Parasite Infection, Carcinogenesis and Human Malignancy

[sukgansu]

EBioMedicine. 2017 Feb; 15: 12–23.

Published online 2016 Dec 2. doi: 10.1016/j.ebiom.2016.11.034

PMCID: PMC5233816

PMID: 27956028

Parasite Infection, Carcinogenesis and Human Malignancy

Hoang van Tong,^a,b,⁎,1 Paul J. Brindley,^c Christian G. Meyer,^a,d,e,f and Thirumalaisamy P. Velavan^a,e,f,⁎,1

Hoang van Tong

^aInstitute of Tropical Medicine, University of Tübingen, Tübingen, Germany

^bBiomedical and Pharmaceutical Applied Research Center, Vietnam Military Medical University, Hanoi, Vietnam

Find articles by Hoang van Tong

Paul J. Brindley

^cResearch Center for Neglected Diseases of Poverty, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine & Health Sciences, George Washington University, Washington, D.C., USA

Find articles by Paul J. Brindley

Christian G. Meyer

^aInstitute of Tropical Medicine, University of Tübingen, Tübingen, Germany

^dHealth Focus GmbH, Potsdam, Germany

^eDuy Tan University, Da Nang, Viet Nam

^fVietnamese - German Centre for Medical Research (VG-CARE), Hanoi, Viet Nam

Find articles by Christian G. Meyer

Thirumalaisamy P. Velavan

^aInstitute of Tropical Medicine, University of Tübingen, Tübingen, Germany

^eDuy Tan University, Da Nang, Viet Nam

^fVietnamese - German Centre for Medical Research (VG-CARE), Hanoi, Viet Nam

Find articles by Thirumalaisamy P. Velavan

Author information Article notes Copyright and License information Disclaimer

^aInstitute of Tropical Medicine, University of Tübingen, Tübingen, Germany

^bBiomedical and Pharmaceutical Applied Research Center, Vietnam Military Medical University, Hanoi, Vietnam

^cResearch Center for Neglected Diseases of Poverty, Department of Microbiology, Immunology and Tropical Medicine, School of Medicine & Health Sciences, George Washington University, Washington, D.C., USA

^dHealth Focus GmbH, Potsdam, Germany

^eDuy Tan University, Da Nang, Viet Nam

^fVietnamese - German Centre for Medical Research (VG-CARE), Hanoi, Viet Nam

Hoang van Tong: ed.negnibeut-inu@gnaoh-nav.gnot; Thirumalaisamy P. Velavan: ed.negnibeut-inu.nizidem@navalev

^⁎Corresponding authors at: Institute of Tropical Medicine University of Tübingen, Wilhelmstrasse 27, 72074 Tübingen, Germany.Institute of Tropical Medicine University of TübingenWilhelmstrasse 27Tübingen72074Germany ed.negnibeut-inu@gnaoh-nav.gnot, ed.negnibeut-inu.nizidem@navalev

¹Both authors share equal and corresponding authorship.

Received 2016 Oct 20; Revised 2016 Nov 24; Accepted 2016 Nov 29.

Copyright © 2016 The Authors

This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

This article has been cited by

Go to:

Abstract

Cancer may be induced by many environmental and physiological conditions. Infections with viruses, bacteria and parasites have been recognized for years to be associated with human carcinogenicity. Here we review current concepts of carcinogenicity and its associations with parasitic infections. The helminth diseases schistosomiasis, opisthorchiasis, and clonorchiasis are highly carcinogenic while the protozoan Trypanosoma cruzi, the causing agent of Chagas disease, has a dual role in the development of cancer, including both carcinogenic and anticancer properties. Although malaria per se does not appear to be causative in carcinogenesis, it is strongly associated with the occurrence of endemic Burkitt lymphoma in areas holoendemic for malaria. The initiation of Plasmodium falciparum related endemic Burkitt lymphoma requires additional transforming events induced by the Epstein-Barr virus. Observations suggest that Strongyloides stercoralis may be a relevant co-factor in HTLV-1-related T cell lymphomas. This review provides an overview of the mechanisms of parasitic infection-induced carcinogenicity.

