Expression of MUC1 (EMA) and E-cadherin in renal cell carcinoma: a systematic immunohistochemical analysis of 188 cases

Langner, Cord; Ratschek, Manfred; Rehak, Peter; Schips, Luigi; Zigeuner, Richard

doi:10.1038/modpathol.3800032

Cited by 82 publications

(53 citation statements)

References 43 publications

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“…Chromophobe RCC has been reported to express E-cadherin, while papillary RCC has been shown to be a non-expresser of E-cadherin. 32 As expected, chromophobe RCC cells exhibited membranous E-cadherin immunoreactivity, but no nuclear protein was found. Papillary RCC was negative for E-cadherin immunoreactivity (Figure 1c).…”

Section: Nuclear Localization Of E-cadherin Is Associated With Cc-rccmentioning

confidence: 75%

“…Notably, chromophobe RCC is known to express E-cadherin, while papillary RCC has been shown to be a non-expresser of E-cadherin. 32 Nuclear E-cadherin and VHL in CC-RCC ML Gervais et al in the representative Figure 1b (and data not shown) representing a CC-RCC sample from patient no. 9 shown to have F136S substitution mutation in VHL (Table 1).…”

Section: Nuclear Localization Of E-cadherin Is Associated With Cc-rccmentioning

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: Nuclear Localization Of E-cadherin Is Associated With Cc-rccmentioning

confidence: 75%

Section: Nuclear Localization Of E-cadherin Is Associated With Cc-rccmentioning

confidence: 99%

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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“…This observation is consistent with a recent study showing that most papillary RCC, which displayed Ecadherin, were of type 2. 8 These observations suggested that a significant portion of RCC display a dual differentiation, which may or may not be appreciated at light microscopic level. The explanation for dual differentiation within a single tumor is not clear.…”

Section: Discussionmentioning

confidence: 99%

“…Some histochemical stains and immunohistochemical markers are shown to be helpful in the differential diagnosis of these tumors. Hale's colloidal iron stain can support the diagnosis for chromophobe RCC, 1,2 and immune markers such as vimentin, 3,4 CD10, 5 parvalbumin, 6,7 E-cadherin, 8 or RCC marker 5,9 have been used to aid in the diagnosis and classification of renal neoplasms. These special studies are, however, quite limited.…”

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confidence: 99%

Kidney-specific cadherin, a specific marker for the distal portion of the nephron and related renal neoplasms

et al. 2005

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Renal cell neoplasms are presumably derived from different cell types of the nephron. Clear cell and papillary renal cell carcinoma (RCC) are thought to be of proximal tubular origin, whereas oncocytoma and chromophobe RCC are derived from intercalated cells of distal nephron. A few molecules, such as RCC marker and CD10, have been shown to be markers for clear cell RCC and papillary RCC. Such markers are not yet available for renal tumors presumably of the distal nephron. The expression of kidney-specific (Ksp) cadherin, a recently cloned gene thought to be transcribed exclusively in the kidney, was studied in normal human kidney, as well as in 105 primary renal neoplasms, including 42 clear cell RCC, 30 papillary RCC, 13 chromophobe RCC, and 20 oncocytomas. The expression patterns were compared with those of RCC marker. The Ksp-cadherin expression was noted preferentially in distal convoluted tubules with a basolateral membrane stain in normal kidney. All 13 chromophobe RCC and 19 of 20 oncocytomas showed diffuse and strong immunoreactivity for Ksp-cadherin, while only 14% clear cell RCC and 13% papillary RCC showed focal positivity. The RCC marker expression was detected in 85%, 98%, 15% and 0% of clear cell RCC, papillary RCC, chromophobe RCC, and oncocytoma, respectively. A few clear cell RCC and papillary RCC showed dual expression of both RCC marker and Kspcadherin, which appear to have distinct histologic features. These results demonstrated high sensitivity and specificity of Ksp-cadherin for distal convoluted tubules, which can be used as adjunct for diagnosis of chromophobe RCC. Modern Pathology (2005) 18, 933-940.

