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Do helminths play a role in carcinogenesis?
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immunogenicity of hookworm (Necator americanus) acetylcholinesterase (AChE) in man. Parasite Immunol. 15, 195–203 Pritchard, D.I. et al. (1990) The epidemiological significance of the immune response to the cuticular collagen of Necator americanus: a preliminary study in a hookworm-endemic area in Papua New Guinea. Acta Trop. 47, 403–407 Brophy, P.M. et al. (1995) Secretory nematode SOD-offensive or defensive? Int. J. Parasitol. 25, 865–866 Taiwo, F.A. et al. (1999) Cu/Zn superoxide dismutase in excretory-secretory products of the human hookworm Necator americanus: an electron paramagnetic study. Eur. J. Biochem. 264, 434–438 Brophy, P.M. et al. (1995) Glutathione S-transferase (GST) expression in the human hookworm Necator americanus: potential roles for excretory-secretory forms of GST. Acta Trop. 59, 259–263 Pritchard, D.I. (1996) Do haematophagous parasites secrete SOD and promote blood flow? Int. J. Parasitol. 26, 1339–1340 Daub, J. et al. (2000) A survey of genes expressed in adults of the human hookworm Necator americanus. Parasitology 120, 171–184 Pritchard, D.I. et al. (1999) A hookworm allergen that strongly resembles calreticulin. Parasite Immunol. 21, 439–450 Chow, S.C. (2000) The human hookworm pathogen Necator americanus induces apoptosis
TRENDS in Parasitology Vol.17 No.4 April 2001
in T lymphocytes. Parasitology 22, 21–29 14 Pritchard, D.I. et al. (1995) Immunity in humans to N. americanus: IgE, parasite weight and fecundity. Parasite Immunol. 71, 71–75 15 Hewitt, C.R.A. et al. (1998) Mite allergens: significance of enzyme activity. Allergy 53, 60–63 16 Machado, D.C. et al. (1996) Potential allergens stimulate the release of mediators of the allergic response from cells of mast cell lineage in the absence of sensitization with antigen specific IgE. Eur. J. Immunol. 26, 2972–2980 17 Culley, F. et al. (2000) Eotaxin is specifically cleaved by hookworm metalloproteases preventing its action in vitro and in vivo. J. Immunol. 165, 6447–6453 18 Daëron, M. et al. (1995) Regulation of highaffinity IgE receptor-mediated mast cell activation by murine low-affinity IgG receptors. J. Clin. Invest. 95, 577–585 19 Shakib, F. et al. (1993) The detection of autoantibodies to IgE in plasma of individuals infected with hookworm (Necator americanus) and the demonstration of a predominant IgG1 anti-IgE autoantibody response. Parasite Immunol. 15, 47–53 20 Ono, M. et al. (1996) Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FcγRIIIB. Nature 383, 263–266 21 Furmidge, B.A. et al. (1995) The anti-haemostatic
Do helminths play a role in carcinogenesis? Luis A. Herrera and Patricia Ostrosky-Wegman
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strategies of the human hookworm Necator americanus. Parasitology 112, 81–87 Haas, H. et al. (1999) Dietary lectins can induce in vitro release of IL-4 and IL-13 from human basophils. Eur. J. Immunol. 29, 918–927 Croese, T.J. et al. (1990) Eosinophilic enteritis presenting as surgical emergecies: a report of six cases. Med. J. Aust. 153, 415–417 Pritchard, D.I. et al. (1997) The relationship between immunological responsiveness controlled by T-helper 2 lymphocytes and infections with parasitic helminths. Parasitology 115, S33–S44 Hagel, I. et al. (1995) Relationship between asthma and immune-response against Ascaris lumbricoides in children from a Venezuelan fishermen community with a high prevalence of asthma. J. Allergy Clin. Immunol. 95, 317 Oppenheimer, S.J. (1994) Iron and infection: a clinical review. J. Singapore Paed. Soc. 36, S112–S122 Nacher, M. et al. (2000) Ascaris lumbricoides infection is associated with protection from cerebral malaria. Parasite Immunol. 22, 107–113 Cooke, A. et al. (1999) Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitis in non-obese diabetic mice. Parasite Immunol. 21, 169–176 Brophy, P.M. and Pritchard, D.I. (1992) Immunity to helminths: ready to tip the biochemical balance? Parasitol. Today 8, 419–422
cancer in humans3–5. It has been estimated that chronic infections by viruses, bacteria and parasites contribute to 13% of the world’s cancer5. Although several parasites, helminths in particular, have been implicated in the etiology of human cancer4, the knowledge of the mechanisms by which parasites induce malignant transformation of host cells is unclear. Figure 1 displays several conditions that disturb key genetic and epigenetic processes that regulate cell proliferation hereby influencing carcinogenesis in infected individuals. Inflammation as a source of genetic instability
Chronic helminthiasis is recognized as a significant factor in cancer development in humans. However, the mechanisms by which helminths initiate and promote malignant transformation of host cells are still not understood fully. Human helminthiasis can cause genetic instability and affect inter- and intracellular communication, ultimately leading to tumour development through inflammation, modulation of the host immune system, and secretion of soluble factors that interact with host cells.
