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

Abstract

Background Hepatocellular 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. Methods This 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. Results We 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. Conclusions Our 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.

Plasmodium infection prevents recurrence and metastasis of hepatocellular carcinoma possibly via inhibition of the epithelial‑mesenchymal transition

“…6 ), providing evidence for the prevention of recurrence and distant metastasis of HCC by regulating the EMT through infection with Plasmodium parasites. In addition, our previous studies have demonstrated that Plasmodium infection displays antitumor effects by activating the innate and acquired antitumor immunity, remodelling the tumour immunosuppressive microenvironment and inhibiting angiogenesis ( 20 – 25 ). Based on these studies, three clinical trials are ongoing in China (trial nos.…”

“…Our previous studies have demonstrated that Plasmodium infection inhibits tumour development and metastasis in a murine Lewis lung cancer model ( 19 – 24 ). However, although Plasmodium infection has been demonstrated to suppress HCC angiogenesis by decreasing the infiltration of tumour-associated macrophages and reducing their matrix metalloproteinase 9 levels ( 25 ), the effects of Plasmodium infection on HCC metastasis and recurrence remain unclear.…”

Role of macrophages in tumor progression and therapy (Review)

“…Changes in the number and activity of macrophages can affect protease production, reduce angiogenesis, and slow tumor growth. By infecting tumor-bearing mice with Plasmodium , Wang et al revealed that Plasmodium hemozoin can reduce the number of infiltrating TAMs and decrease the expression of MMP9 and MMP2, thus suppressing tumor angiogenesis and slowing down metastasis and tumor growth ( 27 ).…”

Cross Talk Between Macrophages and Cancer Cells in the Bone Metastatic Environment

“…For new capillaries to sprout, degradation of the host vessel at specific sites needs to occur and this process is mediated by proteinases such as matrix metalloproteinases (MMPs). In some tumors, TAMs have appeared to be a major source of MMP9 which mediates extracellular matrix degradation and releases VEGF-A from the extracellular matrix reservoir ( 18 , 191 – 193 ). The release of VEGF-A can then induce a positive feedback loop on angiogenesis by further recruiting pro-angiogenic and immunosuppressive macrophages through their VEGF receptor (VEGFR1) ( 194 , 195 ).…”

“…In addition, combining anti-PD1 therapy with metformin-loaded macrophage-derived microparticles that potently polarized TAMs from M2-like to M1-like state, boosts anti-cancer efficacy ( 269 ). Recently, PD-1 blockage was also demonstrated to have an added benefit of inhibiting osteoclastogenesis resulting in reduced bone destruction and pain ( 193 ). Of note, there are also reports indicating that TAMs might limit anti-PD-1 treatments for example through preventing CD8 + T cells from reaching tumor cells ( 147 ) or by removing anti-PD-1 antibodies from T cells through Fc-Fcγ receptors binding ( 270 ), though the latter can be prevented by blocking Fc/Fcγ receptor interactions ( 270 ).…”