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Spheroid-enriched cancer stem-like cells as a model for targeted therapy in oral cancer with distal 11Q loss

Kaseb, Hatem (2016) Spheroid-enriched cancer stem-like cells as a model for targeted therapy in oral cancer with distal 11Q loss. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Oral squamous cell carcinoma (OSCC) has a poor prognosis due to multiple factors including local recurrence, distant metastasis and therapeutic resistance. Our laboratory has demonstrated that the ATR-CHEK1 pathway is a critical modulator of radioresistance in OSCC; we evaluated the effectiveness of targeted CHEK1 inhibition in OSCC cancer stem-like cells (CSLC). To this end, we analyzed CSLC properties and the effect of ionizing radiation (IR) and CHEK1 inhibition on CSLCs isolated from OSCC (parental) cell lines with and without distal 11q loss. The CSLCs, propagated in enriched serum-free medium, demonstrated stem-cell like characteristics including asymmetrical and symmetrical cell division, self-renewal, re-differentiation, colony forming capacity at extreme (limiting) dilutions, and radioresistance.
CHEK1 inhibitors affected the functional CSLC properties, resulting in significant reduction in proliferation, survival, colony initiation, growth, migration. The most drastically affected CSLC property was extracellular matrix migration. As determined by dose-response curves, a drug level ≈100-fold higher than the dose that was effective on parental OSCC cell lines was required to inhibit CSLC migration.
Overall, our results suggest that distal 11q loss may predict radioresistance in CSLC; however, the CSLC response to IR-CHEK1 inhibition is not distal 11q loss-driven. CHEK1 inhibitors increase the radiosensitivity of oral CSLC as they do for OSCC cell lines. Thus, we propose that CHEK1 inhibition may be a useful adjuvant therapy for advanced and/or metastatic OSCC.
PUBLIC HEALTH SIGNIFICANCE: Our results increased the understanding of cancer stem-like cells in oral cancers and establish these cells as a contributing factor to radioresistance that could be potentially reversed in as many as 25% of cancers by CHEK1 inhibitors.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kaseb, Hatemhok9@pitt.eduHOK9
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGollin, Susannegollin@pitt.edu
Committee MemberUrban, Zsolturbanz@pitt.edu
Committee MemberLagasse, Ericlagasse@pitt.edu
Committee MemberParikh, Rahulparikhr@upmc.edu
Date: 29 June 2016
Date Type: Publication
Defense Date: 30 June 2015
Approval Date: 29 June 2016
Submission Date: 31 March 2016
Access Restriction: 3 year -- Restrict access to University of Pittsburgh for a period of 3 years.
Number of Pages: 180
Institution: University of Pittsburgh
Schools and Programs: School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Oral squamous cell carcinoma, cancer stem-like cells
Date Deposited: 29 Jun 2016 17:32
Last Modified: 01 May 2019 05:15
URI: http://d-scholarship.pitt.edu/id/eprint/27518

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