Change of E-Cadherin by Hepatocyte Growth Factor and Effects on the Prognosis of Hypopharyngeal Carcinoma

Kim, Chul‐Ho; Kim, Jang-Hee; Kahng, Hison; Choi, Eun Chang

doi:10.1245/s10434-006-9320-5

Cited by 34 publications

(30 citation statements)

References 23 publications

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“…Particularly, cMET expression was found to be statistically more frequent in The following cut-offs were used: cMET \20 % vs. C20 %, Notch3 \80 % vs. C80 %, pMAPK \40 % vs. C40 % Notch3 has a borderline significance as a predictive biomarker in CUP squamous carcinomas compared to adenocarcinomas and carcinomas. This observation is in line with reports about the emerging role of HGF and its receptor in the pathogenesis of squamous carcinomas [23,24], possibly through down-regulation of E-cadherin and subsequent promotion of epithelial-mesenchymal transition (EMT) phenotype [25,26], as confirmed by our group (cMET down-regulates E-cadherin, unpublished data). Similarly, a link was revealed between squamous histology and Notch3 overexpression, which suggests a common pathogenetic mechanism between cMET and Notch3 in CUP, probably through EMT [27].…”

Section: Discussionsupporting

confidence: 92%

Profiling immunohistochemical expression of NOTCH1–3, JAGGED1, cMET, and phospho-MAPK in 100 carcinomas of unknown primary

Krikelis

Pentheroudakis

Goussia

et al. 2012

Clin Exp Metastasis

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Cancer of unknown primary (CUP) is a heterogeneous entity, managed on the basis of "one size fits all" therapeutic concepts; insights into the molecular biology of CUP are urgently needed. We retrospectively examined the immunohistochemical (IHC) expression of Notch1, 2, 3, Jagged1, cMET, and pMAPK biomolecules in 100 CUP tumors using tissue microarrays, aiming to study their correlation to clinicopathologic characteristics and prognostic utility for patient outcome. Notch3 and pMAPK were most frequently expressed (97 and 91 %, respectively). A linear correlation of Notch3 and cMET expression was found (p = 0.001), while pMAPK emerged as the major adverse prognostic factor (median overall survival OS 9 vs. 17 months, p = 0.016), carrying also a significantly positive predictive value (p = 0.02). Our study indicated a favorable prognostic impact of cMET expression in CUP, both in univariate (median OS 15 vs. 9 months, p = 0.05) and in multivariate analysis (Relative Risk RR for death 0.48, p = 0.025). cMET and Notch3 expression were found to be statistically more frequent in squamous carcinomas (positive in 90 % of cases), associated with a unique metastatic IHC pattern (cMET-high in soft tissue/lymph node metastases, p < 0.001, Notch3-high in visceral, peritoneal/pleural and soft tissue/lymph node metastases, p < 0.001). Our study points to the MAPK and cMET axes as crucial in defining cancer progression and outcome in CUP patients and, if validated, could justify attempts at their therapeutic modulation.

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Section: Discussionsupporting

confidence: 92%

Profiling immunohistochemical expression of NOTCH1–3, JAGGED1, cMET, and phospho-MAPK in 100 carcinomas of unknown primary

Krikelis

Pentheroudakis

Goussia

et al. 2012

Clin Exp Metastasis

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“…(I) HT-29 human colorectal cancer cells were cultured until subconfluency, serum-free fresh medium exchanged and a 12-hour conditioned medium (CM) was prepared and (II) added 50% diluted in fresh medium to primary cultured hepatocytes and stellate cell-derived myofibroblasts obtained from hepatic tissue fragments resected for treatment purposes from patients with hydatid cyst, and approved by our Ethics Committee. Next (III), new conditioned media were obtained from untreated and HT-29-CM-treated hepatocytes and hepatic myofibroblasts and added 50% diluted in fresh medium to HT-29 colon cancer cells may facilitate the mobility of cancer cells required for dissemination, while its overexpression by colon cancer cells at hepatic metastasis sites herein detected, is consistent with previous studies on E-Cadherin regulation in epithelial cancer cells [100,101], and may indicate reactivation of an epithelial cell differentiation program needed for secondary tumor growth. Osteopontin (SPP1) is a hypoxia-regulated extracellular matrix protein that has been proposed as lead marker for tumor progression and metastasis in colon cancer and hepatocellular carcinoma [102,103].…”

Section: Hepatic Microenvironment-dependent Colon Cancersupporting

confidence: 80%

The Liver Prometastatic Reaction of Cancer Patients: Implications for Microenvironment-Dependent Colon Cancer Gene Regulation

Vidal‐Vanaclocha

2011

Cancer Microenvironment

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Colon cancer frequently metastasizes to the liver but the genetic and phenotypic properties of specific cancer cells able to implant and grow in this organ have not yet been established. The contribution of the patient's genetic, physiologic and pathologic backgrounds to the incidence and development of hepatic colon cancer metastases is also presently misunderstood. At a transcriptional level, hepatic metastasis development is in part associated with marked changes in gene expression of colon cancer cells that may originate in the primary tumor. Other changes occur in the liver and are regulated by hepatic cells, which represent the new microenvironment for metastatic colon cancer cells. However, hepatic parenchymal and non-parenchymal cell functions are also affected by both tumor-derived factors and systemic host factors, which suggests that the hepatic metastasis microenvironment is a functional linkage between the hepatic pathophysiology of the colon cancer patient and the biology of its cancer cells. Therefore, together with metastasis-related gene profiles suggesting the existence of liver metastasis potential in primary tumors, new biomarkers of the prometastatic microenvironment supported by the liver reaction to colon cancer factors may be helpful for the individual assessment of hepatic metastasis risk in colon cancer patients. In addition, knowledge on hepatic metastasis gene regulation by the hepatic microenvironment may open multiple opportunities for therapeutic intervention during colon cancer metastasis at both subclinical and advanced stages.

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“…18,21,23,[58][59][60][61][62] In addition, hepatocyte growth factor/scatter factor (HGF/SF) expression has been associated with E-cadherin ectodomain shedding and increased invasiveness of cancer cells. 63 The protease(s) responsible for E-cadherin cleavage in CC-RCC has not been identified. However, it has been shown that VHL regulates the expression of tissue inhibitors of metalloproteinases (TIMPs) and MMP2 and 9, and their deregulation have been shown to promote branching morphogenesis in cells devoid of functional VHL.…”

Section: Discussionmentioning

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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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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Change of E-Cadherin by Hepatocyte Growth Factor and Effects on the Prognosis of Hypopharyngeal Carcinoma

Cited by 34 publications

References 23 publications

Profiling immunohistochemical expression of NOTCH1–3, JAGGED1, cMET, and phospho-MAPK in 100 carcinomas of unknown primary

Profiling immunohistochemical expression of NOTCH1–3, JAGGED1, cMET, and phospho-MAPK in 100 carcinomas of unknown primary

The Liver Prometastatic Reaction of Cancer Patients: Implications for Microenvironment-Dependent Colon Cancer Gene Regulation

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

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