A Mouse Strain Which Responds Poorly to Angiogenic Stimuli Has a Higher Incidence of Irradiation-Induced Hematological Malignancies.

Genetic heterogeneity of murine strains to vasculogenic/ angiogenic stimuli has been suggested to correlate with the susceptibility to carcinogenesis and subsequent tumor growth. A more “angiogenic” strain would, likely, be more prone to carcinogenesis/ tumorigenesis stimuli. To study the importance of the endothelial compartment (vasculogenesis/ angiogenesis) during irradiation-induced hematopoietic malignancies (leukemia and lymphoma) we administered 3 cycles of irradiation (sub-lethally; 3.5 Gy), with one month of interval between them, to 2 angiogenically different mouse strains (12 high angiogenic Balb/c mice vs 12 low angiogenic C57BL-6 mice). Every month after the last irradiation, the levels of circulating endothelial progenitor cells (EPC: Flk-1⁺Sca⁺ cells) in peripheral blood were quantified by flow cytometry. At the end of the assay (∼6 months after last irradiation) the incidence of hematopoietic disease among the 2 mouse strains was scored and the levels of EPC (Flk-1⁺Sca⁺ cells), endothelial cells (Flk-1⁺ cells) and HSC/HPC (Sca⁺c-Kit⁺ cells) were measured in BM (bone marrow) samples of sick and healthy mice. Interestingly, the less angiogenic C57BL-6 mouse strain displayed a significantly higher leukemia and thymic lymphoma incidence (50% - 2x-fold higher than Balb-c). As determined by FACS analysis of BM cells, in both mouse strains, sick mice showed a reduction in the levels of HSC/HPC (hematopoietic progenitor cells) compared to their healthy counterparts. Nonetheless, this reduction was more pronounced in the less angiogenic C57BL-6 mouse strain (2.1 reduction in C57BL-6 vs. 1.4 reduction in Balb-c). Beside the difference in the hematopoietic compartment, C57BL-6 leukemic mice also evidenced a dramatic change in the BM endothelial compartment, where a significant decrease in EPC and endothelial cells was observed compared to leukemic Balb-c and healthy mice. In contrast, C57BL-6 leukemic mice showed a higher number of circulating EPC compared to healthy mice. Taken together, our data suggests that a higher incidence of hematopoietic malignancies observed in the less angiogenic mouse strain may be associated with a deficiency in the BM vascular compartment. Since it is known that whole body irradiation induces the turnover and the mobilization of HSC/HPC inside the BM, we hypothesize that the vascular compartment (EPC/ endothelial cells) regulates HSC/HPC turnover during irradiation-induced carcinogenesis. As such, BM vascular deficiency/ depletion after BM irradiation (particular evident in low angiogenic genetic backgrounds) may promote the turnover of HSC/HPC and increased susceptibility to the irradiation effects. These results may be particularly relevant in the context of irradiation/ chemotherapy-induced secondary tumors in myelodysplastic/ leukemia patients.