Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis

We have previously demonstrated that loss of stromal caveolin-1 (Cav-1) in cancer-associated fibroblasts is a strong and independent predictor of poor clinical outcome in human breast cancer patients. However, the signaling mechanism(s) by which Cav-1 downregulation leads to this tumor-promoting mic...

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Veröffentlicht in:Cell cycle (Georgetown, Tex.) Jg. 10; H. 12; S. 2021 - 2034
Hauptverfasser: Castello-Cros, Remedios, Bonnuccelli, Gloria, Molchansky, Alex, Capozza, Franco, Witkiewicz, Agnieszka K., Birbe, Ruth, Howell, Anthony, Pestell, Richard G., Whitaker-Menezes, Diana, Sotgia, Federica, Lisanti, Michael P
Format: Journal Article
Sprache:Englisch
Veröffentlicht: United States Taylor & Francis 15.06.2011
Landes Bioscience
Schlagworte:
Animals
Autophagy
Binding
Biology
Bioscience
Breast Neoplasms - pathology
Calcium
Cancer
Caveolin 1 - metabolism
Cell
Cell Line, Tumor
Coculture Techniques
Cycle
Extracellular Matrix - metabolism
Fibroblasts - pathology
Humans
Landes
Mice
Mitochondria - metabolism
Mitochondria - pathology
Neoplasm Metastasis
Neoplasms - pathology
Neoplasms - ultrastructure
Organogenesis
Plasminogen Activator Inhibitor 1 - metabolism
Plasminogen Activator Inhibitor 2 - metabolism
Proteins
Stromal Cells - pathology
Transplantation, Heterologous
Tumor Microenvironment
ISSN:1538-4101, 1551-4005, 1551-4005
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Zusammenfassung:We have previously demonstrated that loss of stromal caveolin-1 (Cav-1) in cancer-associated fibroblasts is a strong and independent predictor of poor clinical outcome in human breast cancer patients. However, the signaling mechanism(s) by which Cav-1 downregulation leads to this tumor-promoting microenvironment are not well understood. To address this issue, we performed an unbiased comparative proteomic analysis of wild-type (WT) and Cav-1 -/- null mammary stromal fibroblasts (MSFs). Our results show that plasminogen activator inhibitor type 1 and type 2 (PAI-1 and PAI-2) expression is significantly increased in Cav-1 -/- MSFs. To establish a direct cause-effect relationship, we next generated immortalized human fibroblast lines stably overexpressing either PAI-1 or PAI-2. Importantly, PAI-1/2(+) fibroblasts promote the growth of MDA-MB-231 tumors (a human breast cancer cell line) in a murine xenograft model, without any increases in angiogenesis. Similarly, PAI-1/2(+) fibroblasts stimulate experimental metastasis of MDA-MB-231 cells using an in vivo lung colonization assay. Further mechanistic studies revealed that fibroblasts overexpressing PAI-1 or PAI-2 display increased autophagy ("self-eating") and are sufficient to induce mitochondrial biogenesis/activity in adjacent cancer cells, in co-culture experiments. In xenografts, PAI-1/2(+) fibroblasts significantly reduce the apoptosis of MDA-MB-231 tumor cells. The current study provides further support for the "Autophagic Tumor Stroma Model of Cancer" and identifies a novel "extracellular matrix"-based signaling mechanism, by which a loss of stromal Cav-1 generates a metastatic phenotype. Thus, the secretion and remodeling of extracellular matrix components (such as PAI-1/2) can directly regulate both (1) autophagy in stromal fibroblasts and (2) epithelial tumor cell mitochondrial metabolism.
Bibliographie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:1538-4101
1551-4005
1551-4005
DOI:10.4161/cc.10.12.16002