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ucin1314301864.pdf (3.83 MB)
ETD Abstract Container
Abstract Header
Regulation of cancer stem cell activity and epithelial mesenchymal transition by Rac1 in Human lung adenocarcinoma cells
Author Info
Akunuru, Shailaja
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314301864
Abstract Details
Year and Degree
2011, PhD, University of Cincinnati, Medicine: Molecular and Developmental Biology.
Abstract
The cancer stem cell (CSC) theory predicts that a small fraction of cancer cells possesses unique self-renewal, expansion and differentiation activities in tumorigenesis. While this theory remains controversial in solid tumor studies, the enriched cancer stem cell population has been characterized by drug-resistant side population (SP), CD133pos, ALDHhigh and several other markers in many solid tumors. Using human lung cancer cell lines (A549 and H441) and primary human non-small cell lung adenocarcinoma (NSCLA) cells, we demonstrated that SP cells isolated from NSCLAs have significantly increased migration, invasion and metastatic activities compared to non-SP cells. We show that Rac1, a member of Rho-GTPases, is a critical mediator of the NSCLA SP CSC activity, by regulating SP cell adhesion, migration, invasion, and lung colonization activities. We further established that NSCLAs SP cells represent a distinct population from phenotypic CSC populations marked by CD133pos, ALDHhigh, or CD24lowCD44high, with each displaying enriched CSC activity demonstrated by expression of self-renewal genes and tumor-initiating activity in xenografted mice. Non-CSCs and CSCs defined by either absence or presence of single CSC marker respectively (SP, ALDHhigh, CD133pos, and CD24lowCD44high) are plastic and dynamic, with a distinct inter-conversion kinetics. Epithelial-mesenchymal transition (EMT) previously proposed as one of the underlying mechanisms of CSC plasticity, abolishes NSCLAs SP cells while increasing other CSC markers such as ALDHhigh, CD133pos and CD24lowCD44high. Rac1 activity was significantly increased in cells that have undergone EMT. Inhibition of Rac1 activity by NSC23766, a Rac1 inhibitor, or Rac1 knockdown, partially blocks EMT process and suppresses EMT induced phenotypic non-CSC to CSC conversion. Thus, we propose that there exist multiple, phenotypically distinct cancer cell subpopulations with CSC properties in NSCLA cells and phenotypic non-CSCs and CSCs can be dynamically regulated through EMT. Importantly, targeting Rac1 GTPase that is intimately involved in EMT process may represent a novel strategy in inhibiting CSC activity and suppressing non-CSC to CSC transition.
Committee
Yi Zheng, PhD (Committee Chair)
Leighton Grimes, PhD (Committee Member)
Jose Cancelas-Perez, MD (Committee Member)
Tim Cripe, MDPhD (Committee Member)
Jeffrey Whitsett, MD (Committee Member)
Pages
115 p.
Subject Headings
Cellular Biology
Keywords
Cancer stem cells
;
EMT
;
Rac1
;
Metastasis
;
Lung cancer
;
NSCLA
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Refworks
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Citations
Akunuru, S. (2011).
Regulation of cancer stem cell activity and epithelial mesenchymal transition by Rac1 in Human lung adenocarcinoma cells
[Doctoral dissertation, University of Cincinnati]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314301864
APA Style (7th edition)
Akunuru, Shailaja.
Regulation of cancer stem cell activity and epithelial mesenchymal transition by Rac1 in Human lung adenocarcinoma cells.
2011. University of Cincinnati, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314301864.
MLA Style (8th edition)
Akunuru, Shailaja. "Regulation of cancer stem cell activity and epithelial mesenchymal transition by Rac1 in Human lung adenocarcinoma cells." Doctoral dissertation, University of Cincinnati, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1314301864
Chicago Manual of Style (17th edition)
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Document number:
ucin1314301864
Download Count:
509
Copyright Info
© 2011, all rights reserved.
This open access ETD is published by University of Cincinnati and OhioLINK.