title: Hypoxia after liver surgery imposes an aggressive cancer stem cell phenotype on residual tumor cells.
abstract: OBJECTIVE
  To assess the contribution of hypoxia and bone marrow-derived cells to aggressive outgrowth of micrometastases after liver surgery.
  
  
  BACKGROUND
  Liver surgery generates a microenvironment that fosters aggressive tumor recurrence. These areas are characterized by chronic hypoxia and influx of bone marrow-derived cells.
  
  
  METHODS
  The contribution of hematopoietic cell types was studied in mice lacking specific components of the immune system and in irradiated mice lacking all bone marrow-derived cells. Tumor cells were derived from colorectal cancer patients and from a metastatic tumor cell line. Hypoxia-induced changes in stem cell and differentiation marker expression, clone-forming potential, and metastatic capacity were assessed. The effect of vascular clamping on cancer stem cell (CSC) characteristics was performed in mice bearing patient-derived liver metastases.
  
  
  RESULTS
  Immune cells and bone marrow-derived cells were not required for aggressive outgrowth of micrometastases in livers treated with surgery. Rather, hypoxia was sufficient to promote invasion and accelerate metastatic outgrowth. This was associated with a rapid loss of differentiation markers and increased expression of CSC markers and clone-forming capacity. Likewise, metastases residing in ischemia-reperfusion-injured liver lobes acquired CSC characteristics. Despite their renowned general resistance to chemotherapy, clone-forming CSCs were readily killed by the hypoxia-activated prodrug tirapazamine.
  
  
  CONCLUSIONS
  Surgery-generated hypoxia in the liver causes rapid dedifferentiation of tumor cells into immature CSCs with high clone- and metastasis-forming capacity. The results help explain the phenomenon of aggressive local tumor recurrence after liver surgery and offer a potential strategy to kill aggressive CSCs by hypoxia-activated prodrugs.
authors.affiliation: From the Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Klaas M
authors.initials: KM
authors.lastname: Govaert
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Emmink
authors.forename: Maarten W
authors.initials: MW
authors.lastname: Nijkamp
authors.forename: Zing J
authors.initials: ZJ
authors.lastname: Cheung
authors.forename: Ernst J A
authors.initials: EJ
authors.lastname: Steller
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Fatrai
authors.forename: Menno T
authors.initials: MT
authors.lastname: de Bruijn
authors.forename: Onno
authors.initials: O
authors.lastname: Kranenburg
authors.forename: Inne H M
authors.initials: IH
authors.lastname: Borel Rinkes
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000378:metabolism; D015153:Blotting, Western; D017115:Catheter Ablation; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000473:pathology*; D005434:Flow Cytometry; D006412:Hematopoietic Stem Cells / Q000473:pathology; D006498:Hepatectomy / Q000379:methods; D006801:Humans; D000860:Hypoxia / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D008114:Liver Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000556:secondary* / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000473:pathology; D061206:Neoplasm Micrometastasis / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000378:metabolism / Q000473:pathology*; D018365:Neoplasm, Residual / Q000378:metabolism / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011183:Postoperative Complications / Q000378:metabolism / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D015427:Reperfusion Injury / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D000077704:Tirapazamine; D014227:Triazines / Q000627:therapeutic use
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D014227:Triazines; D000077704:Tirapazamine