Hematopoietic stem cells mobilization and immune response in tumor-bearing mice

Malignant diseases are known to modulate the number and function of myeloid, erythroid, and lymphoid cells. Since these cells are derived from hematopoietic stem cells (HSC), it is not clear if the observed effects of cancer on such cells are direct or indirect via stem cells. The purpose of this study was to evaluate the effect of breast cancer upon the levels and activity of peripheral blood hematopoietic stem cells.

Four weeks following the establishment of 4T1 breast cancers in BALB/c mice, the animals were killed, blood and spleen harvested, and processed for light density mononuclear cells. Colony forming unit in culture assay was used to determine the activity of HSCs. Flow cytometry was used to determine the levels of lineage negative HSCs expressing c-kit and Sca-1 antigen (Lin c-kitSca-1). Mitogenic, cytotoxic and ELISPOT assays were used to evaluate functional properties of cells. Plasma cytokine levels were determined with ELISA assay.

In tumor-bearing mice, there was a 2- and 4-fold increase in the levels and proliferative capacity of HSCs, respectively, compared with controls. Contemporaneously, there was a 13-fold increase in plasma G-CSF in tumor-bearing animals compared with controls (0.225 ng/ml versus 3.0 ng/ml). Furthermore, the number of interferon gamma-secreting cells was significantly increased in tumor-bearing animals. Concurrently, cytotoxic activity of NK cells was significantly increased in tumor-bearing animals as compared with controls (22.4 +/- 10.6 versus 10.3 +/- 2.95; P < 0.05).

These results suggest that (1) breast cancer mobilizes hematopoietic stem cells in mice presumably through G-CSF production, and (2) that such cancer-mobilized stem cells give rise to immune cell lineages which are functionally hyperactive in their cytotoxic activities. Such cells could be expected to have appreciable therapeutic benefit in terms of cancer cell cytotoxic activity when used as part of stem cell transplantation therapy in cancer patients.