Darbepoetin-alpha enhances hepatectomy-associated stimulation of colorectal liver metastatic growth.
BACKGROUND
Liver insufficiency after major hepatectomy still represents a serious challenge in liver surgery. Although some previous studies indicate that erythropoietin (EPO) and its analogue darbepoetin-alpha (DPO) may improve liver function and liver regeneration, little is known on their effect on tumor growth after hepatectomy. Because EPO may promote tumor progression, we herein studied the effect of DPO on tumor growth after major hepatectomy.


METHODS
CT26.WT colorectal cancer cells were implanted into the left liver lobe of BALB/c mice. Animals underwent 50% hepatectomy (Phx) and received 10 microg/kg DPO-treatment. Additional Phx animals received only saline treatment. Nonhepatectomized animals with DPO-treatment or saline treatment served as controls. One week after hepatectomy angiogenic blood vessel formation, leukocyte-endothelial cell interaction, tumor cell proliferation, apoptotic cell death, and tumor growth were studied using intravital fluorescence microscopy, histology, Immunohistochemistry, and Western blot analysis.


RESULTS
Phx significantly enhanced the growth of liver metastases. This was associated with an increase of tumor capillary density and tumor cell proliferation. In nonhepatectomized animals, DPO only slightly affected metastatic growth. In hepatectomized animals, however, DPO significantly enhanced the Phx-induced stimulation of tumor growth. This was associated with an increased tumor capillary density, a decreased leukocyte-endothelial cell interaction, and a reduced cleaved caspase-3 expression of the CT26.WT cells.


CONCLUSIONS
: Our data indicate that DPO significantly enhances the hepatectomy-induced stimulation of colorectal liver metastatic growth by increasing neovascularization, suppressing intratumoral leukocyte recruitment, and reducing tumor cell apoptosis. Thus, EPOs may not be used in patients undergoing hepatectomy for malignant tumor resection.
Rupertus
Kathrin
K
Department of General, Visceral, Vascular and Pediatric Surgery, University of Saarland, Homburg/Saar, Germany.
Sperling
Jens
J
Corsten
Marcus
M
Scheuer
Claudia
C
Nickels
Ruth M
RM
Schilling
Martin K
MK
Menger
Michael D
MD
Kollmar
Otto
O
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000032:analysis; D015179:Colorectal Neoplasms / Q000473:pathology*; D000068256:Darbepoetin alfa; D004921:Erythropoietin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006397:Hematinics / Q000009:adverse effects* / Q000494:pharmacology; D006498:Hepatectomy / Q000009:adverse effects*; D008113:Liver Neoplasms / Q000473:pathology* / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009389:Neovascularization, Pathologic; D020556:Neutrophil Infiltration / Q000187:drug effects; D014407:Tumor Cells, Cultured
D006397:Hematinics; D004921:Erythropoietin; D000068256:Darbepoetin alfa; D053148:Caspase 3