Tissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells.

TitleTissue Stiffness and Hypoxia Modulate the Integrin-Linked Kinase ILK to Control Breast Cancer Stem-like Cells.
Publication TypeJournal Article
Year of Publication2016
AuthorsPang, M-F, Siedlik, MJ, Han, S, Stallings-Mann, M, Radisky, DC, Nelson, CM
JournalCancer Res
Volume76
Issue18
Pagination5277-87
Date Published2016 09 15
ISSN1538-7445
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.

DOI10.1158/0008-5472.CAN-16-0579
Alternate JournalCancer Res.
PubMed ID27503933
PubMed Central IDPMC5026611
Grant ListR01 CA187692 / CA / NCI NIH HHS / United States
R01 GM083997 / GM / NIGMS NIH HHS / United States
R01 HL120142 / HL / NHLBI NIH HHS / United States
R21 HL110335 / HL / NHLBI NIH HHS / United States
R21 HL118532 / HL / NHLBI NIH HHS / United States