Exosomes from Plasmodium-infected hosts inhibit tumor angiogenesis in a murine Lewis lung cancer model

Abstract

Previous research to investigate the interaction between malaria infection and tumor progression has revealed that malaria infection can potentiate host immune response against tumor in tumor-bearing mice. Exosomes may play key roles in disseminating pathogenic host-derived molecules during infection because several studies have shown the involvement and roles of extracellular vesicles in cell–cell communication. However, the role of exosomes generated during Plasmodium infection in tumor growth, progression and angiogenesis has not been studied either in animals or in the clinics. To test this hypothesis, we designed an animal model to generate and isolate exosomes from mice which were subsequently used to treat the tumor. Intra-tumor injection of exosomes derived from the plasma of Plasmodium-infected mice provided significantly reduced Lewis lung cancer growth in mice. We further co-cultured the isolated exosomes with endothelial cells and observed significantly reduced expression of VEGFR2 and migration in the endothelial cells. Interestingly, high level of micro-RNA (miRNA) 16/322/497/17 was detected in the exosomes derived from the plasma of mice infected with Plasmodium compared with those from control mice. We observed that overexpression of the miRNA 16/322/497/17 in endothelial cell corresponded with decreased expression of VEGFR2, inhibition of angiogenesis and inhibition of the miRNA 16/322/497/17 significantly alleviated these effects. These data provide novel scientific evidence of the interaction between Plasmodium infection and lung cancer growth and angiogenesis.

Plasmodium infection inhibits tumor angiogenesis through effects on tumor-associated macrophages in a murine implanted hepatoma model

“…Considering the findings of our previous studies [5,8,24,47], which showed that Plasmodium parasite infection induces antitumor immunity and inhibits tumor angiogenesis in animal models of cancer, we conclude that Plasmodium infection or component vaccination provides a potent therapeutic strategy for cancer treatment. Three clinical trials of Plasmodium immunotherapy for advanced lung cancer (clinicaltrials.gov/ct2/show/NCT02786589), advanced breast and liver cancers (clinicaltrials.gov/ct2/show/NCT03474822), and advanced cancers (clinicaltrials.gov/ct2/show/NCT03375983) have been approved and are ongoing in China.…”

“…For a long time, it has been recognized that parasite infection may serve to enhance immune surveillance mechanisms against some types of solid cancers [5,8,24]. Furthermore, our global epidemiological data analysis also suggested an inverse correlation between malaria incidence and cancer mortality [24].…”

“…Blocking angiogenesis significantly inhibits tumor growth [7]. Although our previous study demonstrated that Plasmodium infection inhibits tumor angiogenesis by releasing plasma exosomes that contain endogenous functional microRNAs in a murine LLC model [8], the more precise mechanisms underlying the inhibition of tumor angiogenesis by Plasmodium infection remain unclear.…”

“…In the tumor microenvironment, tumor-associated macrophages (TAMs) are polarized into the alternatively activated phenotype (M2 type) and promote tumor angiogenesis through the production of several proangiogenic factors, such as matrix metalloproteinases (MMPs) [6,9,10]. MMP-2 and -9 are well documented to play crucial roles in the process of angiogenesis, mainly by degrading the extracellular matrix (ECM) [8,11,12]. A recent study showed that increased type 1 insulin-like growth factor (IGF-1) signaling is associated with an upregulation of MMP-2 and -9 expressions [13][14][15].…”

Brain‐Cortex Microglia‐Derived Exosomes: Nanoparticles for Glioma Therapy

“…[28][29][30] This mechanisms was confirmed in recent study which showed that exosomes from plasma of malaria-infected hosts reduced tumor via suppressed angiogenesis through overexpression of the miRNA. [31]…”