Increased circulating LDL cholesterol increases myeloma tumour burden in vivo

Abstract

Gámez B., Morris EV., Olechnowicz S., Sowman, A., Turner, C. and Edwards CM.

Multiple myeloma (MM) is a fatal malignancy characterized by an expansion of malignant
plasma cells in the bone marrow (BM) and associated with osteolytic bone disease. MM is
preceded by the benign condition, monoclonal gammopathy of undetermined significance
(MGUS). Understanding MGUS progression and development of MM bone disease is key for
patient management. We and others have previously demonstrated that diet-induced obesity
promotes myeloma progression, but the mechanisms underlying this remain unknown. The aim
of the current study was to determine the effect of dietary cholesterol on MM development. A
2% cholesterol diet was used to increase circulating LDL in mice. Mice were randomly
distributed to either a) cholesterol diet 4 weeks prior to 5TGM1 MM inoculation (pretreatment)
or b) cholesterol diet 4 weeks prior to MM inoculation and continued for the entire experiment
(continuous). Mice on the continuous cholesterol diet had increased tumour burden, associated
with an increase in lipid droplet content of MM cells. No differences in tumour burden were
seen in those mice where cholesterol diet was halted at time of MM inoculation. In vitro,
myeloma cells cultured with delipidated FBS had a 50% reduction in viability after 72 hours. Rich
cholesterol content lipoproteins (LDL) but not VLDL could restore MM cell viability, suggesting
that cholesterol is responsible for this lipid-depletion effect. Taken together, our results show
that high cholesterol promotes myeloma and results in a higher lipid content in myeloma cells,
ultimately increasing BM tumour burden. Pretreatment with a cholesterol diet did not alter
disease progression suggesting a direct pro-tumourigenic effect of cholesterol. These results
demonstrate both the detrimental effect of cholesterol on myeloma progression and the
potential for dietary intervention approaches.