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Tissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells
- Source :
- Cancer Research. 76:5277-5287
- Publication Year :
- 2016
- Publisher :
- American Association for Cancer Research (AACR), 2016.
-
Abstract
- Breast tumors are stiffer and more hypoxic than nonmalignant breast tissue. Here we report that stiff and hypoxic microenvironments promote the development of breast cancer stem-like cells (CSC) through modulation of the integrin-linked kinase ILK. Depleting ILK blocked stiffness and hypoxia-dependent acquisition of CSC marker expression and behavior, whereas ectopic expression of ILK stimulated CSC development under softer or normoxic conditions. Stiff microenvironments also promoted tumor formation and metastasis in ovo, where depleting ILK significantly abrogated the tumorigenic and metastatic potential of invasive breast cancer cells. We further found that the ILK-mediated phenotypes induced by stiff and hypoxic microenvironments are regulated by PI3K/Akt. Analysis of human breast cancer specimens revealed an association between substratum stiffness, ILK, and CSC markers, insofar as ILK and CD44 were expressed in cancer cells located in tumor regions predicted to be stiff. Our results define ILK as a key mechanotransducer in modulating breast CSC development in response to tissue mechanics and oxygen tension. Cancer Res; 76(18); 5277–87. ©2016 AACR.
- Subjects :
- 0301 basic medicine
Cancer Research
Pathology
medicine.medical_specialty
animal structures
Immunoblotting
Breast Neoplasms
Protein Serine-Threonine Kinases
Real-Time Polymerase Chain Reaction
Time-Lapse Imaging
Article
Metastasis
Mice
03 medical and health sciences
Breast cancer
Cell Line, Tumor
Image Processing, Computer-Assisted
Tumor Microenvironment
medicine
Animals
Humans
Integrin-linked kinase
PI3K/AKT/mTOR pathway
Tumor microenvironment
biology
Chemistry
CD44
Flow Cytometry
medicine.disease
Cell Hypoxia
Oxygen tension
030104 developmental biology
Oncology
embryonic structures
Cancer cell
Neoplastic Stem Cells
biology.protein
Cancer research
Female
Subjects
Details
- ISSN :
- 15387445 and 00085472
- Volume :
- 76
- Database :
- OpenAIRE
- Journal :
- Cancer Research
- Accession number :
- edsair.doi.dedup.....401a375f79a9746d102f14d3ba560def