title: IL6/JAK1/STAT3 Signaling Blockade in Endometrial Cancer Affects the ALDHhi/CD126+ Stem-like Component and Reduces Tumor Burden.
abstract: Cancer stem-like cells (CSC) may be critical to maintain the malignant behavior of solid and hematopoietic cancers. Recently, patients with endometrial cancer whose tumors expressed high levels of aldehyde dehydrogenase (ALDH), a detoxifying enzyme characteristic of many progenitor and stem cells, exhibited a relative reduction in survival compared with patients with low levels of ALDH. Given evidence of its role as a CSC marker, we hypothesized that high level of ALDH activity (ALDH(hi)) in a tumor might positively correlate with the presence of stem- and progenitor-like tumor cells in this disease setting. In support of this hypothesis, ALDH could be used to enrich for CSC in endometrial cancer cell lines and primary tumors, as illustrated by the increased tumor-initiating capacity of ALDH(hi) cells in immunodeficient mice. ALDH(hi) cells also exhibited greater clonogenic and organoid-forming capacity compared with ALDH(lo) cells. Notably, the number of ALDH(hi) cells in tumor cell lines and primary tumors inversely correlated with differentiation grade. Expression analysis revealed upregulation of IL6 receptor subunits and signal transducers CD126 and GP130 in ALDH(hi) endometrial cancer cells. Accordingly, targeted inhibition of the IL6 receptor and its downstream effectors JAK1 and STAT3 dramatically reduced tumor cell growth. Overall, our results provide a preclinical rationale to target IL6 or its effector functions as a novel therapeutic option in endometrial cancer.
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands. Department of Obstetrics and Gynaecology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Marten
authors.initials: M
authors.lastname: van der Zee
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Sacchetti
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Medine
authors.initials: M
authors.lastname: Cansoy
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Joosten
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Teeuwssen
authors.affiliation: Department of Obstetrics and Gynaecology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Claudia
authors.initials: C
authors.lastname: Heijmans-Antonissen
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Patricia C
authors.initials: PC
authors.lastname: Ewing-Graham
authors.affiliation: Department of Obstetrics and Gynaecology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Curt W
authors.initials: CW
authors.lastname: Burger
authors.affiliation: Department of Obstetrics and Gynaecology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands.
authors.forename: Leen J
authors.initials: LJ
authors.lastname: Blok
authors.affiliation: Department of Pathology, Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands. r.fodde@erasmusmc.nl.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Fodde
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000008:administration & dosage; D016889:Endometrial Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis* / Q000235:genetics; D053613:Janus Kinase 1 / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D019947:Receptors, Interleukin-6 / Q000037:antagonists & inhibitors; D050796:STAT3 Transcription Factor / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D047368:Tumor Burden / Q000235:genetics
chemical_list: C508600:IL6 protein, human; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000444:Aldehyde Dehydrogenase; C507904:JAK1 protein, human; D053613:Janus Kinase 1; D002945:Cisplatin