TY - JOUR
T1 - Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers
AU - Witkiewicz, Agnieszka K.
AU - Kline, Jessica
AU - Queenan, Maria
AU - Brody, Jonathan R.
AU - Tsirigos, Aristotelis
AU - Bilal, Erhan
AU - Pavlides, Stephanos
AU - Ertel, Adam
AU - Sotgia, Federica
AU - Lisanti, Michael P.
N1 - Funding Information:
This project is funded, in part, under a grant with the Pennsylvania Department of Health (to M.P.L.). The Department specifically disclaims responsibility for any analyses, interpretations or conclusions.
Funding Information:
M.P.L. and his laboratory were supported by grants from the NIH/ NCI (R01-CA-080250; R01-CA-098779; R01-CA-120876; R01-AR-055660) and the Susan G. Komen Breast Cancer Foundation. A.K.W. was supported by a Young Investigator Award from Breast Cancer Alliance, Inc., and a Susan G. Komen Career Catalyst Grant. F.S. was supported by grants from the W.W. Smith Charitable Trust, the Breast Cancer Alliance (BCA) and a Research Scholar Grant from the American Cancer Society (ACS). Funds were also contributed by the Margaret Q. Landenberger Research Foundation (to M.P.L.).
PY - 2011/6/1
Y1 - 2011/6/1
N2 - Breast 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.
AB - Breast 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.
KW - Aging
KW - Biomarkers
KW - Breast cancer
KW - Caveolin-1
KW - Clinical outcome
KW - Gene signatures
KW - Metastasis
KW - Recurrence
KW - Transcriptional profiling
KW - Tumor stroma
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UR - http://www.scopus.com/inward/citedby.url?scp=79957927705&partnerID=8YFLogxK
U2 - 10.4161/cc.10.11.15675
DO - 10.4161/cc.10.11.15675
M3 - Article
C2 - 21521946
AN - SCOPUS:79957927705
SN - 1538-4101
VL - 10
SP - 1794
EP - 1809
JO - Cell Cycle
JF - Cell Cycle
IS - 11
ER -