Abstract
Metabolic transformation in cancer is increasingly well understood. However, little is known about the metabolic responses of cancer cells that permit their survival in different microenvironments. We have used a nuclear magnetic resonance based approach to monitor metabolism in living primary chronic lymphoid leukemia (CLL) cells and to interrogate their real-time metabolic responses to hypoxia. Our studies demonstrate considerable metabolic plasticity in CLL cells. Despite being in oxygenated blood, circulating CLL cells are primed for hypoxia as measured by constitutively low level hypoxia-inducible factor (HIF-1α) activity and modest lactate production from glycolysis. Upon entry to hypoxia we observed rapid upregulation of metabolic rates. CLL cells that had adapted to hypoxia returned to the ‘primed' state when re-oxygenated and again showed the same adaptive response upon secondary exposure to hypoxia. We also observed HIF-1α independent differential utilization of pyruvate in oxygenated and hypoxic conditions. When oxygenated, CLL cells released pyruvate, but in hypoxia imported pyruvate to protect against hypoxia-associated oxidative stress. Finally, we identified a marked association of slower resting glucose and glutamine consumption, and lower alanine and lactate production with Binet A0 stage samples indicating that CLL may be divided into tumors with higher and lower metabolic states that reflect disease stage.
Highlights
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Western countries1–3 which despite recent improvements in prolonging survival, remains incurable.1,4 CLL patients present with elevated lymphocyte counts in the peripheral blood
nuclear magnetic resonance (NMR) experiments were conducted in 5-mm NMR tubes using 5–10 × 107 primary CLL cells suspended in 0.1% agarose in serumfree RPMI growth medium to prevent their sedimentation during the acquisition of spectra over 24 h
This study shows that NMR is uniquely capable of monitoring such changes in real time using primary patient cells
Summary
Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in Western countries which despite recent improvements in prolonging survival, remains incurable. CLL patients present with elevated lymphocyte counts in the peripheral blood. CLL patients present with elevated lymphocyte counts in the peripheral blood. In most patients these lymphocyte numbers increase progressively over months and years. These circulating cancer cells are out of cell cycle and superficially highly quiescent. Isotopic labeling studies have determined that peripheral blood CLL cells have undergone a number of divisions and that rates of cell death within the tumor are high.. The picture that emerges is that circulating CLL cells represent a large pool of non-dividing cancer cells that are able to enter and exit tissue sites, predominantly lymph nodes, spleen and bone marrow, wherein they proliferate and drive the progressive expansion of the tumor.. Studying CLL as an unusual cancer where a large proportion of cells within the tumor exhibit motility between different sites in the body may permit the potential discovery of mechanisms pertinent to metastasis of other cancers
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