Keywords: Schistosomiasis, Opisthorchiasis, Malaria, Chagas disease, Strongyloidiasis, Carcinogenesis, Infection-associated cancer

Go to:

1. Introduction

Cancers are characterized by uncontrolled growth of abnormal and transformed cells, which can invade adjacent tissues. The global burden of cancer in 2012 was estimated to be 14.1 million new cases and 8.2 million related deaths (WHO, 2015WHO, 2015WHO, 2015Bouvard et al., 2009, IARC, 2012

Infections with eleven species of pathogens associated with cancers are classified as Group 1 carcinogens, definitely “carcinogenic to humans”, by the IARC. These agents include Helicobacter pylori, hepatitis B virus (HBV), hepatitis C virus (HCV), Opisthorchis viverrini, Clonorchis sinensis, Schistosoma haematobium, human papillomavirus (HPV), Epstein-Barr virus (EBV), human T-cell lymphotropic virus type 1 (HTLV-1), human herpes virus type 8 (HHV-8) and human immunodeficiency virus type 1 (HIV-1) (Bouvard et al., 2009, IARC, 2012, de Martel et al., 2012Opisthorchis viverrini and Clonorchis sinensis, can induce cholangiocarcinoma, and infection with the blood fluke Schistosoma haematobium may cause cancer of the urinary bladder (Bouvard et al., 2009per se is not considered carcinogenic to humans by the IARC, the geographical association between the occurrence of malaria and that of Burkitt lymphoma provides a clue that malaria plays as a co-carcinogenic factor, together with EBV infection, for the development of Burkitt lymphoma (Molyneux et al., 2012Opisthorchis and Schistosoma are thought likely to be carcinogenic (Sripa et al., 2007, Pakharukova and Mordvinov, 2016Trypanosoma cruzi, the etiological agents of Chagas disease, displays apparently paradoxical roles in malignancy in exerting carcinogenic and anticancer properties (Krementsov, 2009, Sacerdote de et al., 1980Machicado and Marcos, 2016

Here, we summarize current concepts and facts on associations of parasite infections, namely schistosomiasis, opisthorchiasis, clonorchiasis, strongyloidiasis, malaria, and Chagas disease with human cancers and review mechanisms by which parasites may promote, or impede carcinogenesis (Table 1

Table 1

Parasitic pathogens and infection-associated malignancy.

Parasitic pathogens	Disease	Endemic areas	Associated cancer	Proposed mechanism of carcinogenesis
Blood flukes
Schistosoma haematobium	Schistosomiasis	sub-Saharan Africa	Urinary bladder cancer, adenocarcinoma, squamous cell carcinoma	Inflammation, oxidative stress caused by parasite-derived molecules
Schistosoma japonicum	Schistosomiasis	sub-Saharan Africa	Colorectal cancer, rectal cancer, squamous cell carcinoma, membranous nephropathy, metastatic lung cancer	Inflammation, oxidative stress caused by parasite-derived molecules
Schistosoma mansoni	Schistosomiasis	sub-Saharan Africa	Adenocarcinoma, colorectal cancer, hepatocellular carcinoma	Inflammation, oxidative stress caused by parasite-derived molecules
Liver flukes
Opisthorchis viverrini	Opisthorchiasis	Southeast Asia	Cholangiocarcinoma	Inflammation, oxidative stress caused by parasite-derived molecules, cell proliferation, H. pylori mediated induction
Clonorchis sinensis	Clonorchiasis	China, Korea, northern Vietnam	Cholangiocarcinoma	Inflammation, oxidative stress caused by parasite-derived molecules, cell proliferation
Opisthorchis felineus	Opisthorchiasis	Europe and Russia	Cholangiocarcinoma	Inflammation, oxidative stress caused by parasite-derived molecules, cell proliferation
Plasmodia species
Plasmodium falciparum Plasmodium vivax Plasmodium ovale Plasmodium malariae Plasmodium knowlesi	Malaria	sub-Saharan Africa, Southeast Asia	Burkitt lymphoma (indirect carcinogenicity)	Expansion of the EBV-infected B cell population, Suppression of EBV-specific T-cell immunity, Reactivation of EBV, AID-dependent genomic translocation
Strongyloides stercoralis	Strongyloidiasis	sub-Saharan Africa, South and Central America Southeast Asia	HTLV-1 induced lymphomas/leukemias (indirect carcinogenicity) Colon adenocarcinoma	Stimulate HTLV-1 replication, Oligoclonal expansion of HTLV-1-infected lymphocytes
Trypanosoma cruzi	Chagas' disease	South and Central America	Gastrointestinal cancer, Uterine leiomyoma	Unknown

