E-cadherin and N-cadherin Immunohistochemical Expression in Proliferating Urothelial Lesions: Potential Novel Cancer Predictive EMT Profiles

Shash, Lobna S; Ibrahim, Riham; Elgohary, Shimaa Abdelraouf

doi:10.1097/pai.0000000000000940

Cited by 10 publications

(9 citation statements)

References 51 publications

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“…The current studies have found that EMT is the 'first step' in tumor metastasis, and tumor cells can acquire higher invasion ability and metastasis ability after EMT occurs. Loss or downregulation of E-cadherin expression is considered to be a key important step in the process of tumorigenesis and development as well as EMT (Shash et al 2021). In addition, one of the EMT mechanisms is the conversion between cadherins, and the main conversion process is manifested as the conversion of E-cadherin into N-cadherin (Kaszak et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Rhaponticin suppresses the hypoxia-induced factor-1 alpha-mediated aggressive phenotype of tongue squamous cell carcinoma

Wan

Shao

et al. 2023

Mol. Cell. Toxicol.

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Background Emerging evidence suggests that rhaponticin, a stilbene monomeric compound isolated from North China rhubarb, has been shown to exhibit significant biological activity against tumors. However, the anticancer effects and mechanisms of rhaponticin in tongue squamous cell carcinoma (TSCC) remain elusive. Objective We investigated the changes of migration and invasion abilities and EMT progression of TSCC cells treated with different concentrations of rhaponticin under hypoxia, as well as the possible mechanisms, in order to initially explore the effects of rhaponticin on the biological characteristics of TSCC cells under hypoxia. Results The number of cell migration and invasion was prominently increased, E-cadherin protein was down-regulated, and N-cadherin and HIF-1α protein expression was elevated under hypoxia. Rhaponticin intervention strikingly prevented the increased abilities of migration and invasion and EMT of TSCC cells under hypoxia. This was followed by further validation finding that rhaponticin indeed leads to reduced HIF-1α post-transcriptional activity. Mechanistically, rhaponticin may bind to aryl-hydrocarbon nuclear translocator (ARNT) domain of HIF-1α. Conclusions Rhaponticin repressed the invasion and migration abilities and EMT process of TSCC cells under a hypoxic environment in vitro by targeted suppression of HIF-1α.

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Section: Discussionmentioning

confidence: 99%

Rhaponticin suppresses the hypoxia-induced factor-1 alpha-mediated aggressive phenotype of tongue squamous cell carcinoma

Wan

Shao

et al. 2023

Mol. Cell. Toxicol.

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“…Recent studies have found that the loss of E-cadherin expression in some tumors is often accompanied by the up-regulation of N-cadherin expression ( 32 , 33 ), which is also known as “the cadherin switch” ( 33 , 34 ). N-cadherin molecule, also known as neural cadherin, has a molecular weight of 140KD and is mainly expressed in mesenchymal cells, endothelial cells, muscle cells, and hematopoietic stem cells ( 11 ).…”

Section: Discussionmentioning

confidence: 99%

“…These studies suggest that N-cadherin can not only directly induce cell migration but also promote the survival of tumor cells and facilitate tumor cell invasion. In addition, studies have also shown that N-cadherin-mediated adhesion between tumor cells and mesenchymal cells plays an important role in the process of tumor dissemination and metastasis ( 34 ). For example, in the invasive growth of melanoma ( 39 ), N-cadherin mediates the interaction between tumor cells and other cells in the dermis.…”

Section: Discussionmentioning

confidence: 99%

[18F]AlF-NOTA-ADH-1: A new PET molecular radiotracer for imaging of N-cadherin-positive tumors

et al. 2023

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BackgroundThe cell adhesion molecule (CAM) N-cadherin has become an important target for tumor therapy. The N-cadherin antagonist, ADH-1, exerts significant antitumor activity against N-cadherin-expressing cancers.MethodsIn this study, [18F]AlF-NOTA-ADH-1 was radiosynthesized. An in vitro cell binding test was performed, and the biodistribution and micro-PET imaging of the probe targeting N-cadherin were also studied in vivo.ResultsRadiolabeling of ADH-1 with [18F]AlF achieved a yield of up to 30% (not decay-corrected) with a radiochemical purity of >97%. The cell uptake study showed that Cy3-ADH-1 binds to SW480 cells but weakly binds to BXPC3 cells in the same concentration range. The biodistribution results demonstrated that [18F]AlF-NOTA-ADH-1 had a good tumor/muscle ratio (8.70±2.68) in patient-derived xenograft (PDX) tumor xenografts but a lower tumor/muscle ratio (1.91±0.69) in SW480 tumor xenografts and lowest tumor/muscle ratio (0.96±0.32) in BXPC3 tumor xenografts at 1 h post-injection (p.i.) These findings were in accordance with the immunohistochemistry results. The micro PET imaging results revealed good [18F]AlF-NOTA-ADH-1 tumor uptake in pancreatic cancer PDX xenografts with strong positive N-calcium expression, while lower tumor uptake in SW480 xenografts with positive expression of N-cadherin, and significantly lower tumor uptake in BXPC3 xenografts with low expression of N-cadherin, which was consistent with the biodistribution and immunohistochemistry results. The N-cadherin-specific binding of [18F]AlF-NOTA-ADH-1 was further verified by a blocking experiment involving coinjection of a non radiolabeled ADH-1 peptide, resulting in a significant reduction in tumor uptake in PDX xenografts and SW480 tumor.Conclusion[18F]AlF-NOTA-ADH-1 was successfully radiosynthesized, and Cy3-ADH-1 showed favorable N-cadherin-specific targeting ability by in vitro data. The biodistribution and microPET imaging of the probe further showed that [18F]AlF-NOTA-ADH-1 could discern different expressions of N-cadherin in tumors. Collectively, the findings demonstrated the potential of [18F]AlF-NOTA-ADH-1 as a PET imaging probe for non-invasive evaluation of the N-cadherin expression in tumors.

