Chemotherapy induces adaptive drug resistance and metastatic potentials via phenotypic CXCR4-expressing cell state transition in ovarian cancer. Academic Article uri icon

Overview

abstract

  • Ovarian cancer (OVC) patients who receive chemotherapy often acquire drug resistance within one year. This can lead to tumor reoccurrence and metastasis, the major causes of mortality. We report a transient increase of a small distinctive CXCR4High/CD24Low cancer stem cell population (CXCR4High) in A2780 and SKOV-3 OVC cell lines in response to cisplatin, doxorubicin, and paclitaxel, treatments. The withdrawal of the drug challenges reversed this cell-state transition. CXCR4High exhibits dormancy in drug resistance and mesenchymal-like invasion, migration, colonization, and tumor formation properties. The removal of this cell population from a doxorubicin-resistant A2780 lineage (A2780/ADR) recovered the sensitivity to drug treatments. A cytotoxic peptide (CXCR4-KLA) that can selectively target cell-surface CXCR4 receptor was further synthesized to investigate the therapeutic merits of targeting CXCR4High. This peptide was more potent than the conventional CXCR4 antagonists (AMD3100 and CTCE-9908) in eradicating the cancer stem cells. When used together with cytotoxic agents such as doxorubicin and cisplatin, the combined drug-peptide regimens exhibited a synergistic cell-killing effect on A2780, A2780/ADR, and SKOV-3. Our data suggested that chemotherapy could establish drug-resistant and tumor-initiating properties of OVC via reversible CXCR4 cell state transition. Therapeutic strategies designed to eradicate rather than antagonize CXCR4High might offer a far-reaching potential as supportive chemotherapy.

publication date

  • February 14, 2017

Research

keywords

  • Cytotoxins
  • Drug Resistance, Neoplasm
  • Neoplasm Proteins
  • Neoplastic Stem Cells
  • Ovarian Neoplasms
  • Peptides
  • Receptors, CXCR4

Identity

PubMed Central ID

  • PMC5308810

Scopus Document Identifier

  • 85012931517

Digital Object Identifier (DOI)

  • 10.1158/0008-5472.CAN-08-0364

PubMed ID

  • 28196146

Additional Document Info

volume

  • 12

issue

  • 2