Abstract
Background
Hepatic pedicle clamping is often required to reduce blood loss and transfusion during
liver resection. However, the question remains whether use of hepatic pedicle clamping
promotes tumor growth. Endothelial progenitor cells (EPCs) are mobilized from bone
marrow in response to tissue ischemia, which allows neovascularization of ischemic
tissue. It has been suggested that EPCs are involved in tumor progression. We hypothesized
that hepatic ischemia reperfusion (I/R)-induced mobilization of EPCs could enhance
growth of microscopic tumor, therefore promoting liver metastasis in a mouse model
of colorectal cancer.
Materials and methods
We used mouse models of hepatic I/R and hind limb ischemia. For comparison, we studied
mice that underwent limb ischemia as positive controls of EPC mobilization. At day
0, we divided 40 mice into four groups: hepatic I/R, hind limb ischemia, combined
hepatic I/R and hind limb ischemia, and control (sham midline incision laparotomy).
At day 2, we induced liver metastasis in all mice by injecting CT-26 cells into the
spleen. Time-dependent circulating EPCs were determined by flow cytometry. We evaluated
liver metastasis and microvascular density on day 21.
Results
The number of circulating progenitor cells increased rapidly in the ischemic groups
compared with the control group. Hepatic I/R significantly increased tumor outgrowth
compared with the control group. Increased tumor growth was associated with enhanced
CD31-positive microvascular density in liver tissue.
Conclusions
Hepatic I/R leads to mobilization of bone marrow–derived EPCs and enhanced intra-hepatic
angiogenesis, which is associated with increased tumor burden in an animal model of
colorectal liver metastasis.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of Surgical ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Oncologic resection for malignant tumors of the liver.Ann Surg. 2011; 253: 656
- Recurrence and outcomes following hepatic resection, radiofrequency ablation, and combined resection/ablation for colorectal liver metastases.Ann Surg. 2004; 239 (discussion 825): 818
- Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial.Lancet. 2008; 371: 1007
- Perioperative blood transfusion as a prognostic indicator in patients with hepatocellular carcinoma.World J Surg. 1999; 23: 676
- Hepatic resection for colorectal metastases: value for risk scoring systems?.Ann Surg. 2007; 246: 183
- Hepatic ischemia-reperfusion promotes liver metastasis of colon cancer.J Surg Res. 2002; 105: 243
- Warm hepatic ischemia-reperfusion promotes growth of colorectal carcinoma micrometastases in mouse liver via matrix metalloproteinase-9 induction.Cancer Res. 2007; 67: 2720
- Ischemia/reperfusion accelerates the outgrowth of hepatic micrometastases in a highly standardized murine model.Hepatology. 2005; 42: 165
- Hepatic ischemia-reperfusion increases vascular endothelial growth factor and cancer growth in rats.J Surg Res. 2008; 148: 158
- Vessel counts and expression of vascular endothelial growth factor as prognostic factors in node-negative colon cancer.Arch Surg. 1997; 132: 541
- Angiogenesis in synchronous and metachronous colorectal liver metastases: the liver as a permissive soil.Ann Surg. 2012; 255: 86
- VEGF as a key mediator of angiogenesis in cancer.Oncology. 2005; 69: 4
- Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth.Nat Med. 2001; 7: 1194
- Isolation of putative progenitor endothelial cells for angiogenesis.Science. 1997; 275: 964
- Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization.Nat Med. 1999; 5: 434
- Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization.Circ Res. 1999; 85: 221
- Bone marrow-derived endothelial progenitor cells contribute to the angiogenic switch in tumor growth and metastatic progression.Biochim Biophys Acta. 2009; 1796: 33
- The definition of EPCs and other bone marrow cells contributing to neoangiogenesis and tumor growth: is there common ground for understanding the roles of numerous marrow-derived cells in the neoangiogenic process?.Biochim Biophys Acta. 2009; 1796: 50
- The multifaceted circulating endothelial cell in cancer: towards marker and target identification.Nat Rev Cancer. 2006; 6: 835
