The Activation of β1-integrin by Type I Collagen Coupling with the Hedgehog Pathway Promotes the Epithelial-Mesenchymal Transition in Pancreatic Cancer

2014 ◽  
Vol 14 (5) ◽  
pp. 446-457 ◽  
Author(s):  
Wanxing Duan ◽  
Jiguang Ma ◽  
Qingyong Ma ◽  
Qinhong Xu ◽  
Jianjun Lei ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Type I Collagen ◽  
Epithelial Mesenchymal Transition ◽  
Hedgehog Pathway ◽  
Type I ◽  
Mesenchymal Transition

scholarly journals Pancreatic Cancer Cells Respond to Type I Collagen by Inducing Snail Expression to Promote Membrane Type 1 Matrix Metalloproteinase-dependent Collagen Invasion

2011 ◽  
Vol 286 (12) ◽  
pp. 10495-10504 ◽  
Author(s):  
Mario A. Shields ◽  
Surabhi Dangi-Garimella ◽  
Seth B. Krantz ◽  
David J. Bentrem ◽  
Hidayatullah G. Munshi
Keyword(s):  
Pancreatic Cancer ◽  
Cancer Cells ◽  
Type I Collagen ◽  
Epithelial Mesenchymal Transition ◽  
Three Dimensional ◽  
Type I ◽  
Collagen Gels ◽  
Mesenchymal Transition ◽  
Pancreatic Cancer Cells ◽  
Membrane Type

Pancreatic ductal adenocarcinoma (PDAC) is characterized by pronounced fibrotic reaction composed primarily of type I collagen. Although type I collagen functions as a barrier to invasion, pancreatic cancer cells have been shown to respond to type I collagen by becoming more motile and invasive. Because epithelial-mesenchymal transition is also associated with cancer invasion, we examined the extent to which collagen modulated the expression of Snail, a well known regulator of epithelial-mesenchymal transition. Relative to cells grown on tissue culture plastic, PDAC cells grown in three-dimensional collagen gels induced Snail. Inhibiting the activity or expression of the TGF-β type I receptor abrogated collagen-induced Snail. Downstream of the receptor, we showed that Smad3 and Smad4 were critical for the induction of Snail by collagen. In contrast, Smad2 or ERK1/2 was not involved in collagen-mediated Snail expression. Overexpression of Snail in PDAC cells resulted in a robust membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14)-dependent invasion through collagen-coated transwell chambers. Snail-expressing PDAC cells also demonstrated MT1-MMP-dependent scattering in three-dimensional collagen gels. Mechanistically, Snail increased the expression of MT1-MMP through activation of ERK-MAPK signaling, and inhibiting ERK signaling in Snail-expressing cells blocked two-dimensional collagen invasion and attenuated scattering in three-dimensional collagen. To provide in vivo support for our findings that Snail can regulate MT1-MMP, we examined the expression of Snail and MT1-MMP in human PDAC tumors and found a statistically significant positive correlation between MT1-MMP and Snail in these tumors. Overall, our data demonstrate that pancreatic cancer cells increase Snail on encountering collagen-rich milieu and suggest that the desmoplastic reaction actively contributes to PDAC progression.

scholarly journals Crotoxin Modulates Events Involved in Epithelial–Mesenchymal Transition in 3D Spheroid Model

Toxins ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 830
Author(s):  
Ellen Emi Kato ◽  
Sandra Coccuzzo Sampaio
Keyword(s):  
Tumor Cells ◽  
Type I Collagen ◽  
Epithelial Mesenchymal Transition ◽  
Metastatic Cancer ◽  
A549 Cells ◽  
The Body ◽  
Antitumor Action ◽  
Type I ◽  
Collagen Gels ◽  
Mesenchymal Transition

Epithelial–mesenchymal transition (EMT) occurs in the early stages of embryonic development and plays a significant role in the migration and the differentiation of cells into various types of tissues of an organism. However, tumor cells, with altered form and function, use the EMT process to migrate and invade other tissues in the body. Several experimental (in vivo and in vitro) and clinical trial studies have shown the antitumor activity of crotoxin (CTX), a heterodimeric phospholipase A2 present in the Crotalus durissus terrificus venom. In this study, we show that CTX modulates the microenvironment of tumor cells. We have also evaluated the effect of CTX on the EMT process in the spheroid model. The invasion of type I collagen gels by heterospheroids (mix of MRC-5 and A549 cells constitutively prepared with 12.5 nM CTX), expression of EMT markers, and secretion of MMPs were analyzed. Western blotting analysis shows that CTX inhibits the expression of the mesenchymal markers, N-cadherin, α-SMA, and αv. This study provides evidence of CTX as a key modulator of the EMT process, and its antitumor action can be explored further for novel drug designing against metastatic cancer.

scholarly journals Hsp47 promotes cancer metastasis by enhancing collagen-dependent cancer cell-platelet interaction

2020 ◽  
Vol 117 (7) ◽  
pp. 3748-3758 ◽  
Author(s):  
Gaofeng Xiong ◽  
Jie Chen ◽  
Guoying Zhang ◽  
Shike Wang ◽  
Kunito Kawasaki ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Cancer Metastasis ◽  
Type I Collagen ◽  
Epithelial Mesenchymal Transition ◽  
Type I ◽  
Sequencing Data ◽  
Mesenchymal Transition ◽  
Collagen Secretion ◽  
Cell Colonization

