Abrogation of E-Cadherin-Mediated Adhesion Induces Tumor Cell Invasion in Human Skin-Like Organotypic Culture

Margulis, Alexander R.; Andriani, Frank; Fusenig, Norbert E.; Hashimoto, Koji; Hanakawa, Yasushi; Garlick, Jonathan A.

doi:10.1046/j.1523-1747.2003.12523.x

Cited by 21 publications

(15 citation statements)

References 38 publications

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“…Gap junctional communication was not essential for the contractual inhibition of transformed by normal cells, because the effect persisted when the normal cells were taken from gap junction knockout mice. The postulate that adherence junctions were important was consistent with the finding that reexpression of E-cadherin could suppress the transformed phenotype in isolated cancer cells (47), whereas the blocking of cadherin function by a dominant negative mutant enhanced invasion (48).…”

Section: Intercellular Surveillance (Microenvironmental Control)supporting

confidence: 79%

Toward a genetics of cancer resistance

Klein

2009

Proc. Natl. Acad. Sci. U.S.A.

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Two of three humans never get cancer. Even the majority of heavy smokers remain cancer free. Is this a matter of chance, or are there cancer-resistant genotypes? Based on the evidence discussed, it would appear that evolution has favored a limited number of relatively common resistance genes that may nip incipient cancerous foci in the bud, i.e., to stop them at their inception. It is further suggested that resistance genes may act at the level of tissue organization in a dominant fashion.

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Section: Intercellular Surveillance (Microenvironmental Control)supporting

confidence: 79%

Toward a genetics of cancer resistance

Klein

2009

Proc. Natl. Acad. Sci. U.S.A.

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“…3a, asterisks inset) as previously described for II-4 cells. 23 Under higher magnification, well-formed desmosomes were found (Fig. 3a, inset), indicating that control II-4 cells retained their capacity to form these structures.…”

Section: Loss Of Cell-cell Adhesion Structures Is Associated With Rapmentioning

confidence: 82%

Loss of intercellular adhesion activates a transition from low‐ to high‐grade human squamous cell carcinoma

Margulis

Zhang

Alt-Holland

et al. 2005

Intl Journal of Cancer

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The relationship between loss of intercellular adhesion and the biologic properties of human squamous cell carcinoma is not well understood. We investigated how abrogation of E-cadherin-mediated adhesion influenced the behavior and phenotype of squamous cell carcinoma in 3D human tissues. Cell-cell adhesion was disrupted in early-stage epithelial tumor cells (HaCaT-II-4) through expression of a dominant-negative form of E-cadherin (H-2K dEcad). Three-dimensional human tissue constructs harboring either H-2K d -Ecad-expressing or control II-4 cells (pBabe, H-2K dEcadDC25) were cultured at an air-liquid interface for 8 days and transplanted to nude mice; tumor phenotype was analyzed 2 days and 2 and 4 weeks later. H-2Kd -Ecad-expressing tumors demonstrated a switch to a high-grade aggressive tumor phenotype characterized by poorly differentiated tumor cells that infiltrated throughout the stroma. This high-grade carcinoma revealed elevated cell proliferation in a random pattern, loss of keratin 1 and diffuse deposition of laminin 5 c2 chain. When II-4 cell variants were seeded into type I collagen gels as an in vitro assay for cell migration, we found that only E-cadherin-deficient cells detached, migrated as single cells and expressed N-cadherin. Functionblocking studies demonstrated that this migration was matrix metalloproteinase-dependent, as GM-6001 and TIMP-2, but not TIMP-1, could block migration. Gene expression profiles revealed that E-cadherin-deficient II-4 cells demonstrated increased expression of proteases and cell-cell and cell-matrix proteins. These findings showed that loss of E-cadherin-mediated adhesion plays a causal role in the transition from low-to high-grade squamous cell carcinomas and that the absence of E-cadherin is an important prognostic marker in the progression of this disease. ' 2005 Wiley-Liss, Inc.Key words: E-cadherin; squamous cell carcinoma; matrix metalloproteinase; laminin 5; tumor microenvironment E-cadherin is known to be a tumor suppressor gene since the loss of E-cadherin function in tumor progression during the advanced stages of carcinoma progression is well established [1][2][3] and has been linked to a poor clinical prognosis in vivo.4-6 Studies using 2D monolayer cultures have demonstrated the direct influence of E-cadherin function on the malignant properties of transformed cells at an advanced stage. For example, abrogation of E-cadherin-mediated adhesion 7-10 induced tumor cell invasion in vitro while restoration of E-cadherin function resulted in growth retardation and inhibition of invasive properties.3,9 However, the role that loss of E-cadherin-mediated adhesion may play in early stages of carcinoma progression is poorly understood, as studies have demonstrated either a reduction 11,12 or an increase 13,14 of E-cadherin function during the initial stages of epithelial cancer progression.Further elucidation of the impact of altered cell-cell adhesion on early events in squamous cell carcinoma progression has been limited by the inability of monolayer culture t...