Luis A. Herrera* Patricia Ostrosky-Wegman Instituto de Investigaciones Biomédicas, Universidad Nacional Autonoma de Mexico. Dept Genética y Toxicología Ambiental, PO Box 70-228, Ciudad Universitaria, México D.F. 04510, Mexico. *e-mail: [email protected]
Carcinogenesis is a complex process in which normal cell growth is modified as a result of the interaction of multiple factors, including xenobiotics and endogenous constituents. It is accepted currently that the carcinogenic process results from the accumulation of both genetic and epigenetic changes that are driven by instability of the cellular genome and alterations in inter- and intra-cellular communication, which disrupt the regulation of cell proliferation1,2. There is strong evidence to suggest that biological carcinogens are a major cause of
Inflammation is a common feature of helminthiasis in which inflammatory cells generate reactive oxygen and nitrogen species that, apart from killing invading pathogens, are capable of inducing genetic instability in normal surrounding tissue, which can lead to malignant transformation. The reactive oxygen and nitrogen species can oxidize and damage DNA, either directly or after interaction with other radicals or cellular components6,7. Activated inflammatory cells reduce oxygen by the plasma membrane-associated nicotinamide adenine dinucleotide phosphate oxidase to the free radical superoxide anion, which can participate in the transition metal-catalyzed Haber–Weiss reaction and generate the more reactive hydroxyl radical8. Alternatively, the superoxide anion can form hydrogen peroxide that reacts with reduced transition metals bound to macromolecules such as DNA to form activated metal complexes that can
http://parasites.trends.com 1471-4922/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0169-4758(00)01859-7
Opinion
TRENDS in Parasitology Vol.17 No.4 April 2001
Inflammatory response
Inflammatory response
(nitrosamine formation, nitrogen and oxygen radicals, altered xenobiotic metabolism)
(increased cell proliferation)
Secretion of genotoxic factors
Secretion of soluble factors Persistent antigen stimulation
Genetic instability and epigenetic events
Initiation
Promotion
Progression
Altered immunological surveillance TRENDS in Parasitology
Fig. 1. Events during human parasitic infections that might influence the multistage carcinogenic process. Parasites might initiate carcinogenesis by direct action of genotoxic factors, either secreted by them or produced during the inflammatory response. Instability of the host genome and disruption of the inter- and intra-cellular communication processes can be influenced by products of the inflammatory response, an increased proliferative response of host cells to repair the tissue damage incurred during inflammation, soluble factors secreted by the parasite, and by the clonal expansion of some host cells induced by a persistent antigen stimulation. Genetic instability of host cells causes modifications in regulation of oncogenes and tumour-suppressor genes, and, together with epigenetic events, interferes with control of cell proliferation, which plays an important role in tumour formation. An altered immunological surveillance might enable the clonal expansion of initiated cells, thereby enhancing the development of malignancy.
cause extensive and site-specific damage8. Oxidative DNA damage leads to single- or double-strand DNA breaks, to point and frameshift mutations, and to chromosome abnormalities9. Nitric oxide and its derivatives produced by activated phagocytes also play a role in the multistage carcinogenesis process. Nitric oxide can be oxidized directly to nitrogen dioxide, which induces DNA damage10. Nitric oxide reacts also with the superoxide anion to form peroxynitrite, which can be cytotoxic and can decompose to hydroxyl radicals and nitrogen dioxide11. Peroxynitrite oxidizes sulfhydril groups and induces lipid peroxidation7. Several products derived from primary lipid peroxidation react directly with DNA, such as malondialdehyde and 4-hydroxynonenal, which are highly mutagenic and genotoxic7. Inflammatory cells also have been shown to participate in the metabolic activation of procarcinogens, such as aflatoxins and polycyclic aromatic hydrocarbons12, and in the formation of carcinogenic nitrosamines from nitric oxide13. In addition, the altered metabolic capacity of cells surrounding the site of inflammation to xenobiotics might increase susceptibility to toxic agents that http://parasites.trends.com
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individuals are normally exposed to14. Once DNA damage has been generated, it might be transmitted to the next cell generations, giving rise to clones of transformed cells, an event that could be enhanced by the proliferative response of host cells to repair the tissue damage incurred during inflammation15. Eosinophilia and inflammation might lead to the induction of genes important for carcinogenesis. Recent experiments suggested that the development of brain injury by eosinophilia in mice infected with Angiostrongylus cantonensis, the causative agent of human eosinophilic meningoencephalitis in the Pacific islands and Southeast Asia, is associated with NF-κB and nuclear protooncogene expression, which is activated by the tyrosine phosphorylation pathway16. Modulation of host immune system
Malignancies suspected of originating with chronic inflammation occur near the site of inflammation, for example, bladder cancer in schistosomiasis patients4,12. However, systemic cancers might also result from chronic infections.17 Therefore, other events, not related to the inflammatory process could also be involved in parasite-induced carcinogenesis. Parasites have evolved mechanisms to avoid immune recognition by the host. These strategies include the production of antigenic variants, inhibition of host proteins such as histocompatibility antigens, disruption of the antigen-processing pathway and inactivation of complement and antibody function18. The mechanisms by which parasites evade the immune attack frequently lead to immunopathological changes that can affect immunological surveillance, a condition that might contribute to the clonal expansion of transformed cells19. However, some reports have indicated a higher frequency of genetic damage in bone marrow cells and peripheral lymphocytes of parasitized animals and patients, than to that observed in uninfected donors or treated individuals20–22. If this genetic damage is not repaired, the persistent antigenic stimulation characteristic of several helminthiases might increase the proliferation rate of damaged cells and ultimately represent a promoting factor for hematological malignancies in parasitized individuals. Soluble factors secreted by parasites that might participate in carcinogenesis
