BACKGROUND: Clinical and experimental studies on prevention and treatment of hepatic metastasis after colonic cancer treatment by allogeneic hematopoietic stem cell transplantation have yet to be well reported. A mixed chimera is expected to achieve certain effects in patients with low-tumor burden after colorectal cancer resection.
OBJECTIVE: To investigate the inhibitory effect of allogeneic hematopoietic stem cell transplantation on colorectal cancer liver metastasis as well as the effect on chimera level and graft-versus-host disease and to study the anti-tumor mechanism.
METHODS: CB6F1 mice were hybridized by BALB/c×C57BL/6 mice and injected with CT-26 cells to make animal models of colorectal cancer liver metastasis. Then, model mice were randomized into four groups (n=8 per group): control group, cyclophosphamide group, HLA-identical spleen cells plus bone marrow cell transplantation+cyclophosphamide group (HLA-identical transplantation group), and haploidentical spleen cells plus bone marrow cell transplantation+cyclophosphamide group (haploidentical transplantation group). Mixture of spleen cells and bone marrow cells from CB6F1 and C57BL/6 mice were injected via the tail vein followed by a non-myeloablative pretreatment with intraperitoneal injection of cyclophosphamide, and thereafter, lymphocytes were given via infusion. Survival time, tumor liver metastasis and the occurrence of graft-versus-host disease were observed in mice. The chimera was analyzed by flow cytometry, and levels of plasma interleukin-2, interferon-γ, interleukin-4, and transforming growth factor β were determined by ELISA
RESULTS AND CONCLUSION: The survival time and inhibition rate of liver metastasis in the haploidentical transplantation group were significantly prolonged and increased compared with cyclophosphamid and HLA-identical transplantation group, respectively. At 7 days after transplantation, the chimera level in the haploidentical transplantation group was significantly increased up to over 99% at 28 days of transplantation, indicating that donor cells were basically substituted by recipient cells. Significantly enhanced anti-tumor effect was found in the haploidentical transplantation group, while there were no signs of severe graft-versus-host disease. Moreover, the levels of plasma interleukin-2 and interferon-γ in mice were significantly higher than those in the other groups, and the level of transforming growth factor β was significantly reduced. However, there was no significant difference in the interleukin 4 level. To conclude, co-transplantation of cyclophosphamide-pretreated allogeneic bone marrow cells and lymphocytes significantly increases the chimera level, accompanied by the production of obvious anti-tumor effect of the graft that has an inhibitory effect on colorectal cancer liver metastasis. Changes in levels of plasma interleukin-2, interferon-γ, interleukin-4, and transforming growth factor β are associated with tumor growth inhibition.