Transforming growth factor-β1 induces matrix metalloproteinase-9 and cell migration in astrocytes: roles of ROS-dependent ERK- and JNK-NF-κB pathways

Hsieh, Hsi‐Lung; Wang, Hui-Hsin; Wu, Wen‐Bin; Chu, Po‐Ju; Yang, Che‐Hua

doi:10.1186/1742-2094-7-88

Cited by 171 publications

(144 citation statements)

References 77 publications

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“…The FASEB Journal x www.fasebj.org also secrete MMPs, application of an MMP inhibitor to the ACM may also inhibit MMPs produced by the tumor cells, thus confounding interpretation of the results. It has been found that TGF-b1 increases MMP production by astrocytes (48); however, the TGF-b treatment of astrocytes actually decreased the velocity of the subsequent ACMtreated tumor cells as compared to vehicle control-treated ACM. This suggests that MMPs are not the only, and potentially not the dominant, molecular mechanism at play in astrocyte-induced increased cell migration.…”

Section: Discussionmentioning

confidence: 97%

Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells

et al. 2017

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Tumor cell metastasis to the brain involves cell migration through biochemically and physically complex microenvironments at the blood-brain barrier (BBB). The current understanding of tumor cell migration across the BBB is limited. We hypothesize that an interplay between biochemical cues and physical cues at the BBB affects the mechanisms of brain metastasis. We found that astrocyte conditioned medium (ACM) applied directly to tumor cells increased tumor cell velocity, induced elongation, and promoted actin stress fiber organization. Notably, treatment of the extracellular matrix with ACM led to even more significant increases in tumor cell velocity in comparison with ACM treatment of cells directly. Furthermore, inhibiting matrix metalloproteinases in ACM reversed ACM's effect on tumor cells. The effects of ACM on tumor cell morphology and migration also depended on astrocytes' activation state. Finally, using a microfluidic device, we found that the effects of ACM were abrogated in confinement. Overall, our work demonstrates that astrocyte-secreted factors alter migration and morphology of metastatic breast tumor cells, and this effect depends on the cells' mechanical microenvironment. Metastasis to the brain is one of the most deadly aspects of breast cancer, leading to a particularly poor prognosis for patients (1). During metastasis, breast tumor cells break away from the primary tumor, travel through the circulatory system, preferentially infiltrate the brain, and form secondary tumors that are notoriously difficult to treat (1). During metastasis, tumor cells encounter many heterogeneous microenvironments containing an array of biochemical and physical cues (2), both of which regulate the migration, mechanobiology, and signaling mechanisms used by tumor cells to navigate these environments (3). It has been shown that astrocytes in the brain microenvironment promote brain metastasis and facilitate tumor cell invasion (4-8). We hypothesize that astrocyte-secreted biochemical cues regulate the morphology and migration of metastatic breast tumor cells and that this effect depends on the astrocyte activation state, as well as the mechanical microenvironment of the tumor cells.In healthy physiology, astrocytes provide support for neurons by maintaining an ionic, neurotransmitter, amino acid, and water balance in the brain (9). The endfeet of astrocytes support the blood-brain barrier (BBB) by assisting with the exchange of chemical signals between the circulatory system and the brain (9) and modulating the physiology of brain endothelial cells (9, 10). Although astrocytes are important regulators of brain homeostasis, they also play a role in brain metastasis. It has been reported that astrocyte-secreted serpins are involved in tumor cell survival during metastasis across the BBB in vivo (4). Another report demonstrated an increased invasiveness of tumor cells in response to astrocyte-conditioned medium (ACM), and they attributed this response to astrocyte-secreted matrix metalloproteinases (MMPs) (...

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Section: Discussionmentioning

confidence: 97%

Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells

et al. 2017

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“…The tyrosine kinase Src and phosphatidylinositol 3'-kinase (PI3K), and that phosphorylation of ERK1/2 can be inhibited by blocking TGF-βRI, Smad3, or the Nox oxidases (5,37). It is well established that ROS can activate MAPKs to exert functions in proliferation, differentiation and apoptosis (38,39), and ROS-dependent activation of ERK1/2 and JNK1/2 by TGF-β1 can induce MMP-9 expression and enzymatic activity, resulting in the promotion of cell migration in RBA-1 cells (40). Our results support the involvement of an additional signaling pathway, TGF-β1/ TGF-βRI/Smad2/ERK1/2/HIF-1α/GPx-1, in colorectal cancer (Fig.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor-β1 induces glutathione peroxidase-1 and protects from H2O2-induced cell death in colon cancer cells via the Smad2/ERK1/2/HIF-1α pathway

