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Article: Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

TitleCritical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy
Authors
KeywordsBreast Neoplasms/*enzymology/pathology
Cell Line
Tumor
Epithelial-Mesenchymal Transition
Female
Humans
Mesenchymal Stromal Cells/*enzymology
Neoplasm Invasiveness
Neoplasm Metastasis
Neoplastic Stem Cells/enzymology
Protein-Lysine 6-Oxidase/genetics/*metabolism
RNA, Messenger/genetics
Issue Date2012
PublisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org
Citation
Proceedings of the National Academy of Sciences, 2012, v. 109 n. 43, p. 17460-17465 How to Cite?
AbstractMesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to differentiate into multiple mesoderm lineages in the course of normal tissue homeostasis or during injury. We have previously shown that MSCs migrate to sites of tumorigenesis, where they become activated by cancer cells to promote metastasis. However, the molecular and phenotypic attributes of the MSC-induced metastatic state of the cancer cells remained undetermined. Here, we show that bone marrow-derived human MSCs promote de novo production of lysyl oxidase (LOX) from human breast carcinoma cells, which is sufficient to enhance the metastasis of otherwise weakly metastatic cancer cells to the lungs and bones. We also show that LOX is an essential component of the CD44-Twist signaling axis, in which extracellular hyaluronan causes nuclear translocation of CD44 in the cancer cells, thus triggering LOX transcription by associating with its promoter. Processed and enzymatically active LOX, in turn, stimulates Twist transcription, which mediates the MSC-triggered epithelial-to-mesenchymal transition (EMT) of carcinoma cells. Surprisingly, although induction of EMT in breast cancer cells has been tightly associated with the generation of cancer stem cells, we find that LOX, despite being critical for EMT, does not contribute to the ability of MSCs to promote the formation of cancer stem cells in the carcinoma cell populations. Collectively, our studies highlight a critical role for LOX in cancer metastasis and indicate that the signaling pathways controlling stroma-induced EMT are distinct from pathways regulating the development of cancer stem cells.
Persistent Identifierhttp://hdl.handle.net/10722/219913
ISSN
2015 Impact Factor: 9.423
2015 SCImago Journal Rankings: 6.883
PubMed Central ID
ISI Accession Number ID

 

DC FieldValueLanguage
dc.contributor.authorEl-Haibi, CP-
dc.contributor.authorBell, GW-
dc.contributor.authorZhang, J-
dc.contributor.authorCollmann, AY-
dc.contributor.authorWood, D-
dc.contributor.authorScherber, CM-
dc.contributor.authorCsizmadia, E-
dc.contributor.authorMariani, O-
dc.contributor.authorZhu, C-
dc.contributor.authorCampagne, A-
dc.contributor.authorToner, M-
dc.contributor.authorBhatia, SN-
dc.contributor.authorIrimia, D-
dc.contributor.authorVincent-Salomon, A-
dc.contributor.authorKarnoub, AE-
dc.date.accessioned2015-10-02T04:14:05Z-
dc.date.available2015-10-02T04:14:05Z-
dc.date.issued2012-
dc.identifier.citationProceedings of the National Academy of Sciences, 2012, v. 109 n. 43, p. 17460-17465-
dc.identifier.issn0027-8424-
dc.identifier.urihttp://hdl.handle.net/10722/219913-
dc.description.abstractMesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to differentiate into multiple mesoderm lineages in the course of normal tissue homeostasis or during injury. We have previously shown that MSCs migrate to sites of tumorigenesis, where they become activated by cancer cells to promote metastasis. However, the molecular and phenotypic attributes of the MSC-induced metastatic state of the cancer cells remained undetermined. Here, we show that bone marrow-derived human MSCs promote de novo production of lysyl oxidase (LOX) from human breast carcinoma cells, which is sufficient to enhance the metastasis of otherwise weakly metastatic cancer cells to the lungs and bones. We also show that LOX is an essential component of the CD44-Twist signaling axis, in which extracellular hyaluronan causes nuclear translocation of CD44 in the cancer cells, thus triggering LOX transcription by associating with its promoter. Processed and enzymatically active LOX, in turn, stimulates Twist transcription, which mediates the MSC-triggered epithelial-to-mesenchymal transition (EMT) of carcinoma cells. Surprisingly, although induction of EMT in breast cancer cells has been tightly associated with the generation of cancer stem cells, we find that LOX, despite being critical for EMT, does not contribute to the ability of MSCs to promote the formation of cancer stem cells in the carcinoma cell populations. Collectively, our studies highlight a critical role for LOX in cancer metastasis and indicate that the signaling pathways controlling stroma-induced EMT are distinct from pathways regulating the development of cancer stem cells.-
dc.languageeng-
dc.publisherNational Academy of Sciences. The Journal's web site is located at http://www.pnas.org-
dc.relation.ispartofProceedings of the National Academy of Sciences-
dc.rightsProceedings of the National Academy of Sciences. Copyright © National Academy of Sciences.-
dc.subjectBreast Neoplasms/*enzymology/pathology-
dc.subjectCell Line-
dc.subjectTumor-
dc.subjectEpithelial-Mesenchymal Transition-
dc.subjectFemale-
dc.subjectHumans-
dc.subjectMesenchymal Stromal Cells/*enzymology-
dc.subjectNeoplasm Invasiveness-
dc.subjectNeoplasm Metastasis-
dc.subjectNeoplastic Stem Cells/enzymology-
dc.subjectProtein-Lysine 6-Oxidase/genetics/*metabolism-
dc.subjectRNA, Messenger/genetics-
dc.titleCritical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy-
dc.typeArticle-
dc.identifier.emailZhang, J: jzhang1@hku.hk-
dc.identifier.authorityZhang, J=rp01713-
dc.identifier.doi10.1073/pnas.1206653109-
dc.identifier.pmid23033492-
dc.identifier.pmcidPMC3491529-
dc.identifier.scopuseid_2-s2.0-84867902937-
dc.identifier.volume109-
dc.identifier.issue43-
dc.identifier.spage17460-
dc.identifier.epage17465-
dc.identifier.isiWOS:000311147800036-
dc.publisher.placeUnited States-

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