Open in a separate window

Go to:

2. Schistosomiasis and Cancer

Schistosomiasis is a neglected disease caused by infection with blood fluke trematodes of the genus Schistosoma. Out of 207 million cases of schistosomiasis currently estimated worldwide, 90% occur in sub-Saharan Africa (Steinmann et al., 2006Schistosoma that infect humans are Schistosoma haematobium, S. mansoni, S. japonicum, S. intercalatum, and S. mekongi. Most human infections are due to S. haematobium, S. mansoni, and S. japonicum. Of those, S. haematobium is the most ubiquitous species in Egypt and in sub-Saharan Africa and causes urogenital schistosomiasis (UGS). The preval‎ence of schistosomiasis is associated with exposure-related factors, in particular with a favourable environment for the imperative intermediate host snails, sub-optimal sanitation infrastructure, and host genetic factors. Adult worms are usually found in human hosts; their interactions with the host and parasite-derived products including their eggs strongly induce carcinogenesis (Brindley et al., 2015i.e. chronic infection with S. haematobium, is carcinogenic and thus classified as a Group 1 carcinogen by the IARC (IARC, 2012S. japonicum is classified by the IARC as Group 2B, i.e. possibly carcinogenic to humans (IARC, 2012, IARC, 1994

Bladder cancer is a common malignancy of the urinary tract with approximately 400,000 new cases and 150,000 deaths occurring annually (Ferlay et al., 2010Knowles and Hurst, 2015Fig. 1

Open in a separate window

Fig. 1

Proposed mechanisms of carcinogenicity induced by infection with the liver and blood flukes Clonorchis, Opisthorchis and Schistosoma species.

The chronic inflammation during Clonorchis, Opisthorchis and Schistosoma infections leads to the activation of signaling pathways including p53, NF-κB, Jak/Stat and Rb that could generate somatic mutations and/or activate oncogenes. Fluke-derived products and metabolites secreted to the host microenvironment may induce metabolic processes including oxidative stress that facilitate damage to the chromosomal DNA of proximal epithelial cells, specially cholangiocytes and urothelial cells for the liver and blood flukes, respectively. In addition, physical damage of host tissues during the development of parasites together with the active wound healing process lead to increased cell transformation and proliferation, which also are associated with the DNA damage. Combined parasite-host interaction events (chronic inflammation, parasite-derived products, and physical damage) and their combined effects on the chromosomes and fates of cells lead to the modification of the cell growth, proliferation and survival that in turn initiate and promote malignancy.

