Collagen Type I Induces Disruption of E-Cadherin–Mediated Cell-Cell Contacts and Promotes Proliferation of Pancreatic Carcinoma Cells

Köenig, Alexander; Mueller, Claudia; Hasel, Cornelia; Adler, Guido; Menke, André

doi:10.1158/0008-5472.can-05-2804

Cited by 237 publications

(204 citation statements)

References 51 publications

(57 reference statements)

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“…20,[44][45][46] In addition, the detection of aligned collagen signatures in routine histopathology slides can predict disease 16 In pancreatic ductal adenocarcinoma, cancer cells in contact with collagen type I show enhanced migratory capabilities through upregulation of Snail, a regulator of epithelial-to-mesenchymal transition. [47][48][49][50][51] Epithelial-to-mesenchymal transition is a process that dissemination-competent cells undergo. It has been shown to be prevalent in pancreatic ductal adenocarcinoma tissue and to negatively impact patient prognosis.…”

Section: Discussionmentioning

confidence: 99%

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

et al. 2015

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Pancreatic ductal adenocarcinoma continues to be one of the most difficult diseases to manage with one of the highest cancer mortality rates. This is due to several factors including nonspecific symptomatology and subsequent diagnosis at an advanced stage, aggressive metastatic behavior that is incompletely understood, and limited response to current therapeutic regimens. As in other cancers, there is great interest in studying the role of the tumor microenvironment in pancreatic ductal adenocarcinoma and whether components of this environment could serve as research and therapeutic targets. In particular, attention has turned toward the desmoplastic collagen-rich pancreatic ductal adenocarcinoma stroma for both biological and clinical insight. In this study, we used quantitative second harmonic generation microscopy to investigate stromal collagen organization and structure in human pancreatic ductal adenocarcinoma pathology tissues compared with non-neoplastic tissues. Collagen topology was characterized in whole-tissue microarray cores and at specific pathology-annotated epithelial-stroma interfaces representing 241 and 117 patients, respectively. We quantitatively demonstrate that a unique collagen topology exists in the periductal pancreatic ductal adenocarcinoma stroma. Specifically, collagen around malignant ducts shows increased alignment, length, and width compared with normal ducts and benign ducts in a chronic pancreatitis background. These findings indicate that second harmonic generation imaging can provide quantitative information about fibrosis that complements traditional histopathologic insights and can serve as a rich field for investigation into pathogenic and clinical implications of reorganized collagen as a pancreatic ductal adenocarcinoma disease marker. Pancreatic ductal adenocarcinoma is one of the most devastating human malignancies. It is currently the fourth leading cause of cancer death and projects to become the second leading cause by 2030. 1 The 5-year relative survival rate has remained in the single digits for decades. Pancreatic ductal adenocarcinoma is notoriously difficult to detect before an advanced, inoperable stage is reached due to nonspecific symptomatology and the retroperitoneal location of the pancreas, which makes palpation or routine biopsy of suspicious masses difficult. Recent advances in the sensitivity and specificity of preoperative imaging modalities such as computer tomography, magnetic resonance imaging, positron emission tomography, endoscopic ultrasonography, and endoscopic retrograde cholangiopancreatography have played an important role in enhancing pancreatic ductal adenocarcinoma diagnosis, detailing the relationship of lesions to nearby anatomical structures, and determining the course of management. 2 Despite these advances, only 10-15% of patients are diagnosed at a localized disease stage when surgical resection is possible as a potential curative therapy. However, postsurgical recurrence rates are high with 5-year survival rate of

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Section: Discussionmentioning

confidence: 99%

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

et al. 2015

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“…2 b). Moreover, integrinactivated focal adhesion kinase (FAK) can phosphorylate β-catenin and thus induce its ubiquitylation and degradation and the disassembly of the E-cadherin cell adhesion complex [59]. Endocytosis of E-cadherin can occur via clathrin or caveolin-dependent mechanisms [60][61][62].…”

Section: Transcriptional Control Of E-cadherinmentioning

confidence: 99%

EMT, the cytoskeleton, and cancer cell invasion

Yilmaz

Christofori

2009

Cancer Metastasis Rev

1,533

1,314

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The metastatic process, i.e. the dissemination of cancer cells throughout the body to seed secondary tumors at distant sites, requires cancer cells to leave the primary tumor and to acquire migratory and invasive capabilities. In a process of epithelial-mesenchymal transition (EMT), besides changing their adhesive repertoire, cancer cells employ developmental processes to gain migratory and invasive properties that involve a dramatic reorganization of the actin cytoskeleton and the concomitant formation of membrane protrusions required for invasive growth. The molecular processes underlying such cellular changes are still only poorly understood, and the various migratory organelles, including lamellipodia, filopodia, invadopodia and podosomes, still require a better functional and molecular characterization. Notably, direct experimental evidence linking the formation of migratory membrane protrusions and the process of EMT and tumor metastasis is still lacking. In this review, we have summarized recent novel insights into the molecular processes and players underlying EMT on one side and the formation of invasive membrane protrusions on the other side.

