Increased expression of integrin β‐4 in papillary thyroid carcinoma with gross lymph node metastasis

Hosaka, Naoki; Hiraumi, Harukazu; Hirose, Tomoko; Ikehara, Susumu

doi:10.1046/j.1440-1827.2002.01379.x

Cited by 28 publications

(22 citation statements)

References 14 publications

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“…12 Furthermore, the potential role of the a6b4 integrin in metastasis is supported by studies in papillary thyroid carcinoma which suggested that the increased expression of the integrin b4 subunit in cancer lesions could play a role in the development of lymph node metastasis. 27 Certainly, the in vivo data coupled with extensive in vitro data suggest that the a6b4 is associated with the invasiveness and metastatic potential of late stage cancers. 16,[24][25][26][27] In our study, the six pancreatic adenocarcinoma cases that were associated with lymph node metastasis displayed overexpression of the integrin b4 subunit in cancer cells (Figure 1i-j).…”

Section: Discussionmentioning

confidence: 99%

“…27 Certainly, the in vivo data coupled with extensive in vitro data suggest that the a6b4 is associated with the invasiveness and metastatic potential of late stage cancers. 16,[24][25][26][27] In our study, the six pancreatic adenocarcinoma cases that were associated with lymph node metastasis displayed overexpression of the integrin b4 subunit in cancer cells (Figure 1i-j). When pancreatic cells were found invading the peripheral nerves, the invading cancer cells also overexpressed integrin a6b4.…”

Section: Discussionmentioning

confidence: 99%

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Upregulation and redistribution of integrin α6β4 expression occurs at an early stage in pancreatic adenocarcinoma progression

et al. 2007

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Pancreatic adenocarcinomas are highly invasive cancers for reasons that are currently unclear. Here we sought to determine if the proinvasive integrin a6b4 may be related to pancreatic adenocarcinoma tumor progression. Expression of integrin a6b4 was analyzed via immunohistochemistry for the b4 subunit in normal pancreas, pancreatic intraepithelial neoplasia (PanIN) lesions, pancreatic adenocarcinomas and chronic pancreatitis. In normal pancreatic ducts, integrin a6b4 was noted only at the cell's basal interface with the basement membrane. In pancreatic adenocarcinomas, 92% (104/113) demonstrated overexpression of integrin a6b4 and altered localization to the cytoplasm and membranous regions. This pattern of expression was observed in all PanIN lesions as early as PanIN-1A, and was evident in lesions that were juxtapositioned to normal epithelium. In contrast, 93% (13/14) of chronic pancreatitis samples resembled the staining pattern of normal pancreas. When cancer was present in areas of chronic pancreatitis, this altered expression of a6b4 integrin identified the cancer. We conclude that integrin a6b4 is expressed only on the basal surface of ductal cells in normal pancreas and chronic pancreatitis. During pancreatic adenocarcinoma progression, the a6b4 integrin is dramatically overexpressed and displays altered localization at the earliest stages of PanIN, thus representing an early event in pancreatic adenocarcinoma progression. Keywords: pancreatic intraepithelial neoplasia (PanINs); immunohistochemistry; precursor lesion; integrins; pancreatic cancer; chronic pancreatitis Pancreatic carcinoma is the fourth leading cause of cancer death in the US and has the highest death to incidence ratio of all cancers. 1 Poor prognosis of pancreatic cancer patients relates to a high incidence of tumor cell invasion and metastasis. Treatment options are limited and patients succumb to the disease shortly after diagnosis unless eligible for tumor resection. 2 Of those patients that undergo resection, only 15-20% will survive to 5 years. 1 Over 90% of pancreatic cancers are adenocarcinomas that are thought to arise from proliferative premalignant pancreatic intraepithelial neoplasia (PanIN) of the ductal epithelium. PanIN lesions start as low cuboidal epithelial cells that become columnar due to increased mucin production. Cells then present with nuclear atypia and enhanced proliferation, which lead to luminal shedding and/ or invasion into the stroma. 3 These morphological alterations correlate with increased genetic abnormalities such as the activation of K-ras, loss of tumor suppressors (eg p16, p53 and DPC4) and upregulation of telomerases. 4 Although PanIN-1A and PanIN-1B are considered early cancer precursor lesions, molecular studies have shown that PanIN-2 and PanIN-3 lesions represent a distinct step toward invasive carcinoma. 5 Moreover, PanIN lesions can be found in patients with chronic pancreatitis 6 and these patients have an increased risk of developing pancreatic cancer. 7,8 Infiltrating duct-like and tubul...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Upregulation and redistribution of integrin α6β4 expression occurs at an early stage in pancreatic adenocarcinoma progression

