DC Field | Value | Language |
---|---|---|
dc.contributor.author | Jang, Minjeong | ko |
dc.contributor.author | Oh, Seung Won | ko |
dc.contributor.author | Lee, Yunji | ko |
dc.contributor.author | Kim, Jin Young | ko |
dc.contributor.author | Ji, Eun Sun | ko |
dc.contributor.author | Kim, Pilnam | ko |
dc.date.accessioned | 2022-07-12T03:00:21Z | - |
dc.date.available | 2022-07-12T03:00:21Z | - |
dc.date.created | 2022-07-11 | - |
dc.date.created | 2022-07-11 | - |
dc.date.issued | 2022-03 | - |
dc.identifier.citation | ACTA BIOMATERIALIA, v.141, pp.255 - 263 | - |
dc.identifier.issn | 1742-7061 | - |
dc.identifier.uri | http://hdl.handle.net/10203/297347 | - |
dc.description.abstract | The extracellular matrix (ECM) of the tumor microenvironment undergoes constant remodeling that alters its biochemical and mechano-physical properties. Non-enzymatic glycation can induce the formation of advanced glycation end-products (AGEs), which may cause abnormal ECM turnover with excessively cross-linked collagen fibers. However, the subsequent effects of AGE-mediated matrix remodeling on the characteristics of stromal cells in tumor microenvironments remain unclear. Here, we demonstrate that AGEs accumulated in the ECM alter the fibroblast phenotype within a three-dimensional collagen matrix. Both the AGE interaction with its receptor (RAGE) and integrin-mediated mechanotransduction signaling were up-regulated in glycated collagen matrix, leading to fibroblast activation to acquire a cancer-associated fibroblast (CAF)-like phenotype. These effects were blocked with neutralizing antibodies against RAGE or the inhibition of focal adhesion (FA) signaling. An AGE cross-link breaker, phenyl-4,5dimethylthiazolium bromide (ALT 711), also reduced the transformation of fibroblasts into the CAF-like phenotype because of its dual inhibitory role in the AGE-modified matrix. Apart from targeting the AGE & ndash; RAGE interaction directly, the decreased matrix stiffness attenuated fibroblast activation by inhibiting the downstream cellular response to matrix stiffness. Our results suggest that indirect/direct targeting of accumulated AGEs in the ECM has potential for targeting the tumor stroma to improve cancer therapy. Statement of significance Advanced glycated end-products (AGEs)-modified extracellular matrix (ECM) is closely associated with pathological states and is recognized as a critical factor that precedes tumorigenesis. While increased matrix stiffness is known to induce fibroblast activation, less is known about how both biochemical and mechano-physical changes in AGE-mediated matrix-remodeling cooperate to produce a myofibroblastic cancer-associated fibroblast (CAF)-like phenotype. For the first time, we found that both the AGE interaction with its receptor (RAGE) and integrin-mediated mechanotransduction were up-regulated in glycated collagen matrix, leading to fibroblast activation. We further demonstrated that an AGE cross-link breaker, ALT-711, reduced the CAF-like transformation because of its dual inhibitory role in the AGE-modified matrix. Our findings offer promising extracellular-reversion strategies targeting the non-enzymatic ECM glycation, to regulate fibroblast activation. (C) 2022 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved. | - |
dc.language | English | - |
dc.publisher | ELSEVIER SCI LTD | - |
dc.title | Targeting extracellular matrix glycation to attenuate fibroblast activation | - |
dc.type | Article | - |
dc.identifier.wosid | 000820110800001 | - |
dc.identifier.scopusid | 2-s2.0-85123724937 | - |
dc.type.rims | ART | - |
dc.citation.volume | 141 | - |
dc.citation.beginningpage | 255 | - |
dc.citation.endingpage | 263 | - |
dc.citation.publicationname | ACTA BIOMATERIALIA | - |
dc.identifier.doi | 10.1016/j.actbio.2022.01.040 | - |
dc.contributor.localauthor | Kim, Pilnam | - |
dc.contributor.nonIdAuthor | Lee, Yunji | - |
dc.contributor.nonIdAuthor | Kim, Jin Young | - |
dc.contributor.nonIdAuthor | Ji, Eun Sun | - |
dc.description.isOpenAccess | N | - |
dc.type.journalArticle | Article | - |
dc.subject.keywordAuthor | Extracellular matrix (ECM) | - |
dc.subject.keywordAuthor | Advanced Glycation End-products (AGEs) | - |
dc.subject.keywordAuthor | Fibroblast activation | - |
dc.subject.keywordAuthor | ECM-targeting | - |
dc.subject.keywordPlus | END-PRODUCTS | - |
dc.subject.keywordPlus | CANCER | - |
dc.subject.keywordPlus | COLLAGEN | - |
dc.subject.keywordPlus | MODEL | - |
dc.subject.keywordPlus | BETA | - |
dc.subject.keywordPlus | AGE | - |
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