh8). They also indicated that the adaxial cells expressed pcdh8 but not pcdh10. We propose that Pcdh10 is involved in the morphogenic movements of PAM cells and somite segmentation and that differential adhesion of Pcdh8 and Pcdh10 plays a role in the morphogenic machinery of somites and adaxial cells. Developmental Dynamics 235:506 -514, 2006.

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Cadherins as Modulators of Cellular Phenotype

Cited by 596 publications

References 160 publications

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

Combinatorial synergy induced by adenoviral-mediated mda-7 and Herceptin in Her-2+ breast cancer cells

Phenotypic plasticity of neoplastic ovarian epithelium: unique cadherin profiles in tumor progression

Zebrafish protocadherin 10 is involved in paraxial mesoderm development and somitogenesis

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