et al. 2007

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“…[9][10][11] Prior reports indicate that ITGB4 is upregulated in multiple tumor types, including pancreatic cancer. 8 In several cancers, high levels of ITGB4 expression have been linked to poor prognosis or aggressive behavior, [12][13][14][15][16] but the clinicopathological significance of ITGB4 overexpression in PDA remains unclear. The aim of the current study was to clarify the clinicopathological significance of ITGB4 overexpression in PDA and to suggest the potential function of ITGB4 in cancer EMT.…”

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confidence: 99%

Upregulation of integrin β4 promotes epithelial–mesenchymal transition and is a novel prognostic marker in pancreatic ductal adenocarcinoma

Masugi

Yamazaki

Emoto

et al. 2015

Laboratory Investigation

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Pancreatic ductal adenocarcinoma (PDA) is a highly aggressive and often lethal malignant tumor. Several studies have shown that epithelial-mesenchymal transition (EMT) is frequently observed in clinical samples of PDA and is related to high metastatic rates and poor outcomes. To identify candidate molecules regulating EMT in PDA, we previously used cDNA microarray analysis and identified integrin b4 (ITGB4) as one of the genes upregulated in high-EMT xenografts derived from PDA patients. The aim of the current study was to clarify the clinicopathological and functional significance of ITGB4 overexpression in PDA. ITGB4 upregulation in high-EMT xenografts was confirmed by immunohistochemistry. Immunohistochemical analyses of 134 surgically resected PDA cases revealed intratumoral heterogeneity with respect to ITGB4 expression and showed that cancer cells undergoing EMT often display strong diffuse ITGB4 expression. High levels of ITGB4 expression were significantly correlated with the hallmarks of EMT (solitary cell infiltration, reduced E-cadherin expression, and increased vimentin expression), with high tumor grade, and with the presence of lymph node metastasis, and showed an independent prognostic effect. Immunocytochemical analyses of PDA cell lines revealed that localization of ITGB4 changed from regions of cell-cell contact to diffuse cytoplasm and cell edges with occasional localization in filopodia during EMT. Knockdown of ITGB4 reduced the migratory and invasive ability of PDA cells. Overexpression of ITGB4 promoted cell scattering and cell motility in combination with downregulation of E-cadherin and upregulation of vimentin expression. In conclusion, we elucidated the prognostic and clinicopathological significance of ITGB4 overexpression in PDA and also the potential role for ITGB4 in the regulation of cancer invasion and EMT. Pancreatic cancer is the fourth most common cause of cancer death in men and women in the United States. 1 Despite medical improvements, pancreatic cancer remains one of the most lethal malignancies: the 5-year survival rate for patients with pancreatic cancer is only about 6%. 1 Pancreatic ductal adenocarcinoma (PDA), characterized by the formation of ducts resembling pancreatic ducts, is the most common histologic type of pancreatic cancer. Resectability is considered to be the most significant prognostic factor; however, at the time of diagnosis, only about 20% of patients with PDA are surgically resectable because of distant metastases or major vessel involvement. 2 Even after curative surgery, the 5-year survival rate is 10%-25%, mainly due to the highly aggressive biological behavior of this tumor, such as the high rate of local recurrence, peritoneal dissemination, liver metastases, and lymph node recurrence. 3 The epithelial-mesenchymal transition (EMT) is a series of cellular and molecular processes during which polarized epithelial cells lose cell-cell and cell-basement membrane interactions at the same time as acquiring mesenchymal and migratory properties. EMT is no...