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“…Linker sequences carrying a 5V NotI restriction site and coding for either (G 4 S) 4 or (G 4 S) 2 C(G 4 S) 2 were introduced in front of the VH domain of a scFv, cloned in pCANTAB 5E, by consecutive insertional mutagenesis using the QuickChange mutagenesis kit (Stratagene, La Jolla, CA); the resulting clones were named LscFv. Final di-scFv-C constructs were assembled by ligation of the NotI insert of the LscFv clones into the unique NotI restriction site present at the 3V end of the corresponding scFv cloned in pCANTAB 5E or pCANTAB 5E-Cys.…”

Section: Pretargeted Radioimmunotherapy Developmentmentioning

confidence: 99%

Enhancement of the Therapeutic Index: From Nonmyeloablative and Myeloablative toward Pretargeted Radioimmunotherapy for Metastatic Prostate Cancer

DeNardo

Richman

Albrecht

et al. 2005

Clinical Cancer Research

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Purpose: New strategies that target selected molecular characteristics and result in an effective therapeutic index are needed for metastatic, hormone-refractory prostate cancer. Experimental Design: A series of preclinical and clinical studies were designed to increase the therapeutic index of targeted radiation therapy for prostate cancer. 111In/ 90 Y-monoclonal antibody (mAb), m170, which targets aberrant sugars on abnormal MUC1, was evaluated in androgenindependent prostate cancer patients to determine the maximum tolerated dose and efficacy of nonmyeloablative radioimmunotherapy and myeloablative combined modality radioimmunotherapy with paclitaxel. To enhance the tumor to liver therapeutic index, a cathepsin degradable mAb linkage ( Y-peptide-m170) was used in the myeloablative combined modality radioimmunotherapy protocol. For tumor to marrow therapeutic index improvement in future studies, anti-MUC1scFvs modules were developed for pretargeted radioimmunotherapy. Anti-MUC1and anti-DOTA scFvs were conjugated to polyethylene glycol scaffolds tested on DU145 prostate cancer cells and prostate tissue arrays, along with mAbs against MUC1epitopes. Results: The nonmyeloablative maximum tolerated dose of 90 Y-m170 was 0.74 GBq/m 2 for patients with not more than 10% axial skeleton involvement. Metastatic prostate cancer was targeted in all 17 patients; mean radiation dose was 10.5 Gy/GBq and pain response occurred in 7 of 13 patients reporting pain. Myeloablative combined modality radioimmunotherapy with 0.4 GBq/m 2 of 90 Y-peptide-m170 and paclitaxel showed therapeutic effects in 4 of 6 patients and 30% less radiation to the liver per unit of activity. Neutropenia was dose limiting without marrow support and patient eligibility was a major limitation to dose escalation. Hypoglycosylated MUC1 epitopes were shown to be abundant in prostate cancer and to increase with disease grade. Anti-MUC1 scFvs binding to prostate cancer tissue and live cells were developed into di-scFv binding modules. Conclusions: The therapeutic index enhancement for prostate radioimmunotherapy was achieved in clinical studies by the addition of cathepsin cleavable linkers to 90 Y-conjugated mAbs and the use of paclitaxel. However, the need for marrow support in myeloablative combined modality radioimmunotherapy restricted eligible patients.Therefore, modular pretargeted radioimmunotherapy, aiming at improving the tumor to marrow therapeutic index, is being developed.Although localized prostate cancer is curable, metastatic hormone-independent prostate cancer is usually fatal. Better understanding of this disease has yielded information useful in designing new therapeutic strategies (1, 2). Studies of epithelial cancer biology have provided insights into the relationship of abnormal glycoproteins and prostate cancer grade of relevance for tumor targeting (3 -7).Cancer-related aberrations in MUC1 epithelial mucin present unique epitopes that can provide targets for site-specific therapy for many epithelial cancers. Normal MUC1 is api...

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Expression of MUC1 (EMA) and E-cadherin in renal cell carcinoma: a systematic immunohistochemical analysis of 188 cases

Cited by 82 publications

References 43 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

Kidney-specific cadherin, a specific marker for the distal portion of the nephron and related renal neoplasms

Enhancement of the Therapeutic Index: From Nonmyeloablative and Myeloablative toward Pretargeted Radioimmunotherapy for Metastatic Prostate Cancer

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