Soluble E-cadherin fragments increased in circulation of cancer patients

Katayama, Masahiko; Hirai, Shyunji; Kamihagi, K; Nakagawa, Kazuo; Yasumoto, Makiko; Kato, Ikunoshin

doi:10.1038/bjc.1994.106

Cited by 168 publications

(142 citation statements)

References 29 publications

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“…The soluble cleaved form of E-cadherin has been observed in serum under non-pathological conditions, but increased levels of the soluble form have been detected in patient peripheral blood samples 24,54 and urine samples 55 in a variety of diseases. 21 It has been suggested that the 80-kDa soluble fragment may serve as a useful biomarker of disease progression for a number of cancers, including prostate, 23 gastric, 24 hepatocellular 24 and bladder cancer.…”

Section: Discussionmentioning

confidence: 99%

“…21 It has been suggested that the 80-kDa soluble fragment may serve as a useful biomarker of disease progression for a number of cancers, including prostate, 23 gastric, 24 hepatocellular 24 and bladder cancer. 55 There has also been a correlation between tumor stage, histological grade and elevated levels of soluble E-cadherin, likely because the detection of soluble E-cadherin has been associated with increased invasiveness.…”

Section: Discussionmentioning

confidence: 99%

“…18 The proteolytic ectodomain release or 'shedding' of E-cadherin is emerging as an important regulatory mechanism and has been suggested to cause rapid changes in cell adhesion, signaling and apoptosis. [19][20][21][22] Furthermore, increased levels of the soluble N-terminal fragment have been associated with several tumors, including prostate, 23 gastric, 24 hepatocellular 24 and bladder cancer and may be of prognostic value. 21 Whether the C-terminal intracellular fragment of E-cadherin has oncogenic roles, for example, via promoting b-cateninmediated signaling, is unclear.…”

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confidence: 99%

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Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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The loss of functional von Hippel-Lindau (VHL) tumor suppressor gene is associated with the development of clear-cell renal cell carcinoma (CC-RCC). Recently, VHL was shown to promote the transcription of E-cadherin, an adhesion molecule whose expression is inversely correlated with the aggressive phenotype of numerous epithelial cancers. Here, we performed immunohistochemistry on CC-RCC tissue microarrays to determine the prognostic value of E-cadherin and VHL with respect to Fuhrman grade and clinical prognosis. Low Fuhrman grade and good prognosis associated with positive VHL and E-cadherin immunoreactivity, whereas poor prognosis and high-grade tumors associated with a lack of E-cadherin and lower frequency of VHL staining. A significant portion of CC-RCC with positive VHL immunostaining correlated with nuclear localization of C-terminally cleaved E-cadherin. DNA sequencing revealed in a majority of nuclear E-cadherin-positive CC-RCC, subtle point mutations, deletions and insertions in VHL. Furthermore, nuclear E-cadherin was not observed in chromophobe or papillary RCC, as well as matched normal kidney tissue. In addition, nuclear E-cadherin localization was recapitulated in CC-RCC xenografts devoid of functional VHL or reconstituted with synthetic mutant VHL grown in SCID mice. These findings provide the first evidence of aberrant nuclear localization of E-cadherin in CC-RCC harboring VHL mutations, and suggest potential prognostic value of VHL and E-cadherin in CC-RCC. [4][5][6][7] Currently, a prediction of patient survival is based on traditional clinical parameters, including tumor size and Fuhrman nuclear grade. 8 However, the emerging understanding of the molecular pathways implicated in CC-RCC genesis and progression is providing previously unappreciated markers, which may serve as additional or better prognostic indicators of CC-RCC.The principal cause of sporadic CC-RCC and familial von Hippel-Lindau (VHL) disease-associated CC-RCC is the inactivating mutations of VHL. Although VHL patients also develop tumors in other organs including the central nervous system, retina and the adrenal gland, CC-RCC remains to be the leading cause of morbidity and death for VHL patients. 9 The most well-established function of VHL is its role in the oxygen-dependent negative regulation of hypoxia-inducible factor (HIF). VHL is a substrate-conferring component of an E3 ubiquitin ligase ECV (elongins/Cul2/VHL) that polyubiquitylates the catalytic a-subunit of HIF that has undergone hydroxylation on conserved prolyl residues within the oxygen-dependent degradation (ODD) domain. Prolyl hydroxylation is mediated by a class of prolyl hydroxylases (PHD1-3) in an oxygen-dependent manner. Thus, under hypoxia or in the absence of a functional VHL, HIFa becomes stabilized and binds to its common and constitutively expressed b-subunit, forming an active HIF transcription factor capable of transactivating numerous hypoxia-inducible genes such as vascular endothelial growth factor (VEGF),

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Gervais

Henry

Saravanan

et al. 2007

Laboratory Investigation

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“…Specifically, the association between the cell-cell adhesion molecule, E-cadherin, and cytoskeletal protein, β-catenin has been shown to be vulnerable to enzymatic attack by multiple MMPs, including MMP-9 and MMP-2 [42,44,45]. Proteolytic cleavage of the N-terminal extracellular domain of E-cadherin by MMPs results in the shedding of E-cadherin and formation of extracellular domain fragments ranging in size from 50 to 85 kDa, that are often secreted into the conditioned media of cultured cells [46] and have been detected in vivo in urine, blister fluid of cutaneous diseases and the circulation of cancer patients [47][48][49]. Interestingly, MMP inhibitors have been shown to stabilize cadherin junctions and more specifically, the MMPI, GM6001, can suppress Ecadherin shedding [23,42,43].…”

