Hemoglobin-based oxygen carrier mitigates transfusion-mediated pancreas cancer progression

Abstract

Background: Perioperative blood transfusion in pancreatic cancer patients is linked to decreased survival; however, a causal mechanism has not been determined. Previously we have shown that the plasma fraction of stored packed red blood cells (pRBCs) promotes pancreas cancer progression and associated morbidity. We hypothesize these untoward effects will be mitigated by use of a hemoglobin-based oxygen carrier (HBOC).

Methods: Cytokines and growth factors were measured in the plasma fraction from stored pRBCs and in an HBOC via cytokine array followed by formal enzyme-linked immunosorbent assay (ELISA). In an immunocompetent murine model, pancreas cancer progression was determined in vivo by bioluminescence, tumor weight, and number of metastases.

Results: Elevated levels of epidermal growth factor (EGF), platelet-derived growth factor BB (PDGF-BB), and regulated upon activation, normal T cell expressed and secreted (RANTES) were present in the plasma fraction of stored pRBCs, but were not found in the HBOC. Intravenous delivery of plasma fraction to mice with pancreatic cancer resulted in increased bioluminescence activity compared with mice that received HBOC. Metastatic events and pancreatic primary tumor weights were significantly higher in animals receiving plasma fraction from stored pRBCs compared with animals receiving HBOC.

Conclusions: Intravenous receipt of the acellular plasma fraction of stored pRBCs promotes pancreatic cancer progression in an immunocompetent mouse model. These untoward events are mitigated by use of an HBOC.

FIG. 1

Chemiarray screening revealed PDGF-BB, RANTES, and EGF were elevated in the plasma fraction of pRBCs. Formal ELISA testing showed significantly elevated (p<0.05) PDGF-BB and EGF in the nonleukoreduced (NLR) plasma fraction from day 42 of storage. ELISA showed no levels of PDGF-BB, RANTES or EGF in HBOC

FIG. 2

Representative figure of mice that underwent orthotopic injection of (2.5 × 10⁵) luciferase-transfected Pan02 cells. Pictures were taken 6 weeks post tumor injection. IVIS demonstrates tumor bioluminescence: a mouse on the left received LTV injection of saline, b center mouse received 2U equivalent of HBOC, c mouse on right received 2U of day 42 NLR pRBCs. Of note, luciferase transfection appeared to significantly decrease Pan02 growth