Antiangiogenic and Antitumor Effects of Trypanosoma cruzi Calreticulin

Abstract

BackgroundIn Latin America, 18 million people are infected with Trypanosoma cruzi, the agent of Chagas' disease, with the greatest economic burden. Vertebrate calreticulins (CRT) are multifunctional, intra- and extracellular proteins. In the endoplasmic reticulum (ER) they bind calcium and act as chaperones. Since human CRT (HuCRT) is antiangiogenic and suppresses tumor growth, the presence of these functions in the parasite orthologue may have consequences in the host/parasite interaction. Previously, we have cloned and expressed T. cruzi calreticulin (TcCRT) and shown that TcCRT, translocated from the ER to the area of trypomastigote flagellum emergence, promotes infectivity, inactivates the complement system and inhibits angiogenesis in the chorioallantoid chicken egg membrane. Most likely, derived from these properties, TcCRT displays in vivo inhibitory effects against an experimental mammary tumor.Methodology and Principal FindingsTcCRT (or its N-terminal vasostatin-like domain, N-TcCRT) a) Abrogates capillary growth in the ex vivo rat aortic ring assay, b) Inhibits capillary morphogenesis in a human umbilical vein endothelial cell (HUVEC) assay, c) Inhibits migration and proliferation of HUVECs and the human endothelial cell line Eahy926. In these assays TcCRT was more effective, in molar terms, than HuCRT: d) In confocal microscopy, live HUVECs and EAhy926 cells, are recognized by FITC-TcCRT, followed by its internalization and accumulation around the host cell nuclei, a phenomenon that is abrogated by Fucoidin, a specific scavenger receptor ligand and, e) Inhibits in vivo the growth of the murine mammary TA3 MTXR tumor cell line.Conclusions/SignificanceWe describe herein antiangiogenic and antitumor properties of a parasite chaperone molecule, specifically TcCRT. Perhaps, by virtue of its capacity to inhibit angiogenesis (and the complement system), TcCRT is anti-inflammatory, thus impairing the antiparasite immune response. The TcCRT antiangiogenic effect could also explain, at least partially, the in vivo antitumor effects reported herein and the reports proposing antitumor properties for T. cruzi infection.

Effect of two hydatid cyst antigens on the growth of melanoma cancer in C57/black mice

“…According to previous researches, some parasites have capability of antitumor activities (Darani and Yousefi 2012;Kim et al 2007;López et al 2010;Oikonomopoulou et al 2013;Pidherney et al 1993;Plumelle et al 1997) and so parasite antigens have been considered as possible targets for cancer immunotherapy (Darani and Yousefi 2012). In a retrospective study with a large population it has been shown that the prevalence of hydatid cysts in patients with cancer was significantly lower than the control group (Akgül et al 2003).…”

<i>Toxoplasma gondii</i> But Not <i>Leishmania major</i> or <i>Trichomonas vaginalis</i> Decreases Cell Proliferation and Increases Cell Death on Fibrosarcoma Cancer Cells in Culture Medium

“…There are scientific evidences indicating that some parasitic and microbial infections interfere with tumor growth and have anticancer activities [1][2][3][4][5][6][7][8] , and it has been shown that some extracts of Trypanosoma cruzi have toxic effects on cancer cells in cell cultures [1,2]. Kim et al (2007) showed that Toxoplasma gondii inhibited Lewis lung carcinoma growth through induction of Th1 immune responses and inhibition of angiogenesis [3].…”

“…It has been shown that some parasitic infections induce antitumor activity against certain types of cancers [1][2][3][4][5][6]. We previously showed that mice immunized with Toxoplasma gondii tachyzoiter or Toxocara canis egg antigens and challenged with fibrosarcoma cells showed less solid tumor growth in comparison with mice that were not immunized but challenged with the same cells [7].…”

Trypanosoma cruzi Calreticulin Topographical Variations in Parasites Infecting Murine Macrophages

“…14 Through a different domain, located in the amino terminal sequences, extracellular TcCRT interacts with endothelial cells, most likely through a collagen-like Scavenger-Receptor class A, because this interaction is inhibited by fucoidan, an homopolymer of sulfated L-fucose, 15 (Abello and others, 2014, unpublished). The interactions of TcCRT with endotheliocytes mediate antiangiogenic and antitumor effects.…”

“…The interactions of TcCRT with endotheliocytes mediate antiangiogenic and antitumor effects. [15][16][17] Monoallelic TcCRT KO parasites, the wild-type, and a transgenic variant (with an extra TcCRT gene copy), display increasing survival capacity in the presence of human complement, and enhanced in vivo infectivity (TcCRT homozygous KO parasites are not viable). 18,19 Parasite TcCRT location once the parasite is inside the mammal cell has not been reported, as well as its functional roles in those new locations.…”