To survive for long periods in a disadvantageous and aggressive environment, helminths secrete several soluble factors that interact with host cells. It is therefore possible that some of these molecules might modify host-cell homeostasis and increase the risk of malignant transformation. A putative RNA molecule, secreted by Taenia solium cysticerci23, has the capacity to transform Syrian hamster embryo cells in vitro24. Recently, we have found that this molecule induces chromosome damage in cultures of human
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lymphocytes (L.A. Herrera and P. Ostrosky-Wegman, unpublished), suggesting that this factor might induce genetic instability in infected individuals. The mechanism by which this molecule could induce genetic damage and transform host cells is unknown; however, a direct interaction between RNA and genomic DNA might be related to the observed effects as has been suggested for other low-molecular-weight RNAs, such as U5, that are able to induce chromosomal aberrations and transform murine cells in vitro25. Parasite-secreted factors could also be involved in tumour promotion and progression. For example, the Schistosoma soluble egg-antigen, one of the most important components in the pathology of schistosomiasis, has been shown to have a weak but significant tumour-promoting activity26. Although not as well characterized as the soluble egg antigen from Schistosoma, some protein components of Taenia taeniaeformis larval excretory–secretory products might induce hyperplasia of the stomach in heavily infected rats27. Accelerated body growth has also been associated with experimental infections with the plerocercoid stage of Spirometra mansonoides28. This response is mediated by a protein that interacts with mammalian growth hormone receptors and mimics many of the biological actions of growth hormone. The sustained inhibition of cell–cell communication plays a key role in the clonal expansion of initiated cells that give rise to tumours2. The potential events that could lead to inhibition of intercellular communication in parasitized tissues are worth investigating because parasites not only represent a physical barrier for intercellular communication, but also secrete factors that might disrupt cell–cell communication processes, thus contributing to the multistage carcinogenic process. Such factors include proteases, which are essential for invasion of host tissues by helminths18,29,30. Final comments
The relationship between helminths and cancer has been suggested before. Indeed, Johanes Fibiger received a Nobel Prize in 1926 for his work on gastric carcinoma induced by Spiroptera neoplastica. In 1919, Fibiger reported the induction of stomach cancer in mice by feeding them cockroaches infected with S. neoplastica larvae. Fibiger’s hypothesis was later questioned because other workers not only failed to reproduce his results, but also suggested that Fibiger misinterpreted hyperplastic lesions associated with vitamin A deficiency as gastric carcinoma. The hypothesis that cancer is caused by some infectious agent was then practically forgotten. Despite all criticism of his work with S. neoplastica (now Gongylonema neoplasticum), Johanes Fibiger made an important contribution to cancer research through the use of experimental models to investigate cancer causality. Today, there is no doubt that helminths can induce cancer in both animals and humans, and that chronic inflammation plays a key http://parasites.trends.com
role in parasite-associated cancers. However, host–parasite relationships are rather complex, and inflammation is not the only mechanism by which parasites could transform host cells. Some studies suggest that parasites could harbour viral particles31,32, raising the possibility of genetic exchange with their hosts, which also might participate in carcinogenesis. Furthermore, parasites might stimulate the proliferation of virus-infected cells, which would shorten the period of latency for cancer development. This has also been suggested for asymptomatic human T-cell leukaemia virus carriers that are also infected with Strongyloides stercoralis and develop adult T-cell leukaemia in a shorter period than non-infected carriers33. In addition to helminths, protozoa are also relevant to this research, especially Theileria spp. Theileria spp. are obligate intracellular parasites of cattle and cause transformation of infected cells, which then exhibit characteristics of tumour cells, proliferating in an uncontrolled manner. Transformation by Theileria spp. seems to be regulated by the interference of host signal-transduction pathways that involve several kinases and transcription factors [e.g. members of the Src family, casein kinase II, and NF-κB (Ref. 34)]. Remarkably, Theileria-induced transformation has neither been associated with permanent alterations of the host genome nor with the integration of foreign DNA sequences; transformation can be reversed by theilericidal drugs. Bladder cancer induced by Schistosoma haematobium is perhaps the best-investigated helminth-associated neoplasia, in which some of the molecular events that cause malignant transformation of normal human cells have been identified [e.g. inactivation of p53, deletion of p16INK4 and overexpression of Bcl-2 (Ref. 35)]. Although the sequence of events during carcinogenesis in humans have been speculated upon, there is not enough supporting evidence, because molecular observations mostly have been in advanced tumour stages. The generation of malignant transformation in animal models could provide a good opportunity to analyze the specific role of each parasite-induced event in carcinogenesis. The International Agency for Research on Cancer of the WHO has found sufficient evidence for a causal association between S. haematobium, Opistorchis viverrini and specific cancers in humans4. Nevertheless, the number of helminthiases for which there is evidence of association with cancer is low, relative to the large number of helminths that can infect humans36. One explanation suggested for this is the difficulty in studying the correlation between human parasitic diseases and cancer, because of their complex natural history. Cancer and most human helminthiases are long-lasting disorders and both have a prolonged asymptomatic period, during which many other endogenous and exogenous factors can interact and obscure a causal relationship. However,
Opinion
Acknowledgements We thank Ana Flisser and Raymond Damian for their helpful advice. L.A.H. is also at the Institute Nacional de Cancerología, Mexico City, Mexico.
