Cadherins and cancer: how does cadherin dysfunction promote tumor progression?

Jeanes, Angela; Gottardi, Cara J.; Yap, Alpha S.

doi:10.1038/onc.2008.343

Cited by 696 publications

(586 citation statements)

References 107 publications

(138 reference statements)

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“…Osteosarcoma has been proposed to be a differentiation-flawed disease [Siclari and Qin, 2010]. In numerous tumors during cancer progression a partial or complete loss of E-cadherin has been described [Jeanes et al, 2008;Mohamet et al, 2011]. E-cadherin controls the levels of free-cytosolic b-catenin and loss of E-cadherin results in the disruption of cell-cell adhesion, in increased cytosolic and nuclear b-catenin levels and in increased cell proliferation.…”

Section: Discussionmentioning

confidence: 99%

Modeling human osteosarcoma in mice through 3AB‐OS cancer stem cell xenografts

Fiore

Guercio

Puleio

et al. 2012

J of Cellular Biochemistry

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Osteosarcoma is the second leading cause of cancer-related death for children and young adults. In this study, we have subcutaneously injected-with and without matrigel-athymic mice (Fox1nu/nu) with human osteosarcoma 3AB-OS pluripotent cancer stem cells (CSCs), which we previously isolated from human osteosarcoma MG63 cells. Engrafted 3AB-OS cells were highly tumorigenic and matrigel greatly accelerated both tumor engraftment and growth rate. 3AB-OS CSC xenografts lacked crucial regulators of beta-catenin levels (E-cadherin, APC, and GSK-3beta), and crucial factors to restrain proliferation, resulting therefore in a strong proliferation potential. During the first weeks of engraftment 3AB-OS-derived tumors expressed high levels of pAKT, beta1-integrin and pFAK, nuclear beta-catenin, c-Myc, cyclin D2, along with high levels of hyperphosphorylated-inactive pRb and anti-apoptotic proteins such as Bcl-2 and XIAP, and matrigel increased the expression of proliferative markers. Thereafter 3AB-OS tumor xenografts obtained with matrigel co-injection showed decreased proliferative potential and AKT levels, and undetectable hyperphosphorylated pRb, whereas beta1-integrin and pFAK levels still increased. Engrafted tumor cells also showed multilineage commitment with matrigel particularly favoring the mesenchymal lineage. Concomitantly, many blood vessels and muscle fibers appeared in the tumor mass. Our findings suggest that matrigel might regulate 3AB-OS cell behavior providing adequate cues for transducing proliferation and differentiation signals triggered by pAKT, beta1-integrin, and pFAK and addressed by pRb protein. Our results provide for the first time a mouse model that recapitulates in vivo crucial features of human osteosarcoma CSCs that could be used to test and predict the efficacy in vivo of novel therapeutic treatments.

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Section: Discussionmentioning

confidence: 99%

Modeling human osteosarcoma in mice through 3AB‐OS cancer stem cell xenografts

Fiore

Guercio

Puleio

et al. 2012

J of Cellular Biochemistry

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“…A Barbáchano et al explained by the potential of E-cadherin to inhibit mitogenic signalling from EGFR and other growth factor receptors and the Wnt/b-catenin pathway, and to maintain the differentiated epithelial phenotype through the regulation of intercellular adhesion and multiple transcription factors (Frixen et al, 1991;Vleminckx et al, 1991;Miyaki et al, 1995;Perl et al, 1998;Christofori and Semb, 1999;Qian et al, 2004;Perrais et al, 2007;Jeanes et al, 2008;Onder et al, 2008). E-cadherin downregulation by SPRY2 is found at both RNA and protein levels, and correlates with the upregulation of ZEB1 RNA and protein.…”

Section: Mutual Regulation Of Sprouty-2 and E-cadherinmentioning

confidence: 99%

SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity

et al. 2010

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SPROUTY-2 (SPRY2) regulates receptor tyrosine kinase signalling and therefore cell growth and differentiation. In this study, we show that SPRY2 expression in colon cancer cells is inhibited by the active vitamin D metabolite 1a,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ) through E-cadherin-dependent and -independent mechanisms. In turn, SPRY2 represses both basal and 1,25(OH) 2 D 3 -induced E-cadherin expression. In line with this, SPRY2 induces ZEB1 RNA and protein, but not that of other epithelial-to-mesenchymal transition inducers that repress the CDH1/E-cadherin promoter. Consistently, SPRY2 and E-cadherin protein levels inversely correlate in colon cancer cell lines and xenografted tumours. Moreover, SPRY2 knockdown by small hairpin RNA increases CDH1/E-cadherin expression and, reciprocally, CDH1/E-cadherin knockdown increases that of SPRY2. In colon cancer patients, SPRY2 is upregulated in undifferentiated high-grade tumours and at the invasive front of low-grade carcinomas. Quantification of protein expression in 34 tumours confirmed an inverse correlation between SPRY2 and E-cadherin. Our data demonstrate a tumourigenic action of SPRY2 that is based on the repression of E-cadherin, probably by the induction of ZEB1, and a reciprocal regulation of SPRY2 and E-cadherin that dictates cell phenotype. We propose SPRY2 as a candidate novel marker for high-grade tumours and a target of therapeutic intervention in colon cancer.

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“…Cell adhesion and polarity in epithelia depends on the formation of adherens junctions in which E-cadherin is a key determinant, providing the physical structure for both cell-cell attachment and the recruitment of signalling complexes (reviewed by Knust and Bossinger, 2002;Perez-Moreno et al, 2003). One of the earliest steps in EMT is the loss of E-cadherin function, and in fact it is generally accepted that EMT-inducing factors initiate epithelial reorganization by impairing the expression or function of E-cadherin (Peinado et al, 2004;Jeanes et al, 2008). The characterization of E-cadherin regulation during EMT has provided important insights into the molecular mechanisms involved in the loss of cell-cell adhesion and in the acquisition of migratory properties during carcinoma progression (Peinado et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of cell polarity in EMT and cancer

2008

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The epithelial-to-mesenchymal transition (EMT) is a crucial process in tumour progression providing tumour cells with the ability to escape from the primary tumour, to migrate to distant regions and to invade tissues. EMT requires a loss of cell-cell adhesion and apical-basal polarity, as well as the acquisition of a fibroblastoid motile phenotype. Several transcription factors have emerged in recent years that induce EMT, with important implications for tumour progression. However, their effects on cell polarity remain unclear. Here, we have re-examined the data available related to the effect of EMT related transcription factors on epithelial cell plasticity, focusing on their impact on cell polarity. Transcriptional and post-transcriptional regulatory mechanisms mediated by several inducers of EMT, in particular the ZEB and Snail factors, downregulate the expression and/or functional organization of core polarity complexes. We also summarize data on the expression of cell polarity genes in human tumours and analyse genetic interactions that highlight the existence of complex regulatory networks converging on the regulation of cell polarity by EMT inducers in human breast carcinomas. These recent observations provide new insights into the relationship between alterations in cell polarity components and EMT in cancer, opening new avenues for their potential use as therapeutic targets to prevent tumour progression.

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Cadherins and cancer: how does cadherin dysfunction promote tumor progression?

Cited by 696 publications

References 107 publications

Modeling human osteosarcoma in mice through 3AB‐OS cancer stem cell xenografts

Modeling human osteosarcoma in mice through 3AB‐OS cancer stem cell xenografts

SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity

Transcriptional regulation of cell polarity in EMT and cancer

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