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“…Integrin-␤4 complexes only with integrin-␣6 and is recognized as important for the formation of epithelial hemidesmosomes and is relevant to cancer biology. Increased integrin-␤4 expression is linked to increased tumor invasiveness in squamous cell carcinomas (26) and papillary carcinomas of the thyroid (14) and portends a poor prognosis in both breast (24) and bladder cancer (10). Until recently, however, little was known about the role of integrin-␤4 in normal EC physiology.…”

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confidence: 99%

Critical role for integrin-β4 in the attenuation of murine acute lung injury by simvastatin

Chen

Sammani

Mitra

et al. 2012

American Journal of Physiology-Lung Cellular and Molecular Phys

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The statins are a class of 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors that are recognized to have pleiotropic properties. We previously reported the attenuation of LPS-induced murine acute lung injury (ALI) by simvastatin in vivo and identified relevant effects of simvastatin on endothelial cell (EC) signaling, activation, and barrier function in vitro. In particular, simvastatin induces the upregulation of integrin-␤4, which in turn inhibits EC inflammatory responses via attenuation of MAPK signaling. The role of integrin-␤4 in murine ALI protection by simvastatin, however, is unknown. We initially confirmed a time-and dose-dependent effect of simvastatin on increased integrin-␤4 mRNA expression in human lung EC with peak protein expression evident at 16 h. Subsequently, reciprocal immunoprecipitation demonstrated an attenuation of LPS-induced integrin-␤4 tyrosine phosphorylation by simvastatin (5 M, 16 h). Increased expression of EC inflammatory cytokines [IL-6, IL-8, monocyte chemoattractant protein (MCP)-1, regulated on activation normal T cell expressed and secreted (RANTES)] by LPS (500 ng/ml, 4 h) was also significantly attenuated by simvastatin pretreatment (5 M, 16 h), but this effect was reversed by cotreatment with an integrin-␤4-blocking antibody. Finally, although simvastatin (20 mg/kg) conferred significant protection in murine ALI as evidenced by decreased bronchoalveolar lavage fluid cell counts, protein, inflammatory cytokines (IL-6, IL-1␤, MCP-1, RANTES), decreased Evans blue dye albumin extravasation in lung tissue, and changes on lung histology, these effects were reversed by the integrin-␤4-blocking antibody (IV, 1 mg/kg, 2 h before LPS). These findings support integrin-␤4 as an important mediator of ALI protection by simvastatin and implicate signaling by integrin-␤4 as a novel therapeutic target in patients with ALI.statins; integrins; endothelial cells THE STATINS ARE A CLASS OF 3-hydroxy-3-methylglutaryl-coenzyme A-reductase inhibitors recognized to have potent antiinflammatory and vascular-protective properties independent of their ability to lower serum cholesterol levels. In this regard, we previously reported the attenuation of murine acute lung injury (ALI) by pretreatment with simvastatin (12). The mechanisms underlying these effects, however, are complex and not fully characterized. For example, we have identified several distinct effects of statins on endothelial cell (EC) signaling and activation that are relevant to the pathophysiology of ALI including actin cytoskeletal rearrangement and EC barrier protection via differential effects on small GTPases RhoA and Rac1 (13) and inhibition of superoxide generation via NADPH oxidase inhibition (4). We have also reported the marked upregulation of integrin-␤4 (13), a molecule that attenuates EC inflammatory responses via effects on MAPK signaling (3). This dramatic upregulation of EC integrin-␤4 by statins has subsequently been corroborated (16); however, the role of integrin-␤4 in murine ALI protection by simvastatin ...

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Increased expression of integrin β‐4 in papillary thyroid carcinoma with gross lymph node metastasis

Cited by 28 publications

References 14 publications

Upregulation and redistribution of integrin α6β4 expression occurs at an early stage in pancreatic adenocarcinoma progression

Upregulation and redistribution of integrin α6β4 expression occurs at an early stage in pancreatic adenocarcinoma progression

Upregulation of integrin β4 promotes epithelial–mesenchymal transition and is a novel prognostic marker in pancreatic ductal adenocarcinoma

Critical role for integrin-β4 in the attenuation of murine acute lung injury by simvastatin

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