et al. 2012

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Abstract.Recent studies have shown that transforming growth factor-β1 (TGF-β1) signaling plays important roles in the redox system in benign and malignant cells. Whether TGF-β mediates an antioxidative damage response in colorectal cancer cells is largely unknown. Herein, using the human colorectal cancer cell lines we found that TGF-β1 induced glutathione peroxidase-1 (GPx-1) expression and enzyme activity, and that the upregulation of GPx-1 by TGF-β1 could protect colorectal cell lines from H 2 O 2 -induced oxidation damage. Further, we used loss-and gain-function approaches to elucidate the underlying mechanism and found that TGF-β1 induced GPx-1 through activation of the TGF-β receptor type I (TGF-βRI)/ Smad2/extracellular-signal-regulated kinase 1/2 (ERK1/2)/ hypoxia-inducible factor-1α (HIF-1α) signaling pathway. This cascade could be blocked by the TGF-βRI inhibitor or ERK1/2 inhibitor. Taken together, our data demonstrated that TGF-β1 induced GPx-1 expression and enzymatic activity via the TGF-βRI/Smad2/ERK1/2/HIF-1α signaling pathway, suggesting a novel antioxidative protective function of TGF-β1 in colorectal cancer cells. IntroductionTransforming growth factor-β (TGF-β) is a multifunctional cytokine and plays very important roles in development, differentiation and in maintaining homeostasis in almost all cell types and tissues (1). TGF-β functions via transmembrane serine/threonine kinase receptors, the type I and type II receptors (TGF-βRI and TGF-βRII) (2) and intracellular Smad transcriptional regulators (3). Increasing evidence has indicated that TGF-β is involved in the redox system in benign and tumor cells, in terms of that TGF-β can induce production of reactive oxygen species (ROS) which stimulates proliferation, invasion, migration and angiogenesis and evade apoptosis in cancer cells (4). TGF-β1 can stimulate a rapid increase in ROS generation to induce kidney myofibroblast activation and matrix synthesis (5). In renal tubular epithelial cells, TGF-β1 induces cellular ROS and mediates the epithelial-mesenchymal transition (EMT). All these effects can be abrogated by antioxidants (6). Low levels of ROS play a very important role in keeping normal cell proliferation by regulating cellular signaling. A great body of evidence indicates that production of ROS is increased in cancer cells and elevated ROS may facilitate tumor cell growth (7). However, a higher level of ROS may act reversely to induce an apoptotic response of tumor cells. Moderate ROS levels provide tumor cells with the advantage to maintain survival. Glutathione peroxidases (GPxs) are of the most important antioxidative enzyme families which can modulate cellular ROS levels to keep the redox balance in tumor cells.GPx-1 is the first identified selenoprotein and is expressed in most cells (8-10). GPx-1 is classified as an antioxidant enzyme and exerts its role to prevent the initiation of cancer by ROS-mediated DNA damage. Previous studies have suggested that GPx-1 is altered in several types of cancer cells (11,12) and overexpres...

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“…Furthermore, TGF-β suppresses phosphatase and tensin homolog (PTEN) in glioma cells through enhanced miR10a/b expression (154). In patient samples, TGFB1I1 (TGF-β1-induced transcript 1) expression was found to be correlated with tumor grade, and activation of EMT pathways (152). In reaction to radiation treatment, the invasion capability of glioma cells is enhanced and TGF-β is upregulated.…”

Section: The Role Of Tgf-β In Glioma Cell Motilitymentioning

confidence: 99%

Molecular Mechanisms of Glioma Cell Motility

et al. 2017

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Gliomas are the most common intracranial tumors in humans. The most malignant among these tumors is glioblastoma (GBM), with an incidence of 3-5 out of 100,000 persons in Western countries. GBM arises either de novo (primary GBM) or develops from a lower grade glioma (secondary GBM). The prognosis is poor. GBMs are lethal tumors and even optimal surgical resection, followed by chemotherapy and irradiation, results in a median survival of about 12-15 months. One characteristic that is responsible for GBM malignancy, and its worse prognosis, is the highly infiltrative growth of GBM cells into the healthy brain. GBM cell migration and invasion is a very complex process that is regulated by several factors, which include changes in the migrating cell itself as well as the tumor microenvironment. This chapter provides an overview of routes of invasion of glioma cells, the signaling pathways that drive glioma cell motility, and the processes through which glioma cells modulate their surrounding environment.

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Transforming growth factor-β1 induces matrix metalloproteinase-9 and cell migration in astrocytes: roles of ROS-dependent ERK- and JNK-NF-κB pathways

Cited by 171 publications

References 77 publications

Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells

Astrocytes from the brain microenvironment alter migration and morphology of metastatic breast cancer cells

Transforming growth factor-β1 induces glutathione peroxidase-1 and protects from H2O2-induced cell death in colon cancer cells via the Smad2/ERK1/2/HIF-1α pathway

Molecular Mechanisms of Glioma Cell Motility

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