Abstract
BackgroundHepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death in China. The lack of an effective treatment for this disease results in a high recurrence rate in patients who undergo radical tumor resection, and the 5-year survival rate of these patients remains low. Our previous studies demonstrated that Plasmodium infection provides a potent antitumor effect by inducing innate and adaptive immunity in a murine Lewis lung carcinoma (LLC) model.MethodsThis study aimed to investigate the inhibitory effect of Plasmodium infection on hepatocellular carcinoma in mice, and various techniques for gene expression analysis were used to identify possible signal regulation mechanisms.ResultsWe found that Plasmodium infection efficiently inhibited tumor progression and prolonged survival in tumor-bearing mice, which served as a murine implanted hepatoma model. The inhibition of tumor progression by Plasmodium infection was related to suppression of tumor angiogenesis within the tumor tissue and decreased infiltration of tumor-associated macrophages (TAMs). Further study demonstrated that matrix metalloprotease 9 (MMP-9) produced by TAMs contributed to tumor angiogenesis in the tumor tissue and that the parasite-induced reduction in MMP-9 expression in TAMs resulted in the suppression of tumor angiogenesis. A mechanistic study revealed that the Plasmodium-derived hemozoin (HZ) that accumulated in TAMs inhibited IGF-1 signaling through the PI3-K and MAPK signaling pathways and thereby decreased the expression of MMP-9 in TAMs.ConclusionsOur study suggests that this novel approach of inhibiting tumor angiogenesis by Plasmodium infection is of high importance for the development of new therapies for cancer patients.DcTAkd_JguhWjRG6hMrBFrVideo abstract
Highlights
Plasmodium infection, which causes malaria in humans and animals, modulates the host’s immunity by inducing the secretion of cytokines, by activating some immune cell populations, and by altering the function of macrophages [1, 2]
The levels of igf-1 RNA and IGF-1 protein were reduced approximately 4-fold in the infected mice (Fig. 4c and d), the level of mmp-2 was only slightly reduced (Fig. S3c). These results suggested that the reduction in Matrix metalloprotease (MMP)-9 and IGF-1 expression in tumor-associated macrophages (TAMs) induced by Plasmodium infection might be responsible for the reduction in tumor angiogenesis
The results from a FACSlike tissue cytometry analysis confirmed that matrix metalloprotease 9 (MMP-9) expression was significantly lower in the Plasmodium-infected group than in the control group (Fig. 4g, Fig. S4). These results suggest that Plasmodium infection might reduce MMP-9 and IGF-1 expression in TAMs and tumor tissue and that this effect is responsible for the reduced angiogenesis within tumors
Summary
Plasmodium infection, which causes malaria in humans and animals, modulates the host’s immunity by inducing the secretion of cytokines, by activating some immune cell populations, and by altering the function of macrophages [1, 2]. Our previous study demonstrated that Plasmodium infection exerts a potent antitumor effect through the induction of innate and adaptive antitumor immune responses in a murine Lewis lung carcinoma (LLC) model [5]. 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]. These effects were observed in rodents infected with malaria parasites, and the Plasmodium species that infect mice are different from those that infect humans. Our previous studies demonstrated that Plasmodium infection provides a potent antitumor effect by inducing innate and adaptive immunity in a murine Lewis lung carcinoma (LLC) model
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