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dc.contributor.authorWitkiewicz, A K
dc.contributor.authorKline, J
dc.contributor.authorQueenan, M
dc.contributor.authorBrody, J R
dc.contributor.authorTsirigos, A
dc.contributor.authorBilal, E
dc.contributor.authorPavlides, S
dc.contributor.authorErtel, A
dc.contributor.authorSotgia, Federica
dc.contributor.authorLisanti, Michael P
dc.date.accessioned2012-11-12T16:53:00Z
dc.date.available2012-11-12T16:53:00Z
dc.date.issued2011-06-01
dc.identifier.citationMolecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers. 2011, 10 (11):1794-809 Cell Cycleen_GB
dc.identifier.issn1551-4005
dc.identifier.pmid21521946
dc.identifier.urihttp://hdl.handle.net/10541/251880
dc.description.abstractBreast cancer progression and metastasis are driven by complex and reciprocal interactions, between epithelial cancer cells and their surrounding stromal microenvironment. We have previously shown that a loss of stromal Cav-1 expression is associated with an increased risk of early tumor recurrence, metastasis and decreased overall survival. To identify and characterize the signaling pathways that are activated in Cav-1 negative tumor stroma, we performed gene expression profiling using laser microdissected breast cancer-associated stroma. Tumor stroma was laser capture microdissected from 4 cases showing high stromal Cav-1 expression and 7 cases with loss of stromal Cav-1. Briefly, we identified 238 gene transcripts that were upregulated and 232 gene transcripts that were downregulated in the stroma of tumors showing a loss of Cav-1 expression (p ≤ 0.01 and fold-change ≥ 1.5). Gene set enrichment analysis (GSEA) revealed "stemness," inflammation, DNA damage, aging, oxidative stress, hypoxia, autophagy and mitochondrial dysfunction in the tumor stroma of patients lacking stromal Cav-1. Our findings are consistent with the recently proposed "Reverse Warburg Effect" and the "Autophagic Tumor Stroma Model of Cancer Metabolism." In these two complementary models, cancer cells induce oxidative stress in adjacent stromal cells, which then forces these stromal fibroblasts to undergo autophagy/mitophagy and aerobic glycolysis. This, in turn, produces recycled nutrients (lactate, ketones and glutamine) to feed anabolic cancer cells, which are undergoing oxidative mitochondrial metabolism. Our results are also consistent with previous biomarker studies showing that the increased expression of known autophagy markers (such as ATG16L and the cathepsins) in the tumor stroma is specifically associated with metastatic tumor progression and/or poor clinical outcome.
dc.language.isoenen
dc.rightsArchived with thanks to Cell cycle (Georgetown, Tex.)en_GB
dc.subject.meshBiological Markers
dc.subject.meshBreast Neoplasms
dc.subject.meshCaveolin 1
dc.subject.meshCell Communication
dc.subject.meshFemale
dc.subject.meshFibroblasts
dc.subject.meshGene Expression Profiling
dc.subject.meshGene Expression Regulation, Neoplastic
dc.subject.meshHumans
dc.subject.meshOxidative Stress
dc.subject.meshTumor Microenvironment
dc.titleMolecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers.en
dc.typeArticleen
dc.contributor.departmentThomas Jefferson University, Philadelphia, PA, USA. agnieszka.witkiewicz@jeferson.eduen_GB
dc.identifier.journalCell Cycleen_GB
html.description.abstractBreast cancer progression and metastasis are driven by complex and reciprocal interactions, between epithelial cancer cells and their surrounding stromal microenvironment. We have previously shown that a loss of stromal Cav-1 expression is associated with an increased risk of early tumor recurrence, metastasis and decreased overall survival. To identify and characterize the signaling pathways that are activated in Cav-1 negative tumor stroma, we performed gene expression profiling using laser microdissected breast cancer-associated stroma. Tumor stroma was laser capture microdissected from 4 cases showing high stromal Cav-1 expression and 7 cases with loss of stromal Cav-1. Briefly, we identified 238 gene transcripts that were upregulated and 232 gene transcripts that were downregulated in the stroma of tumors showing a loss of Cav-1 expression (p ≤ 0.01 and fold-change ≥ 1.5). Gene set enrichment analysis (GSEA) revealed "stemness," inflammation, DNA damage, aging, oxidative stress, hypoxia, autophagy and mitochondrial dysfunction in the tumor stroma of patients lacking stromal Cav-1. Our findings are consistent with the recently proposed "Reverse Warburg Effect" and the "Autophagic Tumor Stroma Model of Cancer Metabolism." In these two complementary models, cancer cells induce oxidative stress in adjacent stromal cells, which then forces these stromal fibroblasts to undergo autophagy/mitophagy and aerobic glycolysis. This, in turn, produces recycled nutrients (lactate, ketones and glutamine) to feed anabolic cancer cells, which are undergoing oxidative mitochondrial metabolism. Our results are also consistent with previous biomarker studies showing that the increased expression of known autophagy markers (such as ATG16L and the cathepsins) in the tumor stroma is specifically associated with metastatic tumor progression and/or poor clinical outcome.


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