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“…Using their cutoff of 50% or more abnormal cells, 25% of grade I, 46% of grade II, and 86% of grade III specimens showed decreased staining for E-cadherin. However, a more recent study found that in muscle-invasive bladder cancer (MIBC), abnormal cadherin patterns (decreased E-cadherin and increased N-cadherin) were highest (70.3% of cases) and associated with adverse prognostic indicators ( Shash et al, 2021 ). More interestingly, 35% of the samples in this study showed a hybrid pattern of cadherin expression (both E- and N-cadherin positive) ( Shash et al, 2021 ), suggesting the possibility of the E-M cooperation we hypothesize.…”

Section: Cell-cell (E-cadherin Cdh1) and Cell-ecm (α6 Integrin Cd49f)...mentioning

confidence: 99%

Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers

Harryman

Marr

Nagle

et al. 2022

Front. Cell Dev. Biol.

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Muscle-invasive lethal carcinomas traverse into and through this specialized biophysical and growth factor enriched microenvironment. We will highlight cancers that originate in organs surrounded by smooth muscle, which presents a barrier to dissemination, including prostate, bladder, esophageal, gastric, and colorectal cancers. We propose that the heterogeneity of cell-cell and cell-ECM adhesion receptors is an important driver of aggressive tumor networks with functional consequences for progression. Phenotype heterogeneity of the tumor provides a biophysical advantage for tumor network invasion through the tensile muscle and survival of the tumor network. We hypothesize that a functional epithelial-mesenchymal cooperation (EMC)exists within the tumor invasive network to facilitate tumor escape from the primary organ, invasion and traversing of muscle, and navigation to metastatic sites. Cooperation between specific epithelial cells within the tumor and stromal (mesenchymal) cells interacting with the tumor is illustrated using the examples of laminin-binding adhesion molecules—especially integrins—and their response to growth and inflammatory factors in the tumor microenvironment. The cooperation between cell-cell (E-cadherin, CDH1) and cell-ECM (α6 integrin, CD49f) expression and growth factor receptors is highlighted within poorly differentiated human tumors associated with aggressive disease. Cancer-associated fibroblasts are examined for their role in the tumor microenvironment in generating and organizing various growth factors. Cellular structural proteins are potential utility markers for future spatial profiling studies. We also examine the special characteristics of the smooth muscle microenvironment and how invasion by a primary tumor can alter this environment and contribute to tumor escape via cooperation between epithelial and stromal cells. This cooperative state allows the heterogenous tumor clusters to be shaped by various growth factors, co-opt or evade immune system response, adapt from hypoxic to normoxic conditions, adjust to varying energy sources, and survive radiation and chemotherapeutic interventions. Understanding the epithelial-mesenchymal cooperation in early tumor invasive networks holds potential for both identifying early biomarkers of the aggressive transition and identification of novel agents to prevent the epithelial-mesenchymal cooperation phenotype. Epithelial-mesenchymal cooperation is likely to unveil new tumor subtypes to aid in selection of appropriate therapeutic strategies.

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E-cadherin and N-cadherin Immunohistochemical Expression in Proliferating Urothelial Lesions: Potential Novel Cancer Predictive EMT Profiles

Cited by 10 publications

References 51 publications

Rhaponticin suppresses the hypoxia-induced factor-1 alpha-mediated aggressive phenotype of tongue squamous cell carcinoma

Rhaponticin suppresses the hypoxia-induced factor-1 alpha-mediated aggressive phenotype of tongue squamous cell carcinoma

[18F]AlF-NOTA-ADH-1: A new PET molecular radiotracer for imaging of N-cadherin-positive tumors

Integrins and Epithelial-Mesenchymal Cooperation in the Tumor Microenvironment of Muscle-Invasive Lethal Cancers

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