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PMID: 22264789 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway.

Cancer cell ·Vol. 21 ·No. 1 ·2012-01-17 ·Pages 66-81

Cooke VG, LeBleu VS, Keskin D, Khan Z, O'Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S, Sugimoto H, Rocha RM, Damascena A, Brentani RR, Kalluri R

Abstract

The functional role of pericytes in cancer progression remains unknown. Clinical studies suggest that low numbers of vessel-associated pericytes correlated with a drop in overall survival of patients with invasive breast cancer. Using genetic mouse models or pharmacological inhibitors, pericyte depletion suppressed tumor growth but enhanced metastasis. Pericyte depletion was further associated with increased hypoxia, epithelial-to-mesenchymal transition (EMT), and Met receptor activation. Silencing of Twist or use of a Met inhibitor suppressed hypoxia and EMT/Met-driven metastasis. In addition, poor pericyte coverage coupled with high Met expression in cancer cells speculates the worst prognosis for patients with invasive breast cancer. Collectively, our study suggests that pericytes within the primary tumor microenvironment likely serve as important gatekeepers against cancer progression and metastasis.

MeSH Terms
Animals Antineoplastic Agents/pharmacology Benzamides Benzenesulfonates/pharmacology Breast Neoplasms/pathology Cell Hypoxia Cell Line, Tumor Crizotinib Epithelial-Mesenchymal Transition Female Humans Hypoxia-Inducible Factor 1, alpha Subunit/metabolism,physiology Imatinib Mesylate Indoles/pharmacology Mice Mice, Inbred BALB C Mice, Inbred C57BL Mice, Transgenic Neoplasm Metastasis Niacinamide/analogs & derivatives Pericytes/pathology,physiology Phenylurea Compounds Piperazines/pharmacology Piperidines/pharmacology Protein Kinase Inhibitors/pharmacology Proto-Oncogene Proteins c-met/antagonists & inhibitors,metabolism,physiology Pyrazoles Pyridines/pharmacology Pyrimidines/pharmacology Pyrroles/pharmacology Signal Transduction Sorafenib Sunitinib Tumor Cells, Cultured
Chemicals
Antineoplastic Agents Benzamides Benzenesulfonates Hif1a protein, mouse Hypoxia-Inducible Factor 1, alpha Subunit Indoles Phenylurea Compounds Piperazines Piperidines Protein Kinase Inhibitors Pyrazoles Pyridines Pyrimidines Pyrroles Niacinamide Crizotinib Imatinib Mesylate Sorafenib Proto-Oncogene Proteins c-met Sunitinib
Authors & Affiliations
15 authors, click to expand affiliations / ORCID
Cooke Vesselina G
Division of Matrix Biology, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA.
LeBleu Valerie S
Keskin Doruk
Khan Zainab
O'Connell Joyce T
Teng Yingqi
Duncan Michael B
Xie Liang
Maeda Genta
Vong Sylvia
Sugimoto Hikaru
Rocha Rafael M
Damascena Aline
Brentani Ricardo R
Kalluri Raghu
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Article Info
Journal
Cancer cell
Abbr.
Cancer Cell
ISSN
1878-3686
DOI
10.1016/j.ccr.2011.11.024
Published
2012-01-17
Pages
66-81
Language
English
Region
United States
NLM ID
101130617
PMCID
PMC3999522
Subset
IM
Grants
NIDDK NIH HHS · 5F32DK082119-02 · United States
NIDDK NIH HHS · DK55001 · United States
NCI NIH HHS · U01 CA151925 · United States
NCI NIH HHS · CA163191 · United States
NCI NIH HHS · CA151925 · United States
NIDDK NIH HHS · R01 DK081576 · United States
NCI NIH HHS · CA155370 · United States
NCI NIH HHS · T32 CA081156 · United States
NIDDK NIH HHS · T32 DK007760 · United States
NIDDK NIH HHS · 2T32DK007760-11 · United States
NCI NIH HHS · R01 CA125550 · United States
NCI NIH HHS · 5T32CA081156-08 · United States
NCI NIH HHS · CA125550 · United States
NIDDK NIH HHS · R01 DK055001 · United States
NHLBI NIH HHS · T32 HL007374 · United States
NCI NIH HHS · R01 CA155370 · United States
NIDDK NIH HHS · DK81576 · United States
NIDDK NIH HHS · F32 DK082119 · United States
NHLBI NIH HHS · 5T32HL007374-30 · United States
Corrections
CommentIn
PMID: 22298191
External Links
PubMed source DOI: 10.1016/j.ccr.2011.11.024 PMC Full Text View journal details
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