Exosomes derived from acute myeloid leukemia cells promote chemoresistance by enhancing glycolysis‐mediated vascular remodeling

Abstract

Acute myeloid leukemia (AML) is the most common type of leukemia in adults. AML cells secrete angiogenic factors to remodel vasculature and acquire chemoresistance; however, antiangiogenic drugs are often ineffective in AML treatment. Cancer cell‐derived exosomes can induce angiogenesis, but their role in vascular remodeling during AML is unclear. Here, we found that exosomes secreted by AML cells promoted proliferation and migration and tube‐forming activity of human umbilical vein endothelial cells (HUVECs), whereas HUVECs conferred chemoresistance to AML cells. AML cell‐derived exosomes contained vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR) messenger RNA and induced VEGFR expression in HUVECs. Furthermore, they enhanced glycolysis, which correlated with HUVEC proliferation, tube formation, and resistance to apoptosis. Thus, AML cells secrete VEGF/VEGFR‐containing exosomes that induce glycolysis in HUVECs leading to vascular remodeling and acquisition of chemoresistance. These findings may contribute to the development of novel therapeutic strategies targeting exosomes in AML.

Exosome-mediated metabolic reprogramming: the emerging role in tumor microenvironment remodeling and its influence on cancer progression

“…Recently, research shows that exosomes secreted by cancer cells can remodel the metabolism of ECs. Wang et al 72 found that exosomes derived from acute myeloid leukemia (AML) cells, containing VEGF/VEGFR, could promote the glycolysis in ECs. Although recent studies have discovered the potential role of exosomes secreted by cancer cells on regulating the metabolism of ECs, few studies have focused on the feedback effects of ECs-derived exosomes on cancer cells in the tumor field.…”

“… 104 , 105 Recently, Huang et al found that exosomes derived from AML cells could regulate vascular reprogramming in AML. 72 VEGF-containing exosomes were transferred into the targeted ECs, and induced the upregulation of glycolytic capacity and angiogenesis activity in ECs through activating VEGF signaling. 72 Virus-encoded microRNAs packed in exosomes from Kaposi’s sarcoma-associated herpesvirus (KSHV) infected cell were incorporated by the neighboring cells, resulting in metabolism shifted toward the glycolysis and reduced mitochondrial biogenesis in surrounding non-infected cells.…”

“… 72 VEGF-containing exosomes were transferred into the targeted ECs, and induced the upregulation of glycolytic capacity and angiogenesis activity in ECs through activating VEGF signaling. 72 Virus-encoded microRNAs packed in exosomes from Kaposi’s sarcoma-associated herpesvirus (KSHV) infected cell were incorporated by the neighboring cells, resulting in metabolism shifted toward the glycolysis and reduced mitochondrial biogenesis in surrounding non-infected cells. The exosomes supported the growth of infected cells by mediating the metabolic remodeling of neighboring cells, thus promoting angiogenesis of Kaposi’s sarcoma.…”

“…After anti-myeloma drug stimulation, ASM expression and protein levels were increased in multiple myeloma cells and their exosomes, which reflected the tumor-protective effect of ASM and promoted the development of drug resistance. 120 Moreover, Huang and colleagues 72 indicated that AML-secreted exosomes increased glycolysis in ECs, and resulted in the remodeling of vascular and the acquisition of chemoresistance. Recently, Petanidis S et al 122 isolated exosomes from patients with Kras chemoresistant lung cancer patients.…”

The Role of Exosomes in Stemness and Neurodegenerative Diseases—Chemoresistant-Cancer Therapeutics and Phytochemicals

“…AML (acute myeloid leukemia)-derived exosomes foster the chemoresistance of AML cells to cytarabine, as they secrete VEGF/VEGFR factors to promote glycolysis in human umbilical vein endothelial cells (HUVECs) [ 174 ]. Several reports described the EV-mediated resistance transfer from resistant AMLs to sensitive AMLs by miRNAs for modulating expression of apoptotic proteins [ 175 , 176 , 177 ].…”