Endothelin receptor-A is required for the recruitment of antitumor T cells and modulates chemotherapy induction of cancer stem cells

Lan Coffman, Collin Mooney, Jaeyoung Lim, Shoumei Bai, Ines Silva, Yusong Gong, Kun Yang, Ronald J. Buckanovich

Research output: Contribution to journalArticlepeer-review

Abstract

Background: The endothelin receptor-A (ETRA) plays an important role in tumor cell migration, metastasis, and proliferation. The endothelin receptor B (ETRB) plays a critical role in angiogenesis and the inhibition of antitumor immune cell recruitment. Thus dual blockade of ETRA and ETRB could have significant antitumor effects. Results: Dual ETRA/ETRB blockade with macitentan (or the combination of the ETRA and ETRB antagonists BQ123 and BQ788) did not enhance antitumor immune cell recruitment. In vitro studies demonstrate that ETRA inhibition prevents the induction of ICAM1 necessary for immune cell recruitment. When used as a single agent against human tumor xenografts, macitentan demonstrated non-significant antitumor activity. However, when used in combination with chemotherapy, macitentan specifically reduced tumor growth in cell lines with CD133+ cancer stem cells. We found that ETRA is primarily expressed on CD133+ CSC in both cell lines and primary human tumor cells. ETRA inhibition of CSC prevented chemotherapy induced increases in tumor stem cells. Furthermore, ETRA inhibition in combination with chemotherapy reduced the formation of tumor spheres. Methods: We tested the dual ETRA/ETRB antagonist macitentan in conjunction with (1) an antitumor vaccine and (2) chemotherapy, in order to assess the impact of dual ETRA/ETRB blockade on antitumor immune cell infiltration and ovarian tumor growth. In vitro murine and human cell line, tumor sphere assays and tumor xenograft models were utilized to evaluate the effect of ETRA/ETRB blockade on cell proliferation, immune cell infiltration and cancer stem cell populations. Conclusions: These studies indicate a critical role for ETRA in the regulation of immune cell recruitment and in the CSC resistance to chemotherapy.

Original languageEnglish (US)
Pages (from-to)184-192
Number of pages9
JournalCancer Biology and Therapy
Volume14
Issue number2
DOIs
StatePublished - Feb 2013

Keywords

  • ETRA
  • ETRB
  • Macitentan
  • Ovarian cancer

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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