LOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapy

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dc.WoS.categoriesBiochemistry & Molecular Biology; Oncology; Cell Biology; Genetics & Heredityen_US
dc.contributor.authorIrmak, Ster
dc.date.accessioned2020-06-15T08:55:55Z
dc.date.available2020-06-15T08:55:55Z
dc.date.issued2018-09-06
dc.description.abstractThe potential of altering the tumor ECM to improve drug response remains fairly unexplored. To identify targets for modification of the ECM aiming to improve drug response and overcome resistance, we analyzed expression data sets from pre-treatment patient cohorts. Cross-evaluation identified a subset of chemoresistant tumors characterized by increased expression of collagens and collagen-stabilizing enzymes. We demonstrate that strong collagen expression and stabilization sets off a vicious circle of self-propagating hypoxia, malignant signaling, and aberrant angiogenesis that can be broken by an appropriate auxiliary intervention: Interfering with collagen stabilization by inhibition of lysyl oxidases significantly enhanced response to chemotherapy in various tumor models, even in metastatic disease. Inhibition of collagen stabilization by itself can reduce or enhance tumor growth depending on the tumor type. The mechanistical basis for this behavior is the dependence of the individual tumor on nutritional supply on one hand and on high tissue stiffness for FAK signaling on the other.en_US
dc.fullTextLevelFull Texten_US
dc.identifier.doi10.1038/s41388-018-0320-2en_US
dc.identifier.issn1476-5594
dc.identifier.issn0950-9232
dc.identifier.pmid29780168en_US
dc.identifier.scopus2-s2.0-85047119286en_US
dc.identifier.urihttps://hdl.handle.net/11411/2214
dc.identifier.urihttps://doi.org/10.1038/s41388-018-0320-2
dc.identifier.wosWOS:000443823600002en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.issue36en_US
dc.language.isoenen_US
dc.nationalInternationalen_US
dc.numberofauthors6en_US
dc.pages4921-4940en_US
dc.publisherNATURE PUBLISHING GROUPen_US
dc.relation.ispartofONCOGENEen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectLYSYL OXIDASEen_US
dc.subjectTUMOR ANGIOGENESISen_US
dc.subjectDRUG-DELIVERYen_US
dc.subjectDOUBLE-BLINDen_US
dc.subjectPHASE-IIen_US
dc.subjectDOXORUBICINen_US
dc.subjectIMPROVESen_US
dc.subjectCOMBINATIONen_US
dc.subjectSIMTUZUMABen_US
dc.subjectINHIBITIONen_US
dc.titleLOX-catalyzed collagen stabilization is a proximal cause for intrinsic resistance to chemotherapyen_US
dc.typeArticleen_US
dc.volume37en_US

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