Abstract
Abnormally low level of interstitial oxygen, or hypoxia, is a hallmark of tumor microenvironment and a known promoter of cancer chemoresistance. Inside a solid tumor mass, the hypoxia stems largely from inadequate supply of oxygenated blood through sparse or misshapen tumor vasculature whilst oxygen utilization rates are low in typical tumor's glycolytic metabolism. In acute leukemias, however, markers of intracellular hypoxia such as increased pimonidazole adduct staining and HIF-1α stabilization are observed in advanced leukemic bone marrows (BM) despite an increase in BM vasculogenesis. We utilized intravital fast scanning two-photon phosphorescence lifetime imaging microscopy (FaST-PLIM) in a BCR-ABL B-ALL mouse model to image the extracellular oxygen concentrations (pO2) in leukemic BM, and we related the extracellular oxygen levels to intracellular hypoxia, vascular markers and local leukemia burden. We observed a transient increase in BM pO2 in initial disease stages with intermediate leukemia BM burden, which correlated with an expansion of blood-carrying vascular network in the BM. Yet, we also observed increased formation of intracellular pimonidazole adducts in leukemic BM at the same time. This intermediate stage was followed by a significant decrease of extracellular pO2 and further increase of intracellular hypoxia as leukemia cellularity overwhelmed BM in disease end-stage. Remarkably, treatment of leukemic mice with IACS-010759, a pharmacological inhibitor of mitochondrial Complex I, substantially increased pO2 in the BM with advanced B-ALL, and it alleviated intracellular hypoxia reported by pimonidazole staining. High rates of oxygen consumption by B-ALL cells were confirmed by Seahorse assay including in ex vivo cells. Our results suggest that B-ALL expansion in BM is associated with intense oxidative phosphorylation (OxPhos) leading to the onset of metabolic BM hypoxia despite increased BM vascularization. Targeting mitochondrial respiration may be a novel approach to counteract BM hypoxia in B-ALL and, possibly, tumor hypoxia in other OxPhos-reliant malignancies.
Highlights
Complex interactions between cancer cells and the tumor microenvironment lead to development of tumor hypoxia, which promotes cancer cell survival and treatment resistance
B-ALL disease, our results show that the state of bone marrow (BM) oxygenation is dynamic during time course of leukemia expansion and driven by a high rate of mitochondrial respiration in leukemic cells factored by leukemic cell burden
By showing reversal of leukemic BM hypoxia in advanced B-ALL by mitochondrial complex I inhibitor IACS-010759, our results identify the metabolic process of oxygen consumption by mitochondrial respiration as a major contributor toward intratumoral hypoxia in B-ALL
Summary
Complex interactions between cancer cells and the tumor microenvironment lead to development of tumor hypoxia, which promotes cancer cell survival and treatment resistance. The hypoxia of a solid tumor core is thought to result largely from a local insufficiency of oxygenated blood supply rather than from oxygen utilization, which should be low in typically glycolytictype tumor metabolism. Our group and others have reported that the BM microenvironment in leukemia is hypoxic with associated stabilization of hypoxia-inducible factor 1 alpha (HIF-1α) in leukemic cells [2,3,4,5,6]. We previously found large areas of hypoxia, as detected by pimonidazole adduct staining, in the BM of patients with advanced stage refractory acute leukemia (AML and ALL) and in a murine ALL model [7, 8]. Whether the origin of hypoxia onset in the BM with evolving acute leukemia is related to blood supply restriction or oxygen metabolism remains unknown
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