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Anti-proliferative but not anti-angiogenic tyrosine kinase inhibitors enrich for cancer stem cells in soft tissue sarcoma

Authors
  • Canter, Robert J1
  • Ames, Erik2
  • Mac, Stephanie2
  • Grossenbacher, Steven K2
  • Chen, Mingyi3
  • Li, Chin-Shang4
  • Borys, Dariusz3
  • Smith, Rachel C2
  • Tellez, Joe2
  • Sayers, Thomas J5
  • Monjazeb, Arta M6
  • Murphy, William J7
  • 1 University of California Davis Medical Center, Department of Surgery, Division of Surgical Oncology, 4501 X Street, Sacramento, CA, 95817, USA , Sacramento (United States)
  • 2 University of California Davis Medical Center, Laboratory of Cancer Immunology, Department of Dermatology, Sacramento, CA, 95817, USA , Sacramento (United States)
  • 3 University of California Davis Medical Center, Department of Pathology and Laboratory Medicine, Sacramento, CA, 95817, USA , Sacramento (United States)
  • 4 University of California Davis, Division of Biostatistics, Department of Public Health Sciences, Sacramento, CA, 95817, USA , Sacramento (United States)
  • 5 Leidos Biomedical Research, Inc, Frederick National Laboratory, Cancer and Inflammation Program, Frederick, Maryland, 21702, USA , Frederick (United States)
  • 6 University of California Davis Medical Center, Department of Radiation Oncology, Sacramento, CA, 95817, USA , Sacramento (United States)
  • 7 University of California Davis Medical Center, Department of Dermatology, Sacramento, CA, 95817, USA , Sacramento (United States)
Type
Published Article
Journal
BMC Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Oct 10, 2014
Volume
14
Issue
1
Identifiers
DOI: 10.1186/1471-2407-14-756
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundIncreasing studies implicate cancer stem cells (CSCs) as the source of resistance and relapse following conventional cytotoxic therapies. Few studies have examined the response of CSCs to targeted therapies, such as tyrosine kinase inhibitors (TKIs). We hypothesized that TKIs would have differential effects on CSC populations depending on their mechanism of action (anti-proliferative vs. anti-angiogenic).MethodsWe exposed human sarcoma cell lines to sorafenib, regorafenib, and pazopanib and assessed cell viability and expression of CSC markers (ALDH, CD24, CD44, and CD133). We evaluated survival and CSC phenotype in mice harboring sarcoma metastases after TKI therapy. We exposed dissociated primary sarcoma tumors to sorafenib, regorafenib, and pazopanib, and we used tissue microarray (TMA) and primary sarcoma samples to evaluate the frequency and intensity of CSC markers after neoadjuvant therapy with sorafenib and pazopanib. Parametric and non-parametric statistical analyses were performed as appropriate.ResultsAfter functionally validating the CSC phenotype of ALDHbright sarcoma cells, we observed that sorafenib and regorafenib were cytotoxic to sarcoma cell lines (P < 0.05), with a corresponding 1.4 – 2.8 fold increase in ALDHbright cells from baseline (P < 0.05). In contrast, we observed negligible effects on viability and CSC sub-populations with pazopanib. At low doses, there was progressive CSC enrichment in vitro after longer term exposure to sorafenib although the anti-proliferative effects were attenuated. In vivo, sorafenib improved median survival by 11 days (P < 0.05), but enriched ALDHbright cells 2.5 – 2.8 fold (P < 0.05). Analysis of primary human sarcoma samples revealed direct cytotoxicity following exposure to sorafenib and regorafenib with a corresponding increase in ALDHbright cells (P < 0.05). Again, negligible effects from pazopanib were observed. TMA analysis of archived specimens from sarcoma patients treated with sorafenib demonstrated significant enrichment for ALDHbright cells in the post-treatment resection specimen (P < 0.05), whereas clinical specimens obtained longitudinally from a patient treated with pazopanib showed no enrichment for ALDHbright cells (P > 0.05).ConclusionsAnti-proliferative TKIs appear to enrich for sarcoma CSCs while anti-angiogenic TKIs do not. The rational selection of targeted therapies for sarcoma patients may benefit from an awareness of the differential impact of TKIs on CSC populations.

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