Pancreatic Cancer Cells Enhance the Ability of Collagen Internalization during Epithelial–Mesenchymal Transition

Ikenaga, Naoki; Ohuchida, Kenoki; Mizumoto, Kazuhiro; Akagawa, Shinobu; Fujiwara, Kenji; Eguchi, Daiki; Kozono, Shingo; Ohtsuka, Takao; Takahata, Shunichi; Tanaka, Masao

doi:10.1371/journal.pone.0040434

Cited by 40 publications

(30 citation statements)

References 37 publications

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“…Indeed, CRK phosphorylation was increased in YSF MEF, indicating that lack of Src may lead to a compensatory upregulation of c-abl with ensuing increase in matrix macropinocytosis in these cells. Although most of our studies were performed in the absence of TGF-␤1 stimulation, the signaling networks we studied are classically downstream from TGF-␤1 stimulation, and this growth factor did stimulate collagen internalization in our studies and in prior studies (18).…”

Section: C628mentioning

confidence: 49%

Endocytosis of collagen by hepatic stellate cells regulates extracellular matrix dynamics

Bi¹,

Mukhopadhyay²,

Drinane³

et al. 2014

American Journal of Physiology-Cell Physiology

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Hepatic stellate cells (HSCs) generate matrix, which in turn may also regulate HSCs function during liver fibrosis. We hypothesized that HSCs may endocytose matrix proteins to sense and respond to changes in microenvironment. Primary human HSCs, LX2, or mouse embryonic fibroblasts (MEFs) [wild-type; c-abl−/−; or Yes, Src, and Fyn knockout mice (YSF−/−)] were incubated with fluorescent-labeled collagen or gelatin. Fluorescence-activated cell sorting analysis and confocal microscopy were used for measuring cellular internalization of matrix proteins. Targeted PCR array and quantitative real-time PCR were used to evaluate gene expression changes. HSCs and LX2 cells endocytose collagens in a concentration- and time-dependent manner. Endocytosed collagen colocalized with Dextran 10K, a marker of macropinocytosis, and 5-ethylisopropyl amiloride, an inhibitor of macropinocytosis, reduced collagen internalization by 46%. Cytochalasin D and ML7 blocked collagen internalization by 47% and 45%, respectively, indicating that actin and myosin are critical for collagen endocytosis. Wortmannin and AKT inhibitor blocked collagen internalization by 70% and 89%, respectively, indicating that matrix macropinocytosis requires phosphoinositide-3-kinase (PI3K)/AKT signaling. Overexpression of dominant-negative dynamin-2 K44A blocked matrix internalization by 77%, indicating a role for dynamin-2 in matrix macropinocytosis. Whereas c-abl−/− MEF showed impaired matrix endocytosis, YSF−/− MEF surprisingly showed increased matrix endocytosis. It was also associated with complex gene regulations that related with matrix dynamics, including increased matrix metalloproteinase 9 (MMP-9) mRNA levels and zymographic activity. HSCs endocytose matrix proteins through macropinocytosis that requires a signaling network composed of PI3K/AKT, dynamin-2, and c-abl. Interaction with extracellular matrix regulates matrix dynamics through modulating multiple gene expressions including MMP-9.

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Section: C628mentioning

confidence: 49%

Endocytosis of collagen by hepatic stellate cells regulates extracellular matrix dynamics

Bi¹,

Mukhopadhyay²,

Drinane³

et al. 2014

American Journal of Physiology-Cell Physiology

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“…In the same study, Endo180 expression was observed in epithelial cells lining the ducts of glandular tissue affected by benign prostatic hyperplasia (BPH) or low-grade prostate cancer (5). Given that Endo180 expression and subcellular localization in constitutively recycling endosomes in mesenchymal-like tumor cells promote extracellular matrix (ECM) remodelling (6)(7)(8)(9)(10), disassembly of cell-cell and cell-matrix adhesions and cell motility (11,12), and enhanced tumor growth (7), we hypothesized that these pro-EMT properties are negatively regulated in normal prostate epithelial cells (PEC). In accordance, this study has identified a novel EMT-suppressor complex between the fourth of eight CTLDs, CTLD4, in Endo180 and the cell adhesion modulator CD147 that is indispensible for PEC stability.…”

Section: Introductionmentioning

confidence: 94%

Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147

Rodriguez-Teja

Gronau

Minamidate

et al. 2015

Molecular Cancer Research

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Epithelial cell-cell contacts maintain normal glandular tissue homeostasis, and their breakage can trigger epithelialto-mesenchymal transition (EMT), a fundamental step in the development of metastatic cancer. Despite the ability of C-type lectin domains (CTLD) to modulate cell-cell adhesion, it is not known if they modulate epithelial adhesion in EMT and tumor progression. Here, the multi-CTLD mannose receptor, Endo180 (MRC2/uPARAP), was shown using the Kaplan-Meier analysis to be predictive of survival outcome in men with early prostate cancer. A proteomic screen of novel interaction partners with the fourth CTLD (CTLD4) in Endo180 revealed that its complex with CD147 is indispensable for the stability of three-dimensional acini formed by nontransformed prostate epithelial cells (PEC). Mechanistic study using knockdown of Endo180 or CD147, and treatment with an Endo180 mAb targeting CTLD4 (clone 39.10), or a dominant-negative GST-CTLD4 chimeric protein, induced scattering of PECs associated with internalization of Endo180 into endosomes, loss of E-cadherin (CDH1/ECAD), and unzipping of cell-cell junctions. These findings are the first to demonstrate that a CTLD acts as a suppressor and regulatory switch for EMT; thus, positing that stabilization of Endo180-CD147 complex is a viable therapeutic strategy to improve rates of prostate cancer survival.Implications: This study identifies the interaction between CTLD4 in Endo180 and CD147 as an EMT suppressor and indicates that stabilization of this molecular complex improves prostate cancer survival rates.

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“…Both pancreatic cancer cells and PSC are able to internalise collagen. Interestingly, the stimulation of epithelial-to-EMT TGF stimulates collagen endocytosis by cancer cells, via upregulation of Endo180 [44] (figure 3C).…”

Section: Ecm Internalisation and Cancermentioning

confidence: 99%

Extracellular matrix endocytosis in controlling matrix turnover and beyond: emerging roles in cancer

Rainero

2016

Biochemical Society Transactions

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The extracellular matrix (ECM) is a network of secreted proteins that, beyond providing support for tissues and organs, is involved in the regulation of a variety of cell functions, including cell proliferation, polarity, migration and oncogenic transformation. ECM homeostasis is maintained through a tightly controlled balance between synthesis, deposition and degradation. While the role of metalloproteases (MMPs) in ECM degradation is widely recognised, the contribution of ECM internalisation and intracellular degradation to ECM maintenance has been mostly overlooked. In this review, I will summarise what is known about the molecular mechanisms mediating ECM endocytosis and how this process impacts on diseases, such as fibrosis and cancer.

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Pancreatic Cancer Cells Enhance the Ability of Collagen Internalization during Epithelial–Mesenchymal Transition

Cited by 40 publications

References 37 publications

Endocytosis of collagen by hepatic stellate cells regulates extracellular matrix dynamics

Endocytosis of collagen by hepatic stellate cells regulates extracellular matrix dynamics

Survival Outcome and EMT Suppression Mediated by a Lectin Domain Interaction of Endo180 and CD147

Extracellular matrix endocytosis in controlling matrix turnover and beyond: emerging roles in cancer

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