Linked Life Data

21646868

Source:http://linkedlifedata.com/resource/pubmed/id/21646868

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
12
pubmed:dateCreated
2011-6-30
pubmed:abstractText
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.
pubmed:grant
pubmed:commentsCorrections
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Jun
pubmed:issn
1551-4005
pubmed:author
pubmed:issnType
Electronic
pubmed:day
15
pubmed:volume
10
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
2021-34
pubmed:dateRevised
2011-11-4
pubmed:meshHeading
pubmed-meshheading:21646868-Animals, pubmed-meshheading:21646868-Autophagy, pubmed-meshheading:21646868-Breast Neoplasms, pubmed-meshheading:21646868-Caveolin 1, pubmed-meshheading:21646868-Cell Line, Tumor, pubmed-meshheading:21646868-Coculture Techniques, pubmed-meshheading:21646868-Extracellular Matrix, pubmed-meshheading:21646868-Fibroblasts, pubmed-meshheading:21646868-Humans, pubmed-meshheading:21646868-Mice, pubmed-meshheading:21646868-Mitochondria, pubmed-meshheading:21646868-Neoplasm Metastasis, pubmed-meshheading:21646868-Neoplasms, pubmed-meshheading:21646868-Plasminogen Activator Inhibitor 1, pubmed-meshheading:21646868-Plasminogen Activator Inhibitor 2, pubmed-meshheading:21646868-Stromal Cells, pubmed-meshheading:21646868-Transplantation, Heterologous, pubmed-meshheading:21646868-Tumor Microenvironment
pubmed:year
2011
pubmed:articleTitle
Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis.
pubmed:affiliation
The Jefferson Stem Cell Biology and Regenerative Medicine Center, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA, USA. remedios.castello@jefferson.edu
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't, Research Support, N.I.H., Extramural