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PMID: 24938788 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Hypoxia-inducible factors and RAB22A mediate formation of microvesicles that stimulate breast cancer invasion and metastasis.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 111 ·No. 31 ·2014-08-05 ·Pages E3234-42

Wang T, Gilkes DM, Takano N, Xiang L, Luo W, Bishop CJ, Chaturvedi P, Green JJ, Semenza GL

Abstract

Extracellular vesicles such as exosomes and microvesicles (MVs) are shed by cancer cells, are detected in the plasma of cancer patients, and promote cancer progression, but the molecular mechanisms regulating their production are not well understood. Intratumoral hypoxia is common in advanced breast cancers and is associated with an increased risk of metastasis and patient mortality that is mediated in part by the activation of hypoxia-inducible factors (HIFs). In this paper, we report that exposure of human breast cancer cells to hypoxia augments MV shedding that is mediated by the HIF-dependent expression of the small GTPase RAB22A, which colocalizes with budding MVs at the cell surface. Incubation of naïve breast cancer cells with MVs shed by hypoxic breast cancer cells promotes focal adhesion formation, invasion, and metastasis. In breast cancer patients, RAB22A mRNA overexpression in the primary tumor is associated with decreased overall and metastasis-free survival and, in an orthotopic mouse model, RAB22A knockdown impairs breast cancer metastasis.

Keywords
mammary fat pad implantation orthotopic transplantation oxygen triple negative breast cancer tumor microenvironment
MeSH Terms
Animals Basic Helix-Loop-Helix Transcription Factors/metabolism Breast Neoplasms/genetics,metabolism,pathology Cell Hypoxia/genetics Cell Line, Tumor Exosomes/metabolism Extracellular Matrix/metabolism Female Focal Adhesions/metabolism Gene Expression Regulation, Neoplastic Gene Knockdown Techniques Humans Hypoxia-Inducible Factor 1, alpha Subunit/metabolism Lung Neoplasms/pathology,secondary Mice Mice, SCID Neoplasm Invasiveness Neoplasm Metastasis Protein Transport RNA, Messenger/genetics,metabolism Survival Analysis rab GTP-Binding Proteins/deficiency,genetics,metabolism
Chemicals
Basic Helix-Loop-Helix Transcription Factors HIF1A protein, human Hypoxia-Inducible Factor 1, alpha Subunit RAB22A protein, human RNA, Messenger endothelial PAS domain-containing protein 1 rab GTP-Binding Proteins
Authors & Affiliations
9 authors, click to expand affiliations / ORCID
Wang Ting
Department of Hematology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China; andVascular Program, Institute for Cell Engineering.
Gilkes Daniele M
Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and Departments of.
Takano Naoharu
Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and Departments of.
Xiang Lisha
Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and Departments of.
Luo Weibo
Vascular Program, Institute for Cell Engineering,Biological Chemistry.
Bishop Corey J
Biomedical Engineering.
Chaturvedi Pallavi
Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and Departments of.
Green Jordan J
Biomedical Engineering.
Semenza Gregg L
Vascular Program, Institute for Cell Engineering,McKusick-Nathans Institute of Genetic Medicine, and Departments ofBiological Chemistry,Oncology,Pediatrics,Medicine, andRadiation Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205 gsemenza@jhmi.edu.
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
1091-6490
DOI
10.1073/pnas.1410041111
Email
gsemenza@jhmi.edu
Published
2014-08-05
Epub
2014-00-17
Pages
E3234-42
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC4128139
Subset
IM
Grants
NCI NIH HHS · U54 CA143868 · United States
NCI NIH HHS · R00 CA168746 · United States
NCI NIH HHS · K99 CA181352 · United States
NCI NIH HHS · K99 CA168746 · United States
NIBIB NIH HHS · R01 EB016721 · United States
NCI NIH HHS · K99-CA168746 · United States
NCI NIH HHS · U54-CA143868 · United States
NIBIB NIH HHS · R01-EB016721 · United States
Corrections
CommentIn
PMID: 25053807
External Links
PubMed source DOI: 10.1073/pnas.1410041111 PMC Full Text View journal details
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