Is the Antitumor Property of Trypanosoma cruzi Infection Mediated by Its Calreticulin?

Abstract

Eight to 10 million people in 21 endemic countries are infected with Trypanosoma cruzi. However, only 30% of those infected develop symptoms of Chagas’ disease, a chronic, neglected tropical disease worldwide. Similar to other pathogens, T. cruzi has evolved to resist the host immune response. Studies, performed 80 years ago in the Soviet Union, proposed that T. cruzi infects tumor cells with similar capacity to that displayed for target tissues such as cardiac, aortic, or digestive. An antagonistic relationship between T. cruzi infection and cancer development was also proposed, but the molecular mechanisms involved have remained largely unknown. Probably, a variety of T. cruzi molecules is involved. This review focuses on how T. cruzi calreticulin (TcCRT), exteriorized from the endoplasmic reticulum, targets the first classical complement component C1 and negatively regulates the classical complement activation cascade, promoting parasite infectivity. We propose that this C1-dependent TcCRT-mediated virulence is critical to explain, at least an important part, of the parasite capacity to inhibit tumor development. We will discuss how TcCRT, by directly interacting with venous and arterial endothelial cells, inhibits angiogenesis and tumor growth. Thus, these TcCRT functions not only illustrate T. cruzi interactions with the host immune defensive strategies, but also illustrate a possible co-evolutionary adaptation to privilege a prolonged interaction with its host.

Anti-Tumor Effect of Parasitic Protozoans

“…Later, researchers developed an anticancer experiment in which T. cruzi extracts were directly inoculated in peritumoral areas over different tumors, and all of the results showed a reduction in tumor size [ 4 ]. However, the work was hampered by controversial results and the complicated international political situation, and so the molecular basis of this phenomenon has remained elusive [ 5 ]. Moreover, several live-attenuated protozoan parasites including Leishmania infantum and L. tropica [ 6 ], Neospora caninum [ 7 ], and Toxoplasma gondii [ 8 ] have all lately been employed as antitumor biological agents via intratumoral injection, all of which decreased tumor development and local inflammation ( Figure 1 ).…”

Modulation of Inflammation-Induced Tolerance in Cancer

“…was proposed that this infection mediates an adaptive immune response with significant antitumor effects (23).…”

“…Another step in the research of increasing cancer-related inflammation was made about 80 years ago by Roskin and colleagues by using Trypanosoma cruzi (the protozoan agent of Chagas' disease). It was proposed that this infection mediates an adaptive immune response with significant antitumor effects ( 23 ).…”

Membrane Proteins in Trypanosomatids Involved in Ca2+ Homeostasis and Signaling

“…It has also been suggested that the translocated calreticulin binds the host complement component C1 and thereby facilitates parasite invasion [ 58 ]. Due to these properties, the T. cruzi calreticulin has also been regarded to possess an inhibitory effect on cancerous cells [ 59 ]. In Leishmania spp., loss of calreticulin affects the parasite secretory pathway and reduces parasite virulence indicating that ER calcium may have an important role in governing virulence of trypanosomatid parasites [ 60 , 61 ].…”