The Metastatic Potential and Chemoresistance of Human Pancreatic Cancer Stem Cells

Vikash J. Bhagwandin, J. Michael Bishop, Woodring E. Wright, Jerry W. Shay

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

Cancer stem cells (CSCs) typically have the capacity to evade chemotherapy and may be the principal source of metastases. CSCs for human pancreatic ductal carcinoma (PDAC) have been identified, but neither the metastatic potential nor the chemoresistance of these cells has been adequately evaluated.We have addressed these issues by examining sidepopulation (SP) cells isolated from the Panc-1 and BxPC3 lines of human PDAC cells, the oncogenotypes of which differ. SP cells could be isolated from monolayers of Panc-1, but only from spheroids of BxPC3. Using orthotopic xenografts into the severely immunocompromised NSG mouse, we found that SP cells isolated from both cell lines produced tumors that were highly metastatic, in contrast to previous experience with PDAC cell lines. SP cells derived from both cell lines expressed the ABCG2 transporter, which was demonstrably responsible for the SP phenotype. SP cells gave rise to non-SP (NSP) cells in vitro and in vivo, a transition that was apparently due to posttranslational inhibition of the ABCG2 transporter. Twenty-two other lines of PDAC cells also expressed ABCG2. The sensitivity of PDAC SP cells to the vinca alkaloid vincristine could be greatly increased by verapamil, a general inhibitor of transporters. In contrast, verapamil had no effect on the killing of PDAC cells by gemcitabine, the current first-line therapeutic for PDAC. We conclude that the isolation of SP cells can be a convenient and effective tool for the study of PDAC CSCs; that CSCs may be the principal progenitors of metastasis by human PDAC; that the ABCG2 transporter is responsible for the SP phenotype in human PDAC cells, and may be a ubiquitous source of drug-resistance in PDAC, but does not confer resistance to gemcitabine; and that inhibition of ABCG2 might offer a useful adjunct in a therapeutic attack on the CSCs of PDAC.

Original languageEnglish (US)
Article numbere0148807
JournalPLoS One
Volume11
Issue number2
DOIs
StatePublished - Feb 1 2016

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Pancreatic Ductal Carcinoma
pancreatic neoplasms
Neoplastic Stem Cells
Stem cells
Pancreatic Neoplasms
stem cells
carcinoma
gemcitabine
Cells
Verapamil
cells
Vinca Alkaloids
transporters
Chemotherapy
Vincristine
Heterografts
verapamil
Tumors
cell lines
Monolayers

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

The Metastatic Potential and Chemoresistance of Human Pancreatic Cancer Stem Cells. / Bhagwandin, Vikash J.; Bishop, J. Michael; Wright, Woodring E.; Shay, Jerry W.

In: PLoS One, Vol. 11, No. 2, e0148807, 01.02.2016.

Research output: Contribution to journalArticle

Bhagwandin, Vikash J. ; Bishop, J. Michael ; Wright, Woodring E. ; Shay, Jerry W. / The Metastatic Potential and Chemoresistance of Human Pancreatic Cancer Stem Cells. In: PLoS One. 2016 ; Vol. 11, No. 2.
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