- Increase in vascular permeability and vasodilation are critical for proangiogenic effects of stem cell therapy.Circulation. 2006; 114: 328
- In vivo release of vascular endothelial growth factor from colorectal carcinomas.Oncology. 2002; 62: 313
- Bone marrow-derived endothelial and hematopoietic precursors cells enhance the metastasis of colon cancer in an orthotopic murine model.Int J Cancer. 2011; 129: 2304
- Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma.N Engl J Med. 1991; 324: 1
- Performance of a simple chromatin-rich segmentation algorithm in quantifying basal cell carcinoma from histology images.BMC Res Notes. 2012; 5: 35
- Quantification of histochemical staining by color deconvolution.Anal Quant Cytol Histol. 2001; 23: 291
- Receptor activator of nuclear factor-kappaB ligand (RANKL) protects against hepatic ischemia/reperfusion injury in mice.Hepatology. 2012; 55: 888
- VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche.Nature. 2005; 438: 820
- Inflammation and cancer: back to Virchow?.Lancet. 2001; 357: 539
- Macrophage responses to hypoxia: implications for tumor progression and anti-cancer therapies.Am J Pathol. 2005; 167: 627
- Distinct role of macrophages in different tumor microenvironments.Cancer Res. 2006; 66: 605
- Role of infiltrated leucocytes in tumour growth and spread.Br J Cancer. 2004; 90: 2053
- Infiltration of neutrophils is required for acquisition of metastatic phenotype of benign murine fibrosarcoma cells: implication of inflammation-associated carcinogenesis and tumor progression.Am J Pathol. 2003; 163: 2221
- Perinecrotic hypoxia contributes to ischemia/reperfusion-accelerated outgrowth of colorectal micrometastases.Am J Pathol. 2007; 170: 1379
- Hallmarks of cancer: the next generation.Cell. 2011; 144: 646
- Microenvironmental regulation of metastasis.Nat Rev Cancer. 2009; 9: 239
- Priming the ”soil” for breast cancer metastasis: the pre-metastatic niche.Breast Dis. 2006; 26: 65
- The metastatic niche: adapting the foreign soil.Nat Rev Cancer. 2009; 9: 285
- Tumour-mediated upregulation of chemoattractants and recruitment of myeloid cells predetermines lung metastasis.Nat Cell Biol. 2006; 8: 1369
- Mobilization of bone marrow-derived hematopoietic and endothelial stem cells after orthotopic liver transplantation and liver resection.Stem Cells. 2006; 24: 2817
- Bone marrow-derived hepatic oval cells differentiate into hepatocytes in 2-acetylaminofluorene/partial hepatectomy-induced liver regeneration.Gastroenterology. 2007; 132: 1077
- Endothelial progenitor cells: characterization and role in vascular biology.Circ Res. 2004; 95: 343
- Stromal cell-derived factor-1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization.Circulation. 2003; 107: 1322
- Bone-marrow-derived cells contribute to endothelial repair after thrombotic microangiopathy.Blood. 2002; 99: 1095
- Statin therapy accelerates reendothelialization: a novel effect involving mobilization and incorporation of bone marrow-derived endothelial progenitor cells.Circulation. 2002; 105: 3017
- Inhibition of prolyl hydroxylase domain proteins promotes therapeutic revascularization.Circulation. 2009; 120: 50
- Minimal contribution of marrow-derived endothelial precursors to tumor vasculature.J Immunol. 2005; 175: 2890
- Endothelial progenitor cells do not contribute to tumor endothelium in primary and metastatic tumors.Int J Cancer. 2009; 125: 1771
- Utilization of bone marrow-derived endothelial cell precursors in spontaneous prostate tumors varies with tumor grade.Cancer Res. 2004; 64: 6137
- Does hepatic pedicle clamping affect disease-free survival following liver resection for colorectal metastases?.Ann Surg. 2010; 252: 1020
- Duration of hepatic vascular inflow clamping and survival after liver resection for hepatocellular carcinoma.Br J Surg. 2011; 98: 1284
- Hepatic pedicle clamping during hepatic resection for colorectal liver metastases: no impact on survival or hepatic recurrence.Ann Surg Oncol. 2012; 20: 285
Article info
Publication history
Published online: May 23, 2013
Accepted:
April 26,
2013
Received in revised form:
April 9,
2013
Received:
March 11,
2013
Identification
Copyright
© 2013 Published by Elsevier Inc. All rights reserved.