TRENDS in Parasitology Vol.17 No.4 April 2001
the secretion of particular parasite factors that alter host cell homeostasis and induce malignant transformation could restrict the association of specific parasitic diseases with cancer. In any case, we emphasize that carcinogenesis associated with parasite infections is a complex process during which host–parasite interactions might initiate several of the steps that lead to tumour formation (Fig. 1).
References 1 Loeb, K. and Loeb, L. (2000) Significance of multiple mutations in cancer. Carcinogenesis 21, 379–385 2 Trosko, J.E. and Ruch, R.J. (1998) Cell–cell communication in carcinogenesis. Front. Biosci. 3, D208–D236 3 Ames, B. and Gold, L. (1997) The causes and prevention of cancer: gaining perspective. Environ. Health Perspect. 105, 865–873 4 International Agency for Research on Cancer. (1994) Schistosomes, Liver Flukes and Helicobacter pylori. IARC Lyon: International Agency for Research on Cancer, Monographs on the Evaluation of Carcinogenic Risks to Humans, Lyon, 7–14 June, 1–241 5 Parkin, D.M. et al. (1999) The global health burden of infection associated cancers. Cancer Surv. 33, 5–33 6 Ohshima, H. and Bartsch, H. (1994) Chronic infections and inflammatory processes as cancer risk factors: possible role of nitric oxide in carcinogenesis. Mutat. Res. 305, 253–264 7 Burcham, P. (1998) Genotoxic lipid peroxidation products: their DNA damaging properties and role in formation of endogenous DNA adducts. Mutagenesis 13, 287–305 8 Frenkel, K. (1992) Carcinogen-mediated oxidant formation and oxidative DNA damage. Pharmacol. Ther. 53, 127–166 9 Feig, D. et al. (1994) Reactive oxygen species in tumorigenesis. Cancer Res. 54, 1890s–1894s 10 Bittrich, T. et al. (1993) NO2-induced DNA single strand breaks are inhibited by antioxidative vitamins in V79 cells. Chem. Biol. Interact. 86, 199–211 11 Beckman, J. et al. (1990) Apparent hydroxyl radical production by peroxynitrite: Implications for endothelial injury from nitric oxide and superoxide. Proc. Natl. Acad. Sci. U. S. A. 87, 1620–1624 12 Rosin, M. et al. (1994) Inflammation, chromosomal instability, and cancer: the schistosomiasis model. Cancer Res. (Suppl.) 54, 1929s–1933s 13 Haswell-Elkins, M. et al. (1994) Liver fluke
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Therefore, the impact of parasitic infections on cancer incidence is important especially in countries where individuals harbouring worms live for long periods, increasing the chance of malignant transformation. In these countries, individuals are normally exposed to other xenobiotics – thus, carcinogenesis in parasitized individuals might result from the interaction of multiple cancer risk factors.
