Hypoxia after liver surgery imposes an aggressive cancer stem cell phenotype on residual tumor cells.
Ann Surg
; 259(4): 750-9, 2014 Apr.
Article
em En
| MEDLINE
| ID: mdl-24253142
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Complicações Pós-Operatórias
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Neoplasias Colorretais
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Neoplasia Residual
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Hepatectomia
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Neoplasias Hepáticas Experimentais
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Hipóxia
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Recidiva Local de Neoplasia
Tipo de estudo:
Etiology_studies
/
Evaluation_studies
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article