TY - JOUR
T1 - Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis
AU - Castello-Cros, Remedios
AU - Bonuccelli, Gloria
AU - Molchansky, Alex
AU - Capozza, Franco
AU - Witkiewicz, Agnieszka K.
AU - Birbe, Ruth C.
AU - Howell, Anthony
AU - Pestell, Richard G.
AU - Whitaker-Menezes, Diana
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. and F.S.). The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. This work was also supported, in part, by a Centre grant in Manchester from Breakthrough Breast Cancer in the UK (to A.H.) and an Advanced ERC Grant from the European Research Council.
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.). R.G.P. was supported by grants from the NIH/NCI (R01-CA-70896, R01-CA-75503, R01-CA-86072 and R01-CA-107382) and the Dr. Ralph and Marian C. Falk Medical Research Trust. The Kimmel Cancer Center was supported by the NIH/NCI Cancer Center Core grant P30-CA-56036 (to R.G.P.).
PY - 2011/6/15
Y1 - 2011/6/15
N2 - 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 micro-environment 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 reveal 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.
AB - 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 micro-environment 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 reveal 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.
KW - Apoptosis
KW - Autophagy
KW - Breast cancer
KW - Cancer-associated fibroblasts
KW - Caveolin-1
KW - Metastasis
KW - Plasminogen activator inhibitor
KW - Tumor stroma
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UR - http://www.scopus.com/inward/citedby.url?scp=79959282414&partnerID=8YFLogxK
U2 - 10.4161/cc.10.12.16002
DO - 10.4161/cc.10.12.16002
M3 - Article
C2 - 21646868
AN - SCOPUS:79959282414
SN - 1538-4101
VL - 10
SP - 2021
EP - 2034
JO - Cell Cycle
JF - Cell Cycle
IS - 12
ER -