infection and cholangiocarcinoma: model of endogenous nitric oxide and extragastric nitrosation in human carcinogenesis. Mutat. Res. 305, 241–252 Montero, R. et al. (1999) Induced expression of CYP2A5 in inflamed trematode-infested mouse liver. Mutagenesis 14, 217–220 Rosin, M. et al. (1994) Involvement of inflammatory reactions and elevated cell proliferation in the development of bladder cancer in schistosomiasis patients. Mutat. Res. 305, 283–292 Lee, H. et al. (2000) Development of brain injury in mice by Angiostrongylus cantonensis infection is associated with the induction of transcription factor NF-κB, nuclear protooncogenes, and protein tryrosine phosphorylation. Exp. Parasitol. 95, 202–208 Herrera, L.A. et al. (1999) Possible relationship between neurocysticercosis and hematological malignancies. Arch. Med. Res. 30, 154–158 White, A.C. et al. (1997) Taenia solium cysticercosis: Host–parasite interactions and immune response. Chem. Immunol. 66, 209–230 Pettit, K. et al. (2000) Immune selection in neoplasia: towards a microevolutionary model of cancer development. Br. J. Cancer 82, 1900–1906 Flisser, A. et al. (1990) Praziquantel treatment of brain and muscle porcine Taenia solium cysticercosis. Immunological and cytogenetic studies. Parasitol. Res. 76, 640–642 Ilyinskikh, E. et al. (1998) Estimation of the mutagenic potential of the trematode Opisthorchis felineus in experimentally infected guinea pigs. Parasitol. Res. 84, 570–572 Herrera, L.A. et al. (2000) Possible association between Taenia solium cysticercosis and cancer: increased frequency of DNA damage in peripheral lymphocytes from neurocysticercosis patients. Trans. R Soc. Trop. Med. Hyg. 94, 61–65 Molinari, J.L. et al. (1990) Depressive effect of a Taenia solium cysticercus factor on cultured human lymphocytes stimulated with phytohaemaglutinin. Ann. Trop. Med Parasitol. 84, 205–208 Herrera, L.A. et al. (1994) Immune response
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impairment, genotoxicity and morphological transformation induced by Taenia solium metacestode. Mutat. Res. 305, 223–228 Hamada, K. and Yokoro, K. (1995) Blocking of DNA synthesis in vitro by a guanosine 2′,3′cyclic phosphate: A possible mechanism of chromosome aberrations induced by U5 snRNA. Mutat. Res. 326, 71–82 Ishii, A. et al. (1989) Evaluation of the mutagenicity and the tumor-promoting activity of parasite extracts: Schistosoma japonicum and Clonorchis sinensis. Mutat. Res. 224, 229–233 Konno, K. et al. (1999) Hyperplasia of gastric mucosa in donor rats orally infected with Taenia taeniaeformis eggs and in recipient rats surgically implanted with the larvae in the abdominal cavity. Parasitol. Res. 85, 431–436 Phares, K. (1996) An unusual host–parasite relationship: the growth hormone-like factor from plerocercoids of spirometrid tapeworms. Int. J. Parasitol. 26, 575–88 McKerrow, J.H. (1989) Parasite proteases. Exp. Parasitol. 68, 111–115 Polzer, M. et al. (1994) Proteinase activity in the plerocercoid of Protocephalus ambloplitis (Cestoda). Parasitology 109, 209–213 Laclette, J. et al. (1990) Crystals of virus-like particles in the metacestodes of Taenia solium and T. crassiceps. J. Invertebr. Pathol. 56, 215–221 Khramtsov, N. et al. (2000) Presence of doublestranded RNAs in human and calf isolates of Cryptosporidium parvum. J. Parasitol. 86, 275–282 Gabet, A.S. et al. (2000) High circulating proviral load with oligoclonal expansion of HTLV-1 bearing T cells in HTLV-1 carriers with strongyloidiasis. Oncogene 19, 4954–4960 Dobbelaere, D. and Heussler, V. (1999) Transformation of leukocytes by Theileria parva and T. annulata. Annu. Rev. Microbiol. 53, 1–42 Mostafa, M. et al. (1999) Relationship between schistosomiasis and bladder cancer. Clin. Microbiol. Rev. 12, 97–111 Crompton, D. (1999) How much human helminthiasis is there in the world? J. Parasitol. 85, 397–403
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immunogenicity of hookworm (Necator americanus) acetylcholinesterase (AChE) in man. Parasite Immunol. 15, 195–203 Pritchard, D.I. et al. (1990) The epidemiological significance of the immune response to the cuticular collagen of Necator americanus: a preliminary study in a hookworm-endemic area in Papua New Guinea. Acta Trop. 47, 403–407 Brophy, P.M. et al. (1995) Secretory nematode SOD-offensive or defensive? Int. J. Parasitol. 25, 865–866 Taiwo, F.A. et al. (1999) Cu/Zn superoxide dismutase in excretory-secretory products of the human hookworm Necator americanus: an electron paramagnetic study. Eur. J. Biochem. 264, 434–438 Brophy, P.M. et al. (1995) Glutathione S-transferase (GST) expression in the human hookworm Necator americanus: potential roles for excretory-secretory forms of GST. Acta Trop. 59, 259–263 Pritchard, D.I. (1996) Do haematophagous parasites secrete SOD and promote blood flow? Int. J. Parasitol. 26, 1339–1340 Daub, J. et al. (2000) A survey of genes expressed in adults of the human hookworm Necator americanus. Parasitology 120, 171–184 Pritchard, D.I. et al. (1999) A hookworm allergen that strongly resembles calreticulin. Parasite Immunol. 21, 439–450 Chow, S.C. (2000) The human hookworm pathogen Necator americanus induces apoptosis
TRENDS in Parasitology Vol.17 No.4 April 2001
in T lymphocytes. Parasitology 22, 21–29 14 Pritchard, D.I. et al. (1995) Immunity in humans to N. americanus: IgE, parasite weight and fecundity. Parasite Immunol. 71, 71–75 15 Hewitt, C.R.A. et al. (1998) Mite allergens: significance of enzyme activity. Allergy 53, 60–63 16 Machado, D.C. et al. (1996) Potential allergens stimulate the release of mediators of the allergic response from cells of mast cell lineage in the absence of sensitization with antigen specific IgE. Eur. J. Immunol. 26, 2972–2980 17 Culley, F. et al. (2000) Eotaxin is specifically cleaved by hookworm metalloproteases preventing its action in vitro and in vivo. J. Immunol. 165, 6447–6453 18 Daëron, M. et al. (1995) Regulation of highaffinity IgE receptor-mediated mast cell activation by murine low-affinity IgG receptors. J. Clin. Invest. 95, 577–585 19 Shakib, F. et al. (1993) The detection of autoantibodies to IgE in plasma of individuals infected with hookworm (Necator americanus) and the demonstration of a predominant IgG1 anti-IgE autoantibody response. Parasite Immunol. 15, 47–53 20 Ono, M. et al. (1996) Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FcγRIIIB. Nature 383, 263–266 21 Furmidge, B.A. et al. (1995) The anti-haemostatic