Increased expression of extracellular matrix (ECM) proteins in circulating tumor cells (CTCs) suggests potential function of cancer cell-produced ECM in initiation of cancer cell colonization. Here, we showed that collagen and heat shock protein 47 (Hsp47), a chaperone facilitating collagen secretion and deposition, were highly expressed during the epithelial-mesenchymal transition (EMT) and in CTCs. Hsp47 expression induced mesenchymal phenotypes in mammary epithelial cells (MECs), enhanced platelet recruitment, and promoted lung retention and colonization of cancer cells. Platelet depletion in vivo abolished Hsp47-induced cancer cell retention in the lung, suggesting that Hsp47 promotes cancer cell colonization by enhancing cancer cell–platelet interaction. Using rescue experiments and functional blocking antibodies, we identified type I collagen as the key mediator of Hsp47-induced cancer cell–platelet interaction. We also found that Hsp47-dependent collagen deposition and platelet recruitment facilitated cancer cell clustering and extravasation in vitro. By analyzing DNA/RNA sequencing data generated from human breast cancer tissues, we showed that gene amplification and increased expression of Hsp47 were associated with cancer metastasis. These results suggest that targeting the Hsp47/collagen axis is a promising strategy to block cancer cell–platelet interaction and cancer colonization in secondary organs.

scholarly journals Chronic lung inflammation and pulmonary fibrosis after multiple intranasal instillation of PM2.5 in mice

2020 ◽  
Author(s):  
Mengmeng Xu ◽  
Hai Zhang ◽  
Lu Xu ◽  
Xiaohui Wang ◽  
Chenfei Li ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Inflammation ◽  
Type I Collagen ◽  
Epithelial Mesenchymal Transition ◽  
Fine Particulate Matter ◽  
Type I ◽  
Mesenchymal Transition ◽  
Pm 2.5 ◽  
Cell Counts ◽  
Intranasal Instillation

Abstract Background: Fine particulate matter (PM 2.5 ) is an important component of air pollution and can induce lung inflammation and oxidative stress. We hypothesised that PM 2.5 could play a role in the induction of pulmonary fibrosis. We examined whether multiple intranasal instillation of PM 2.5 can induce pulmonary fibrosis in the mouse, and also investigated the underlying pro-fibrotic signaling pathways.Methods: C57/BL6 mice were intranasally instilled with 50 μl of PM 2.5 suspension (7.8 μg/g body weight) or PBS three times a week over 3 weeks, 6 weeks or 9 weeks. To observe the recovery of pulmonary fibrosis after the termination of PM 2.5 exposure, 9 week-PM 2.5 instilled mice were also studied at 3 weeks after termination of instillation.Results: There were significant decreases in total lung capacity (TLC) and compliance (Cchord) in the 9-week PM 2.5 -instilled mice, while there was an increase in total cell counts in bronchoalveolar fluid and lung section in 3-week, 6-week and 9-week PM 2.5 -instilled mice and 9 week-PM 2.5 instilled-3 week-air exposed mice. There were increased histological fibrosis scores with enhanced type I collagen and hydroxyproline deposition in lung tissue in 6-week and 9-week PM 2.5 -instilled mice and 9-week-PM 2.5 instilled-3-week-air-exposed mice. Multiple PM 2.5 instillation resulted in increased expression of TGFβ1, increases of N-Cadherin and Vimentin and decrease of E-Cadherin. It also led to decreases in OPA1 and MFN2, and increases in Parkin, SQSTM1/p62, the ratio of light china (LC) 3B II to LC3B I, PI3k/Akt phosphorylation, NOX4 and NLRP3 expression.Conclusions: The intranasal instillation of PM 2.5 for 9 weeks induced lung inflammation and pulmonary fibrosis, which was linked with aberrant epithelial-mesenchymal transition, mitochondrial damage and mitophagy, as well as activation of TGFβ1-PI3K/Akt and TGFβ1-NOX4 -NLRP3 pathways.

Involvement of N-type Ca2+ channels in the fibrotic process of the kidney in rats

2013 ◽  
Vol 304 (6) ◽  
pp. F665-F673 ◽  
Author(s):  
Keiichiro Mishima ◽  
Akito Maeshima ◽  
Masaaki Miya ◽  
Noriyuki Sakurai ◽  
Hidekazu Ikeuchi ◽  
...  
Keyword(s):  
Renal Fibrosis ◽  
Type I Collagen ◽  
Channel Blocker ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Type Iii Collagen ◽  
Type I ◽  
Renal Tubules ◽  
Mesenchymal Transition ◽  
Fibrotic Process

N-type Ca2+ channels are densely distributed in sympathetic nerves that innervate renal tubules. However, the role of N-type Ca2+ channels in renal fibrosis remains unknown. To address this issue, we examined the difference between the effects of amlodipine (an L-type Ca2+ channel blocker) and cilnidipine (a dual L/N-type Ca2+ channel blocker) on fibrotic changes using a rat unilateral ureteral obstruction (UUO) model. The expression of both L-type and N-type Ca2+ channels was significantly upregulated in UUO kidneys compared with that in contralateral kidneys. There were no significant differences in mean blood pressure among the rats tested. Both amlodipine and cilnidipine significantly attenuated fibrotic changes in UUO kidneys. The antifibrotic effect of cilnidipine was more potent than that of amlodipine. Amlodipine as well as cilnidipine reduced type III collagen deposition, α-smooth muscle actin (α-SMA) expression, and interstitial cell proliferation. In addition, cilnidipine significantly reduced deposition of type I collagen and macrophage infiltration in UUO kidneys. With the use of in vivo bromodeoxyuridine labeling, label-retaining cells (LRCs) were identified as a population of tubular cells that participate in epithelial-mesenchymal transition after UUO. Some LRCs migrated into the interstitium, expressed α-SMA and vimentin, and produced several extracellular matrixes in UUO kidneys. The number of interstitial LRCs was significantly decreased by cilnidipine but not amlodipine. These data suggest that N-type Ca2+ channels contribute to multiple steps of renal fibrosis, and its blockade may thus be a useful therapeutic approach for prevention of renal fibrosis.

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