• Annals of surgery · Apr 2014

    Hypoxia after liver surgery imposes an aggressive cancer stem cell phenotype on residual tumor cells.

    • Klaas M Govaert, Benjamin L Emmink, Maarten W Nijkamp, Zing J Cheung, Ernst J A Steller, Szabolcs Fatrai, Menno T de Bruijn, Onno Kranenburg, and Inne H M Borel Rinkes.
    • From the Department of Surgery, University Medical Center Utrecht, Utrecht, The Netherlands.
    • Ann. Surg.. 2014 Apr 1;259(4):750-9.

    ObjectiveTo assess the contribution of hypoxia and bone marrow-derived cells to aggressive outgrowth of micrometastases after liver surgery.BackgroundLiver surgery generates a microenvironment that fosters aggressive tumor recurrence. These areas are characterized by chronic hypoxia and influx of bone marrow-derived cells.MethodsThe 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.ResultsImmune 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.ConclusionsSurgery-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.

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