Do helminths play a role in carcinogenesis? Luis A. Herrera and Patricia Ostrosky-Wegman
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strategies of the human hookworm Necator americanus. Parasitology 112, 81–87 Haas, H. et al. (1999) Dietary lectins can induce in vitro release of IL-4 and IL-13 from human basophils. Eur. J. Immunol. 29, 918–927 Croese, T.J. et al. (1990) Eosinophilic enteritis presenting as surgical emergecies: a report of six cases. Med. J. Aust. 153, 415–417 Pritchard, D.I. et al. (1997) The relationship between immunological responsiveness controlled by T-helper 2 lymphocytes and infections with parasitic helminths. Parasitology 115, S33–S44 Hagel, I. et al. (1995) Relationship between asthma and immune-response against Ascaris lumbricoides in children from a Venezuelan fishermen community with a high prevalence of asthma. J. Allergy Clin. Immunol. 95, 317 Oppenheimer, S.J. (1994) Iron and infection: a clinical review. J. Singapore Paed. Soc. 36, S112–S122 Nacher, M. et al. (2000) Ascaris lumbricoides infection is associated with protection from cerebral malaria. Parasite Immunol. 22, 107–113 Cooke, A. et al. (1999) Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitis in non-obese diabetic mice. Parasite Immunol. 21, 169–176 Brophy, P.M. and Pritchard, D.I. (1992) Immunity to helminths: ready to tip the biochemical balance? Parasitol. Today 8, 419–422
cancer in humans3–5. It has been estimated that chronic infections by viruses, bacteria and parasites contribute to 13% of the world’s cancer5. Although several parasites, helminths in particular, have been implicated in the etiology of human cancer4, the knowledge of the mechanisms by which parasites induce malignant transformation of host cells is unclear. Figure 1 displays several conditions that disturb key genetic and epigenetic processes that regulate cell proliferation hereby influencing carcinogenesis in infected individuals. Inflammation as a source of genetic instability
Chronic helminthiasis is recognized as a significant factor in cancer development in humans. However, the mechanisms by which helminths initiate and promote malignant transformation of host cells are still not understood fully. Human helminthiasis can cause genetic instability and affect inter- and intracellular communication, ultimately leading to tumour development through inflammation, modulation of the host immune system, and secretion of soluble factors that interact with host cells.
Luis A. Herrera* Patricia Ostrosky-Wegman Instituto de Investigaciones Biomédicas, Universidad Nacional Autonoma de Mexico. Dept Genética y Toxicología Ambiental, PO Box 70-228, Ciudad Universitaria, México D.F. 04510, Mexico. *e-mail: [email protected]
Carcinogenesis is a complex process in which normal cell growth is modified as a result of the interaction of multiple factors, including xenobiotics and endogenous constituents. It is accepted currently that the carcinogenic process results from the accumulation of both genetic and epigenetic changes that are driven by instability of the cellular genome and alterations in inter- and intra-cellular communication, which disrupt the regulation of cell proliferation1,2. There is strong evidence to suggest that biological carcinogens are a major cause of
Inflammation is a common feature of helminthiasis in which inflammatory cells generate reactive oxygen and nitrogen species that, apart from killing invading pathogens, are capable of inducing genetic instability in normal surrounding tissue, which can lead to malignant transformation. The reactive oxygen and nitrogen species can oxidize and damage DNA, either directly or after interaction with other radicals or cellular components6,7. Activated inflammatory cells reduce oxygen by the plasma membrane-associated nicotinamide adenine dinucleotide phosphate oxidase to the free radical superoxide anion, which can participate in the transition metal-catalyzed Haber–Weiss reaction and generate the more reactive hydroxyl radical8. Alternatively, the superoxide anion can form hydrogen peroxide that reacts with reduced transition metals bound to macromolecules such as DNA to form activated metal complexes that can
http://parasites.trends.com 1471-4922/01/$ – see front matter © 2001 Elsevier Science Ltd. All rights reserved. PII: S0169-4758(00)01859-7
Opinion
TRENDS in Parasitology Vol.17 No.4 April 2001
Inflammatory response
Inflammatory response
(nitrosamine formation, nitrogen and oxygen radicals, altered xenobiotic metabolism)
(increased cell proliferation)
Secretion of genotoxic factors
Secretion of soluble factors Persistent antigen stimulation
Genetic instability and epigenetic events
Initiation
Promotion
Progression
Altered immunological surveillance TRENDS in Parasitology
Fig. 1. Events during human parasitic infections that might influence the multistage carcinogenic process. Parasites might initiate carcinogenesis by direct action of genotoxic factors, either secreted by them or produced during the inflammatory response. Instability of the host genome and disruption of the inter- and intra-cellular communication processes can be influenced by products of the inflammatory response, an increased proliferative response of host cells to repair the tissue damage incurred during inflammation, soluble factors secreted by the parasite, and by the clonal expansion of some host cells induced by a persistent antigen stimulation. Genetic instability of host cells causes modifications in regulation of oncogenes and tumour-suppressor genes, and, together with epigenetic events, interferes with control of cell proliferation, which plays an important role in tumour formation. An altered immunological surveillance might enable the clonal expansion of initiated cells, thereby enhancing the development of malignancy.
