title: Endothelin receptor-A is required for the recruitment of antitumor T cells and modulates chemotherapy induction of cancer stem cells.
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 anti-tumor immune cell recruitment. Thus dual blockade of ETRA and ETRB could have significant anti-tumor 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 anti-tumor 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 anti-tumor vaccine and (2) chemotherapy, in order to assess the impact of dual ETRA/ETRB blockade on anti-tumor 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.
authors.affiliation: Department of Internal Medicine, Division of Hematology Oncology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Lan
authors.initials: L
authors.lastname: Coffman
authors.forename: Collin
authors.initials: C
authors.lastname: Mooney
authors.forename: Jaeyoung
authors.initials: J
authors.lastname: Lim
authors.forename: Shoumei
authors.initials: S
authors.lastname: Bai
authors.forename: Ines
authors.initials: I
authors.lastname: Silva
authors.forename: Yusong
authors.initials: Y
authors.lastname: Gong
authors.forename: Kun
authors.initials: K
authors.lastname: Yang
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Buckanovich
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000633:toxicity; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000401:mortality; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000401:mortality; D010455:Peptides / Q000378:metabolism; D044022:Receptor, Endothelin A / Q000235:genetics / Q000378:metabolism*; D044023:Receptor, Endothelin B / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology*; D014183:Transplantation, Heterologous
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D018799:Intercellular Adhesion Molecule-1