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: Marten van der Zee, Andrea Sacchetti, Medine Cansoy, Rosalie Joosten, Miriam Teeuwssen, Claudia Heijmans-Antonissen, Patricia C Ewing-Graham, Curt W Burger, Leen J Blok, Riccardo Fodde
• Journal: Cancer research (Cancer Res) Vol. 75 Issue 17 Pg. 3608-22 (Sep 01 2015) ISSN: 1538-7445 [Electronic] United States
• PMID: 26130650 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• IL6 protein, human
• Interleukin-6
• Receptors, Interleukin-6
• STAT3 Transcription Factor
• STAT3 protein, human
• Aldehyde Dehydrogenase
• JAK1 protein, human
• Janus Kinase 1
• Cisplatin

Topics

• Aldehyde Dehydrogenase (biosynthesis, genetics)
• Animals
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (administration & dosage)
• Endometrial Neoplasms (drug therapy, genetics, pathology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Interleukin-6 (biosynthesis, genetics)
• Janus Kinase 1 (biosynthesis, genetics)
• Mice
• Neoplastic Stem Cells (drug effects, pathology)
• Receptors, Interleukin-6 (antagonists & inhibitors)
• STAT3 Transcription Factor (biosynthesis, genetics)
• Signal Transduction (drug effects)
• Tumor Burden (genetics)