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“…Nevertheless, emerging data implicate dysregulated Wnt signaling in EOC progression in the absence of activating mutations in either adenomatous poliosis coli, Axin, or ␤-catenin (23-26). Furthermore, both E-cadherin ectodomain shedding (27) and decreased net E-cadherin expression (28) can promote ␤-catenin-mediated transcription, suggesting that ␤-catenin is released from E-cadherin following disruption of the junctional complex. This study demonstrates that multivalent integrin engagement results in adherens junction disruption, internalization of E-cadherin, inhibition of GSK-3␤, and increased levels of active ␤-catenin.…”

mentioning

confidence: 99%

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Burkhalter

Symowicz

Hudson

et al. 2011

Journal of Biological Chemistry

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Reversible modulation of integrin-regulated cell-matrix adhesion and epithelial (E)-cadherin-mediated cell-cell adhesion plays a critical role in the establishment of ovarian cancer metastases. In contrast to most epithelial cell-derived tumors that down-regulate E-cadherin expression during progression, acquisition of E-cadherin expression accompanies malignant transformation of the ovarian surface epithelium and is maintained in peritoneal metastases. Metastatic epithelial ovarian cancer cells are disseminated intraperitoneally and preferentially adhere via integrins to interstitial collagens in the peritoneal cavity. This study was undertaken to determine whether integrin engagement influences E-cadherin and ␤-catenin localization and function. The data demonstrate that multivalent integrin engagement results in increased internalization of E-cadherin, inhibition of GSK-3␤, elevated levels of nuclear ␤-catenin, increased ␤-catenin-regulated promoter activation, and transcriptional activation of Wnt/␤-catenin target genes. Blocking ␤-catenin transcriptional control with inhibitor of ␤-catenin and Tcf-4 reduces cellular invasion, suggesting a key role for ␤-catenin nuclear signaling in EOC invasion and metastasis. These studies support a model wherein cell-matrix engagement regulates the functional integrity of cell-cell contacts, leading to increased ␤-catenin nuclear signaling and enhanced cellular invasive activity. Furthermore, these results provide a mechanism for activation of Wnt/␤-catenin signaling in the absence of activating mutations in this pathway.Epithelial (E) 3 -cadherin is a single-span transmembrane glycoprotein that mediates calcium-dependent cell-cell adhesion via interaction with the extracellular domains of cadherins on the surface of neighboring cells (1, 2). Key functions of E-cadherin include the regulation of cell polarity and the maintenance of epithelial organization (3). Although most normal epithelia express high levels of E-cadherin, this cadherin is absent in the mesenchymally derived normal ovarian surface epithelium, which expresses neural (N)-cadherin. In most carcinomas, E-cadherin expression is down-regulated or lost, facilitating cellular dispersal, invasion, and metastasis (4). However, a unique feature of EOC is that E-cadherin becomes more abundant in primary differentiated carcinomas, with all histotypes displaying strong immunoreactivity (reviewed in Refs. 5, 6). There is less clarity regarding relative E-cadherin levels during ovarian tumor progression and metastasis. Although complete loss of E-cadherin is uncommon, reduced staining is often detected in late stage tumors and in ascites-derived tumor cells (7-9), and negative E-cadherin is predictive of poor overall survival (10, 11).␤-Catenin is found predominantly in association with the E-cadherin cytoplasmic domain at cell-cell junctions (12). In the absence of cell-cell contact and Wnt signaling, cytosolic ␤-catenin forms a complex with adenomatous poliosis coli, Axin/conductin, casein kinases 1␣ and 1⑀, and glyc...

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Collagen Type I Induces Disruption of E-Cadherin–Mediated Cell-Cell Contacts and Promotes Proliferation of Pancreatic Carcinoma Cells

Cited by 237 publications

References 51 publications

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

EMT, the cytoskeleton, and cancer cell invasion

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

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