Section: Mmp and Ascmentioning

confidence: 99%

Matrix metalloproteinases as mediators of primary and secondary cataracts

West‐Mays

Pino

2007

Expert Review of Ophthalmology

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The matrix metalloproteinases (MMPs) are a family of endopeptidases involved in numerous remodeling and fibrotic disorders. Although MMPs have been shown to play important roles in regenerative and disease processes in many parts of the eye, including the cornea, retina and trabecular meshwork, the role of MMPs in the normal and cataractous lens has only recently been studied. These investigations have shown that multiple MMPs are expressed in the lens and their expression is altered in a number of cataract phenotypes. However, anterior subcapsular cataract and posterior capsular opacification, cataracts of a fibrotic nature, show a particular involvement of MMPs. This review will highlight recent findings that suggest a causative role for MMPs in these fibrotic cataract phenotypes. Keywords cataract; EMT; fibrosis; lens; MMPIs; matrix metalloproteinase Cataract is the leading cause of blindness worldwide despite the availability of effective surgery in the developed countries [1,2]. The etiology of cataract is diverse (see Allen [3] for review) with the majority of cataracts related to aging. Extracapsular cataract extraction provides quick restoration of vision and is the most frequently performed surgical procedure in the developed world, costing over US$3.5 billion each year in the USA alone [4]. However, it is not without its problems and can lead to complications such as the development of secondary cataract (up to 40-50% incidence of patients), also known as posterior capsular opacification (PCO) [5,6]. PCO is a major medical problem with profound consequences to the patient's well-being and is a significant financial burden. PCO is considered a proliferative, fibrotic disorder that involves the aberrant deposition of matrix and wrinkling of the lens capsule [7]. Another cataract type, also of a fibrotic nature, is anterior subcapsular cataract (ASC) [6,8,9]. ASC, unlike PCO, is a primary cataract that occurs when lens epithelial cells (LECs), in situ, are stimulated to transition into myofibroblasts. These fibroblasts form subcapsular plaques directly beneath the lens capsule. Despite these differences, recent evidence has shown that in both cataract phenotypes the matrix metalloproteinases (MMPs), matrix-degrading enzymes, †Author

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“…Proteolytic cleavage of E-cadherin from the cell surface may account for the soluble form (Matsuura et al, 1992), which has been found in serum (Katayama et al, 1994a;Griffiths et al, 1996) and in urine (Katayama et al, 1994b;Banks et al, 1995) with elevated levels in patients with a variety of cancers. Following the recent finding of elevated serum sE-cadherin concentrations in patients with bladder tumours (Griffiths et al, 1996), we have performed a preliminary cross-sectional study measuring urinary sE-cadherin levels in patients with bladder cancer, non-neoplastic conditions and healthy volunteers and compared these with urinary total protein levels to establish whether such measurements may be of use clinically for diagnostic or monitoring purposes.…”

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confidence: 99%

Urinary concentrations of the soluble adhesion molecule E-cadherin and total protein in patients with bladder cancer

et al. 1999

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Summary Reduced expression of the adhesion molecule E-cadherin has been associated with increased invasiveness and poorer survival in patients with bladder cancer. We have examined soluble E-cadherin (sE-cadherin) and total protein concentrations in urine from patients with bladder cancer (n = 34), non-neoplastic benign urological diseases (n = 14) and healthy controls (n = 21) to determine their diagnostic and prognostic significance. Soluble E-cadherin concentrations of the cancer group were significantly higher (P < 0.001) than those of the controls but the benign group was not significantly different from either the cancer group or the controls. When sE-cadherin concentrations were adjusted for creatinine, similar but more statistically significant results were obtained and the benign group was significantly elevated compared with the controls (P < 0.01). No differences were apparent between the invasive (pT1-4) and non-invasive (pTa) cancers. Urinary total protein concentrations in the cancer group were significantly higher than the controls (P < 0.001) and the benign group (P < 0.05) although no difference was seen between the benign group and patients with non-invasive (pTa) cancer or between the benign group and controls. When expressed as the protein/creatinine index, results were similar but more statistically significant and a significant difference was seen between invasive and non-invasive cancers (P < 0.01). Only the protein/creatinine index correlated significantly with stage of the tumour (P < 0.01). It is concluded that urinary sE-cadherin measurements are of no greater value than urinary total protein.

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Soluble E-cadherin fragments increased in circulation of cancer patients

Cited by 168 publications

References 29 publications

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Nuclear E-cadherin and VHL immunoreactivity are prognostic indicators of clear-cell renal cell carcinoma

Matrix metalloproteinases as mediators of primary and secondary cataracts

Urinary concentrations of the soluble adhesion molecule E-cadherin and total protein in patients with bladder cancer

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