cause extensive and site-specific damage8. Oxidative DNA damage leads to single- or double-strand DNA breaks, to point and frameshift mutations, and to chromosome abnormalities9. Nitric oxide and its derivatives produced by activated phagocytes also play a role in the multistage carcinogenesis process. Nitric oxide can be oxidized directly to nitrogen dioxide, which induces DNA damage10. Nitric oxide reacts also with the superoxide anion to form peroxynitrite, which can be cytotoxic and can decompose to hydroxyl radicals and nitrogen dioxide11. Peroxynitrite oxidizes sulfhydril groups and induces lipid peroxidation7. Several products derived from primary lipid peroxidation react directly with DNA, such as malondialdehyde and 4-hydroxynonenal, which are highly mutagenic and genotoxic7. Inflammatory cells also have been shown to participate in the metabolic activation of procarcinogens, such as aflatoxins and polycyclic aromatic hydrocarbons12, and in the formation of carcinogenic nitrosamines from nitric oxide13. In addition, the altered metabolic capacity of cells surrounding the site of inflammation to xenobiotics might increase susceptibility to toxic agents that http://parasites.trends.com
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individuals are normally exposed to14. Once DNA damage has been generated, it might be transmitted to the next cell generations, giving rise to clones of transformed cells, an event that could be enhanced by the proliferative response of host cells to repair the tissue damage incurred during inflammation15. Eosinophilia and inflammation might lead to the induction of genes important for carcinogenesis. Recent experiments suggested that the development of brain injury by eosinophilia in mice infected with Angiostrongylus cantonensis, the causative agent of human eosinophilic meningoencephalitis in the Pacific islands and Southeast Asia, is associated with NF-κB and nuclear protooncogene expression, which is activated by the tyrosine phosphorylation pathway16. Modulation of host immune system
Malignancies suspected of originating with chronic inflammation occur near the site of inflammation, for example, bladder cancer in schistosomiasis patients4,12. However, systemic cancers might also result from chronic infections.17 Therefore, other events, not related to the inflammatory process could also be involved in parasite-induced carcinogenesis. Parasites have evolved mechanisms to avoid immune recognition by the host. These strategies include the production of antigenic variants, inhibition of host proteins such as histocompatibility antigens, disruption of the antigen-processing pathway and inactivation of complement and antibody function18. The mechanisms by which parasites evade the immune attack frequently lead to immunopathological changes that can affect immunological surveillance, a condition that might contribute to the clonal expansion of transformed cells19. However, some reports have indicated a higher frequency of genetic damage in bone marrow cells and peripheral lymphocytes of parasitized animals and patients, than to that observed in uninfected donors or treated individuals20–22. If this genetic damage is not repaired, the persistent antigenic stimulation characteristic of several helminthiases might increase the proliferation rate of damaged cells and ultimately represent a promoting factor for hematological malignancies in parasitized individuals. Soluble factors secreted by parasites that might participate in carcinogenesis
To survive for long periods in a disadvantageous and aggressive environment, helminths secrete several soluble factors that interact with host cells. It is therefore possible that some of these molecules might modify host-cell homeostasis and increase the risk of malignant transformation. A putative RNA molecule, secreted by Taenia solium cysticerci23, has the capacity to transform Syrian hamster embryo cells in vitro24. Recently, we have found that this molecule induces chromosome damage in cultures of human
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lymphocytes (L.A. Herrera and P. Ostrosky-Wegman, unpublished), suggesting that this factor might induce genetic instability in infected individuals. The mechanism by which this molecule could induce genetic damage and transform host cells is unknown; however, a direct interaction between RNA and genomic DNA might be related to the observed effects as has been suggested for other low-molecular-weight RNAs, such as U5, that are able to induce chromosomal aberrations and transform murine cells in vitro25. Parasite-secreted factors could also be involved in tumour promotion and progression. For example, the Schistosoma soluble egg-antigen, one of the most important components in the pathology of schistosomiasis, has been shown to have a weak but significant tumour-promoting activity26. Although not as well characterized as the soluble egg antigen from Schistosoma, some protein components of Taenia taeniaeformis larval excretory–secretory products might induce hyperplasia of the stomach in heavily infected rats27. Accelerated body growth has also been associated with experimental infections with the plerocercoid stage of Spirometra mansonoides28. This response is mediated by a protein that interacts with mammalian growth hormone receptors and mimics many of the biological actions of growth hormone. The sustained inhibition of cell–cell communication plays a key role in the clonal expansion of initiated cells that give rise to tumours2. The potential events that could lead to inhibition of intercellular communication in parasitized tissues are worth investigating because parasites not only represent a physical barrier for intercellular communication, but also secrete factors that might disrupt cell–cell communication processes, thus contributing to the multistage carcinogenic process. Such factors include proteases, which are essential for invasion of host tissues by helminths18,29,30. Final comments
