<i>Trypanosoma cruzi</i>
            Endotoxin (KR) in the Treatment of Malignant Mouse Tumors

Hauschka, Theodore S.; Goodwin, Margaret Blair

doi:10.1126/science.107.2788.600

Cited by 32 publications

(21 citation statements)

References 6 publications

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“…For six decades now, several reports have proposed a possible growth inhibitory effects that several T. cruzi strains may have on multiple transplanted and spontaneous tumors, in animals and humans [16], [17], [38]. The induction of specific immune anti-tumoral responses [39] and/or the secretion of “toxic substances” by the parasite [16], [40] were invoked to explain these effects, but no experimental evidences have been provided. Maybe, TcCRT, by interacting with endothelial cells and preventing neoangiogenesis, interferes in tumor growth and metastasis.…”

Section: Discussionmentioning

confidence: 99%

Antiangiogenic and Antitumor Effects of Trypanosoma cruzi Calreticulin

et al. 2010

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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.

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Section: Discussionmentioning

confidence: 99%

Antiangiogenic and Antitumor Effects of Trypanosoma cruzi Calreticulin

et al. 2010

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“…[20][21][22] However, others have not confirmed these results, especially when the extract of T. cruzi was used in mouse. 23 One possible antitumoral effect could be explained by the release of many endocellular antigens after the destruction of parasitic neoplastic cells, which stimulates an increase in the immune response. Nonetheless, this possible antitumoral effect weighs against our findings.…”

Section: Discussionmentioning

confidence: 99%

Association of uterine leiomyoma and Chagas' disease.

Murta¹,

Oliveira²,

Prado³

et al. 2002

The American Journal of Tropical Medicine and Hygiene

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Abstract. With the aim of studying the frequency of Chagas' disease among sufferers of uterine leiomyoma, we analyzed women older than 35 years who underwent surgery and presented with leiomyoma on anatomicopathological examination. The diagnosis of Chagas infection was based on positivity to at least two of three serological tests: enzyme-linked immunosorbent assay, passive hemagglutination, and immunofluorescence. The study was case controlled, matching for age, skin color, and parity. The control group consisted of women undergoing surgery for other benign gynecological alterations. During this period, 118 women presented with uterine leiomyoma, 27.1% of whom were serologically positive for Chagas' disease versus 16.1% of the controls (P < 0.05). Matching by skin color and parity showed that 40% of the white multiparous women with uterine leiomyoma had Chagas' disease versus 10% of the controls (P < 0.05). We concluded that there appears to be an association between Chagas' disease and uterine leiomyoma.

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“…Later, he published an article demonstrating tumor regression in human patients infected with T. cruzi (38). A growing interest in using T. cruzi to treat cancer was pursued by different research groups (39,40), and T. cruzi preparations for cancer therapy were launched by French and Russian pharmaceutical companies (36). Although similar results were found, the ambiguity of the findings obtained by various investigators regarding efficacy against experimental tumors (41) led to the discontinuation of this line of investigation and commercial distribution of this anticancer compound.…”

Section: Both Attenuated Viruses and Bacteria Have Been Largely Explomentioning

confidence: 95%

Trypanosoma cruzias an effective cancer antigen delivery vector

Junqueira

Santos

Galvão-Filho

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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One of the main challenges in cancer research is the development of vaccines that induce effective and long-lived protective immunity against tumors. Significant progress has been made in identifying members of the cancer testis antigen family as potential vaccine candidates. However, an ideal form for antigen delivery that induces robust and sustainable antigen-specific T-cell responses, and in particular of CD8 + T lymphocytes, remains to be developed. Here we report the use of a recombinant nonpathogenic clone of Trypanosoma cruzi as a vaccine vector to induce vigorous and longterm T cell-mediated immunity. The rationale for using the highly attenuated T. cruzi clone was (i) the ability of the parasite to persist in host tissues and therefore to induce a long-term antigen-specific immune response; (ii) the existence of intrinsic parasite agonists for Toll-like receptors and consequent induction of highly polarized T helper cell type 1 responses; and (iii) the parasite replication in the host cell cytoplasm, leading to direct antigen presentation through the endogenous pathway and consequent induction of antigenspecific CD8 + T cells. Importantly, we found that parasites expressing a cancer testis antigen (NY-ESO-1) were able to elicit human antigen-specific T-cell responses in vitro and solid protection against melanoma in a mouse model. Furthermore, in a therapeutic protocol, the parasites expressing NY-ESO-1 delayed the rate of tumor development in mice. We conclude that the T. cruzi vector is highly efficient in inducing T cell-mediated immunity and protection against cancer cells. More broadly, this strategy could be used to elicit a long-term T cell-mediated immunity and used for prophylaxis or therapy of chronic infectious diseases.cytokine | prophylaxis | protozoa | innate immunity | Trypanosoma cruzi CL-14

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Trypanosoma cruzi Endotoxin (KR) in the Treatment of Malignant Mouse Tumors

Cited by 32 publications

References 6 publications

Antiangiogenic and Antitumor Effects of Trypanosoma cruzi Calreticulin

Antiangiogenic and Antitumor Effects of Trypanosoma cruzi Calreticulin

Association of uterine leiomyoma and Chagas' disease.

Trypanosoma cruzias an effective cancer antigen delivery vector

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