Is it all That Bad When Living with an Intracellular Protozoan? The Role of Trypanosoma cruzi Calreticulin in Angiogenesis and Tumor Growth

Ramírez-Toloza, Galia; Valck, Carolina; Abello, Paula; Ferreira, Arturo

doi:10.3389/fonc.2014.00382

Cited by 8 publications

(10 citation statements)

References 73 publications

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“…In agreement with the previously described facts, the in vivo antitumor capacity of T. cruzi infection is paralleled by the inoculation of rTcCRT, with inhibits by 60–70% the time-course development of a murine mammary methotrexate multiresistant adenocarcinoma (TA3-MTX-R) ( 7 ).…”

Section: Tccrt Participates In the Inhibition Of Tumor Growthsupporting

confidence: 87%

“…In about 30% of those infected, manifests, Chagas’ disease, a worldwide neglected tropical chronic illness ( 4 , 5 ). The disease, originally endemic in Latin America, is now global, mainly because of migrations to USA, Canada, Europe, Oceania, and Asia ( 6 ), where transmission is mainly through blood transfusions, organ transplants, or congenital ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

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

2016

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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.

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Section: Tccrt Participates In the Inhibition Of Tumor Growthsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

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

2016

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“…S1), suggesting a functional evolutionary pressure and providing a potential selective target for future therapeutic strategies. These species differences could also help to better understand the high anti-angiogenic potential of TcCRT and how it favours wound healing (Ramírez-Toloza et al, 2015;Ignacio Arias et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Structures of parasite calreticulins provide insights into their flexibility and dual carbohydrate/peptide-binding properties

Moreau

Cioci

Iannello

et al. 2016

IUCrJ

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“…When ECs were incubated with rTcCRT, we observed that the protein was internalized. This internalization is inhibited by fluid-phase Fucoidan [ 9 , 10 ], a sulfated polysaccharide and ligand for Scavenger Receptors (SR) [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection?

et al. 2016

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BackgroundFor several decades now an antagonism between Trypanosoma cruzi infection and tumor development has been detected. The molecular basis of this phenomenon remained basically unknown until our proposal that T. cruzi Calreticulin (TcCRT), an endoplasmic reticulum-resident chaperone, translocated-externalized by the parasite, may mediate at least an important part of this effect. Thus, recombinant TcCRT (rTcCRT) has important in vivo antiangiogenic and antitumor activities. However, the relevant question whether the in vivo antitumor effect of T. cruzi infection is indeed mediated by the native chaperone (nTcCRT), remains open. Herein, by using specific modified anti-rTcCRT antibodies (Abs), we have neutralized the antitumor activity of T. cruzi infection and extracts thereof, thus identifying nTcCRT as a valid mediator of this effect.MethodsPolyclonal anti-rTcCRT F(ab’)2 Ab fragments were used to reverse the capacity of rTcCRT to inhibit EAhy926 endothelial cell (EC) proliferation, as detected by BrdU uptake. Using these F(ab’)2 fragments, we also challenged the capacity of nTcCRT, during T. cruzi infection, to inhibit the growth of an aggressive mammary adenocarcinoma cell line (TA3-MTXR) in mice. Moreover, we determined the capacity of anti-rTcCRT Abs to reverse the antitumor effect of an epimastigote extract (EE). Finally, the effects of these treatments on tumor histology were evaluated.ResultsThe rTcCRT capacity to inhibit ECs proliferation was reversed by anti-rTcCRT F(ab’)2 Ab fragments, thus defining them as valid probes to interfere in vivo with this important TcCRT function. Consequently, during infection, these Ab fragments also reversed the in vivo experimental mammary tumor growth. Moreover, anti-rTcCRT Abs also neutralized the antitumor effect of an EE, again identifying the chaperone protein as an important mediator of this anti mammary tumor effect. Finally, as determined by conventional histological parameters, in infected animals and in those treated with EE, less invasive tumors were observed while, as expected, treatment with F(ab’)2 Ab fragments increased malignancy.ConclusionWe have identified translocated/externalized nTcCRT as responsible for at least an important part of the anti mammary tumor effect of the chaperone observed during experimental infections with T. cruzi.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2764-5) contains supplementary material, which is available to authorized users.

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Is it all That Bad When Living with an Intracellular Protozoan? The Role of Trypanosoma cruzi Calreticulin in Angiogenesis and Tumor Growth

Cited by 8 publications

References 73 publications

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

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

Structures of parasite calreticulins provide insights into their flexibility and dual carbohydrate/peptide-binding properties

Does native Trypanosoma cruzi calreticulin mediate growth inhibition of a mammary tumor during infection?

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