The relationship between helminths and cancer has been suggested before. Indeed, Johanes Fibiger received a Nobel Prize in 1926 for his work on gastric carcinoma induced by Spiroptera neoplastica. In 1919, Fibiger reported the induction of stomach cancer in mice by feeding them cockroaches infected with S. neoplastica larvae. Fibiger’s hypothesis was later questioned because other workers not only failed to reproduce his results, but also suggested that Fibiger misinterpreted hyperplastic lesions associated with vitamin A deficiency as gastric carcinoma. The hypothesis that cancer is caused by some infectious agent was then practically forgotten. Despite all criticism of his work with S. neoplastica (now Gongylonema neoplasticum), Johanes Fibiger made an important contribution to cancer research through the use of experimental models to investigate cancer causality. Today, there is no doubt that helminths can induce cancer in both animals and humans, and that chronic inflammation plays a key http://parasites.trends.com
role in parasite-associated cancers. However, host–parasite relationships are rather complex, and inflammation is not the only mechanism by which parasites could transform host cells. Some studies suggest that parasites could harbour viral particles31,32, raising the possibility of genetic exchange with their hosts, which also might participate in carcinogenesis. Furthermore, parasites might stimulate the proliferation of virus-infected cells, which would shorten the period of latency for cancer development. This has also been suggested for asymptomatic human T-cell leukaemia virus carriers that are also infected with Strongyloides stercoralis and develop adult T-cell leukaemia in a shorter period than non-infected carriers33. In addition to helminths, protozoa are also relevant to this research, especially Theileria spp. Theileria spp. are obligate intracellular parasites of cattle and cause transformation of infected cells, which then exhibit characteristics of tumour cells, proliferating in an uncontrolled manner. Transformation by Theileria spp. seems to be regulated by the interference of host signal-transduction pathways that involve several kinases and transcription factors [e.g. members of the Src family, casein kinase II, and NF-κB (Ref. 34)]. Remarkably, Theileria-induced transformation has neither been associated with permanent alterations of the host genome nor with the integration of foreign DNA sequences; transformation can be reversed by theilericidal drugs. Bladder cancer induced by Schistosoma haematobium is perhaps the best-investigated helminth-associated neoplasia, in which some of the molecular events that cause malignant transformation of normal human cells have been identified [e.g. inactivation of p53, deletion of p16INK4 and overexpression of Bcl-2 (Ref. 35)]. Although the sequence of events during carcinogenesis in humans have been speculated upon, there is not enough supporting evidence, because molecular observations mostly have been in advanced tumour stages. The generation of malignant transformation in animal models could provide a good opportunity to analyze the specific role of each parasite-induced event in carcinogenesis. The International Agency for Research on Cancer of the WHO has found sufficient evidence for a causal association between S. haematobium, Opistorchis viverrini and specific cancers in humans4. Nevertheless, the number of helminthiases for which there is evidence of association with cancer is low, relative to the large number of helminths that can infect humans36. One explanation suggested for this is the difficulty in studying the correlation between human parasitic diseases and cancer, because of their complex natural history. Cancer and most human helminthiases are long-lasting disorders and both have a prolonged asymptomatic period, during which many other endogenous and exogenous factors can interact and obscure a causal relationship. However,
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Acknowledgements We thank Ana Flisser and Raymond Damian for their helpful advice. L.A.H. is also at the Institute Nacional de Cancerología, Mexico City, Mexico.
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the secretion of particular parasite factors that alter host cell homeostasis and induce malignant transformation could restrict the association of specific parasitic diseases with cancer. In any case, we emphasize that carcinogenesis associated with parasite infections is a complex process during which host–parasite interactions might initiate several of the steps that lead to tumour formation (Fig. 1).
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Therefore, the impact of parasitic infections on cancer incidence is important especially in countries where individuals harbouring worms live for long periods, increasing the chance of malignant transformation. In these countries, individuals are normally exposed to other xenobiotics – thus, carcinogenesis in parasitized individuals might result from the interaction of multiple cancer risk factors.
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