Blood transfusion promotes cancer progression: a critical role for aged erythrocytes

Abstract

Background: In cancer patients, allogeneic blood transfusion is associated with poorer prognosis, but the independent effect of the transfusion is controversial. Moreover, mediating mechanisms underlying the alleged cancer-promoting effects of blood transfusion are unknown, including the involvement of donors' leukocytes, erythrocytes, and soluble factors.

Method: Two syngeneic tumor models were used in Fischer 344 rats, the MADB106 mammary adenocarcinoma and the CRNK-16 leukemia. Outcomes included host ability to clear circulating cancer cells, and host survival rates. The independent impact of blood transfusion was assessed, and potential deleterious characteristics of the transfusion were studied, including blood storage duration; the role of erythrocytes, leukocyte, and soluble factors; and the kinetics of the effects.

Results: Blood transfusion was found to be an independent and significant risk factor for cancer progression in both models, causing up to a fourfold increase in lung tumor retention and doubling mortality rates. Blood storage time was the critical determinant of these deleterious effects, regardless of whether the transfused blood was allogeneic or autogenic. Surprisingly, aged erythrocytes (9 days and older), rather than leukocytes or soluble factors, mediated the effects, which occurred in both operated and nonoperated animals. The effects of erythrocytes transfusion in the MADB106 model emerged immediately and dissipated within 24 h.

Conclusions: In rats, transfusion of fresh blood is less harmful than transfusion of stored blood in the context of progressing malignancies. Further studies should address mediating mechanisms through which erythrocytes' storage duration can impact the rate of complications while treating malignant diseases and potentially other pathologies.

Figure 1. Blood transfusion increases MADB106 lung tumor retention when transfused in close time proximity to tumor inoculation

% of lung tumor retention (mean± SEM) in rats transfused at several time point before MADB106 tumor inoculation (-24, -4, or -1 hours), simultaneously with tumors (0), or 1 hr after tumor inoculation (+1) compared to corresponding saline transfusion. n = 44, 3–6 per group. * indicates significant pair-wise difference from the same time point saline control group (protected least significant difference, p < 0.05).

Figure 2. Both allogeneic and autogenic blood transfusions increased lung tumor retention in a storage time-dependent manner

% of lung tumor retention (mean± SEM) in rats transfused with saline, allogeneic blood (Allotransfusion), or autogenic blood (autotransfusion) that were stored for various durations as packed cells. * indicates significant pair-wise difference from the saline control group (protected least significant difference, p < 0.05). n = 104, saline & 9 days 12–14 per group, other groups 4–8.

Figure 3. Cells but not supernatant of stored blood increase MADB106 lung tumor retention

% of lung tumor retention (mean± SEM) in rats transfused with 14-days stored packed cells, post-storage washed packed cells, post-storage supernatant from packed cells (supernatant), or saline. n = 22, 4–8 per group. * indicates significant pair-wise difference from the saline control group (protected least significant difference, p < 0.05).

Figure 4. Red blood cell (RBC) cell volume, but not leukocyte number, determines the metastasis promoting effects of the transfusion

(A) Numbers (mean± SEM) of leukocytes per a transfusion containing 0, 0.75, 1.5, or 2.25 ml of RBC (diluted in saline to a standard 3 ml volume). Transfusions were conducted following 14-day storage of leukoreduced or non-leukoreduced packed cells. Notice that the two groups contrasted by the horizontal bar have similar number of leukocytes but different RBC volume. (B) % of MADB106 lung tumor retention (mean± SEM) in the different groups. Notice that the same two groups contrasted are significantly different from each other in tumor retention (indicated by **, protected least significant difference, p < 0.05), although having the same number of leukocytes (A). * indicates significant pair-wise difference from the respective saline control group (protected least significant difference, p < 0.05). n = 67, 6–10 per group.

Figure 5. Leukocytes do not increase MADB106 lung tumor retention, whereas leukodepleted red blood cells (leukodepleted packed cells) do increase it

% of lung tumor retention (mean± SEM) in rats transfused with: (A) Packed cells, but not leukocytes significantly increased tumor retention. n = 24, 6–9 per group. (B) Both packed cells and leukodepleted-packed cells (only red blood cells) significantly increased tumor retention. n = 21, 6–8 per group. * indicates significant pair-wise difference from the respective saline control group (protected least significant difference, p < 0.05).

Figure 6. Stored leukodepleted packed cells (red blood cells - RBC) increase MADB106 lung tumor retention in operated rats more than in non-operated rats

% of lung tumor retention (mean± SEM) in rats undergoing or not undergoing surgery, and transfused with stored leukodepleted packed cells (RBC) or with saline. Surgery significantly increased % of lung tumor retention, and blood transfusion further increased it, causing a significantly greater impact in operated than in non-operated animals (p < 0.05). n = 44, 7–9 no surgery groups, 14–16 surgery groups.

Figure 7. Transfusion of stored blood, specifically stored red blood cells (RBC), reduced survival rates in CRNK-16-derived leukemia

Transfusion of stored packed cells and transfusion of stored leukodepleted packed cells (only RBC) significantly reduced survival rates (Tarone-Ware test, p < 0.05), while transfusion of leukocytes or fresh autogenic packed cells had no effect. * indicates significant pairwise difference from the control group. n = 163, 28–39 per group.