title: Hypoxia induces myeloid-derived suppressor cell recruitment to hepatocellular carcinoma through chemokine (C-C motif) ligand 26.
abstract: A population of stromal cells, myeloid-derived suppressor cells (MDSCs), is present in tumors. Though studies have gradually revealed the protumorigenic functions of MDSCs, the molecular mechanisms guiding MDSC recruitment remain largely elusive. Hypoxia, O2 deprivation, is an important factor in the tumor microenvironment of solid cancers, whose growth often exceeds the growth of functional blood vessels. Here, using hepatocellular carcinoma as the cancer model, we show that hypoxia is an important driver of MDSC recruitment. We observed that MDSCs preferentially infiltrate into hypoxic regions in human hepatocellular carcinoma tissues and that hypoxia-induced MDSC infiltration is dependent on hypoxia-inducible factors. We further found that hypoxia-inducible factors activate the transcription of chemokine (C-C motif) ligand 26 in cancer cells to recruit chemokine (C-X3-C motif) receptor 1-expressing MDSCs to the primary tumor. Knockdown of chemokine (C-C motif) ligand 26 in cancer cells profoundly reduces MDSC recruitment, angiogenesis, and tumor growth. Therapeutically, blockade of chemokine (C-C motif) ligand 26 production in cancer cells by the hypoxia-inducible factor inhibitor digoxin or blockade of chemokine (C-X3-C motif) receptor 1 in MDSCs by chemokine (C-X3-C motif) receptor 1 neutralizing antibody could substantially suppress MDSC recruitment and tumor growth.
  
  
  
  This study unprecedentedly reveals a novel molecular mechanism by which cancer cells direct MDSC homing to primary tumor and suggests that targeting MDSC recruitment represents an attractive therapeutic approach against solid cancers. (Hepatology 2016;64:797-813).
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: David Kung-Chun
authors.initials: DK
authors.lastname: Chiu
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Iris Ming-Jing
authors.initials: IM
authors.lastname: Xu
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Robin Kit-Ho
authors.initials: RK
authors.lastname: Lai
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Aki Pui-Wah
authors.initials: AP
authors.lastname: Tse
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Larry Lai
authors.initials: LL
authors.lastname: Wei
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Hui-Yu
authors.initials: HY
authors.lastname: Koh
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Lynna Lan
authors.initials: LL
authors.lastname: Li
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.
authors.forename: Derek
authors.initials: D
authors.lastname: Lee
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
authors.forename: Regina Cheuk-Lam
authors.initials: RC
authors.lastname: Lo
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
authors.forename: Chun-Ming
authors.initials: CM
authors.lastname: Wong
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
authors.forename: Irene Oi-Lin
authors.initials: IO
authors.lastname: Ng
authors.affiliation: Department of Pathology, The University of Hong Kong, Hong Kong.|State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong.
authors.forename: Carmen Chak-Lui
authors.initials: CC
authors.lastname: Wong
mesh_terms: D000818:Animals; D001483:Base Sequence; D000073883:CX3C Chemokine Receptor 1; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D000075906:Chemokine CCL26; D019742:Chemokines, CC / Q000378:metabolism*; D004077:Digoxin; D006801:Humans; D000860:Hypoxia / Q000378:metabolism*; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D008114:Liver Neoplasms, Experimental / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D008969:Molecular Sequence Data; D000072737:Myeloid-Derived Suppressor Cells / Q000502:physiology*; D009389:Neovascularization, Pathologic; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors; D059016:Tumor Microenvironment
chemical_list: C120429:CCL26 protein, human; D000073883:CX3C Chemokine Receptor 1; D000075906:Chemokine CCL26; D019742:Chemokines, CC; C471885:Cx3cr1 protein, mouse; D051793:Hypoxia-Inducible Factor 1; D019707:Receptors, Chemokine; D004077:Digoxin