Original ResearchFull Report: Basic and Translational—LiverTumor-Associated Macrophages Produce Interleukin 6 and Signal via STAT3 to Promote Expansion of Human Hepatocellular Carcinoma Stem Cells
Section snippets
Human Subjects
HCC tissues were obtained from patients undergoing surgical resection as described.13 All patients provided written informed consent. The study was approved by and followed the University of Michigan Institutional Review Board guidelines.
Additional Methods can be found online in the Supplementary information.
HCC Cells Express Multiple Potential CSC Markers
Many cell surface markers have been described to define human HCC CSCs, including CD24, CD44, CD90, CD117, CD133, and epithelial cell adhesion molecule (EpCAM).15, 16, 17 To test whether these markers identify CSCs in a Western HCC patient cohort, surgically resected HCCs (n = 17 patients) (Supplementary Table 1) underwent single-cell suspension and flow cytometry by gating on 7-AAD-CD45- (excluding nonviable and immune cells), and were stained for putative CSC markers (Figure 1A and B). HCC
Discussion
In this study, we examined the CSC profile of a Western HCC patient cohort, patient xenografts, and cell lines and defined CD44 as an important marker of HCC CSCs. We show that HCC CSCs are expanded by patient TAMs. A significant correlation between TAMs and CD44+ HCC cells in patient tumors along with stemness-related gene expression was shown. This was supported by CSC subset expansion after HCC cell exposure to TAMs in vitro. IL6 secretion by TAMs accounts for this effect because IL6 was the
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Conflicts of interest The authors disclose no conflicts.
Funding Supported by National Institutes of Health grants CA151414 (T.H.W.), and 5P30CA46592-24 and CA152470 (W.Z.), and the GI SPORE Career Development Award (T.H.W.).
Author names in bold designate shared co-first authors.