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“…Importantly, HaCaT cells retain a stable chromosome content and remain nontumorigenic throughout 320 passages (29), and, when grown in organotypic cultures, HaCaT cells form differentiated skin, express terminal differentiation markers, and exhibit normal substratum adhesion and cell spreading required for proliferation and prevention of apoptosis (28,42,43). Tumorigenic conversion of the HaCaT cells has been observed after transfection with vH-ras oncogene (39), increased activation of tyrosine kinase receptor PDGF (44)(45)(46)(47)(48), and loss of adhesion (49,50). These phenotypic characteristics are the same that we observe when truncating the O-linked glycans by COSMC knockout.…”

Section: Discussionmentioning

confidence: 99%

Immature truncated O-glycophenotype of cancer directly induces oncogenic features

Radhakrishnan

Dabelsteen²,

Madsen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

266

268

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Aberrant expression of immature truncated O-glycans is a characteristic feature observed on virtually all epithelial cancer cells, and a very high frequency is observed in early epithelial premalignant lesions that precede the development of adenocarcinomas. Expression of the truncated O-glycan structures Tn and sialyl-Tn is strongly associated with poor prognosis and overall low survival. The genetic and biosynthetic mechanisms leading to accumulation of truncated O-glycans are not fully understood and include mutation or dysregulation of glycosyltransferases involved in elongation of O-glycans, as well as relocation of glycosyltransferases controlling initiation of O-glycosylation from Golgi to endoplasmic reticulum. Truncated O-glycans have been proposed to play functional roles for cancer-cell invasiveness, but our understanding of the biological functions of aberrant glycosylation in cancer is still highly limited. Here, we used exome sequencing of most glycosyltransferases in a large series of primary and metastatic pancreatic cancers to rule out somatic mutations as a cause of expression of truncated O-glycans. Instead, we found hypermethylation of core 1 β3-Gal-T-specific molecular chaperone, a key chaperone for O-glycan elongation, as the most prevalent cause. We next used gene editing to produce isogenic cell systems with and without homogenous truncated O-glycans that enabled, to our knowledge, the first polyomic and side-by-side evaluation of the cancer O-glycophenotype in an organotypic tissue model and in xenografts. The results strongly suggest that truncation of O-glycans directly induces oncogenic features of cell growth and invasion. The study provides support for targeting cancer-specific truncated O-glycans with immunotherapeutic measures.epigenetics | glycans | skin | pancreas | keratinocyte

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Abrogation of E-Cadherin-Mediated Adhesion Induces Tumor Cell Invasion in Human Skin-Like Organotypic Culture

Cited by 21 publications

References 38 publications

Toward a genetics of cancer resistance

Toward a genetics of cancer resistance

Loss of intercellular adhesion activates a transition from low‐ to high‐grade human squamous cell carcinoma

Immature truncated O-glycophenotype of cancer directly induces oncogenic features

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