2.1. Schistosoma haematobium and Urinary Bladder Cancer

UGS due to S. haematobium has been consistently reported to be associated with bladder cancer. Early epidemiological findings reported from Zambia have indicated that 65% of patients with bladder cancer had concomitant UGS and 75% of them had well-differentiated squamous cell carcinomas (Bhagwandeen, 1976Cooppan et al., 1984S. haematobium eggs in tumor tissues (Kitinya et al., 1986S. haematobium endemic area of Kenya (Hodder et al., 2000S. haematobium-associated lesions were also detected in 69% of patients with squamous cell bladder carcinoma in Sudan (Sharfi and el SS, 1992Basilio-de-Oliveira et al., 2002, Helling-Giese et al., 1996

Several mechanisms may account for the role of infection with S. haematobium in urinary bladder cancer, among them epithelium damage, chronic inflammatory processes and oxidative stress (Bouvard et al., 2009, Brindley et al., 2015, Honeycutt et al., 2014) (Fig. 1Schistosoma eggs may change proliferation, hyperplasia, and metaplasia of host cells that eventually induce carcinogenesis. Nitrosamines and increased levels of urinary b-glucuronidase and cyclooxygenase-2 derived from adult schistosomes are also recognized as bladder carcinogens. A liquid chromatography-mass spectrometry analysis of urine samples from UGS patients revealed numerous estrogen-like metabolites including catechol estrogen quinones (CEQ), CEQ-DNA-adducts and novel metabolites derived from 8-oxo-7, 8-dihydro-2′-deoxyguanosine (8-oxodG) (Gouveia et al., 2015via oxidative stress as the formation of 8-oxodG is known as a main product of DNA lesion by oxidation. The S. haematobium-derived carcinogens may lead to DNA damage and somatic mutations through chronic inflammation and oxidative stress in oncogenes such as p53, RB (retinoblastoma protein), EGFR (epidermal growth factor receptor), and ERBB2 (erb-b2 receptor tyrosine kinase 2). Of interest is that genomic instability was frequently observed in p53 and KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog) genomic regions of patients with schistosomal bladder cancers (Abd El-Aal et al., 2015, Honeycutt et al., 2015, Lim et al., 2006, Santos et al., 2014, Botelho et al., 2013Rosin et al., 1994S. haematobium-induced bladder cancer (Bernardo et al., 2016

2.2. Schistosoma japonicum and Colorectal and Hepatocellular Carcinoma

Although evidence is sparse, infection with S. japonicum has been implicated in the etiology of colorectal cancer. Epidemiological and clinical studies in China and Japan suggested that S. japonicum may act as a carcinogen (Matsuda et al., 1999, Qiu et al., 2005S. japonicum. A case-control study has shown that HCC developed in 5.4% of patients with chronic schistosomiasis and in 7.5% of those with chronic liver disease. However, a co-contribution of HCV infection to HCC development could not be reliably excluded (Iida et al., 1999S. japonicum were independently associated with both HCC and colon cancer (Qiu et al., 2005), membranous nephropathy, and metastatic lung tumors (Matsuda et al., 1999, Chen, 2014, Sekiguchi et al., 1989S. japonicum infection was reported (Ohtake et al., 1991S. japonicum infection with rectal carcinoid tumor in an asymptomatic patient from the Philippines (Zanger et al., 2010S. japonicum, which has a strong immunogenic activity, may contribute to carcinogenesis through stimulation of chronic inflammation (Ishii et al., 1994p53 gene were examined in Chinese patients with both rectal cancer and S. japonicum infection, and a higher frequency of arginine missense mutations were observed in schistosomal rectal cancer ostensibly induced by schistosome infection compared to non-schistosomiasis rectal cancers (Zhang et al., 1998S. japonicum-derived products may be involved in induction of host genomic instability (Fig. 1

2.3. Schistosoma mansoni and Cancer

S. mansoni infection may constitute a risk for the development of HCC during co-infection with HCV. Case reports have described associations of schistosomiasis mansoni with prostatic adenocarcinoma and sigmoid colonic cancer (Basilio-de-Oliveira et al., 2002, HS et al., 2010S. mansoni and bladder cancer (Kiremit et al., 2015S. mansoni egg antigens can effectively modify subpopulations of T helper cells (Cheever et al., 2002S. mansoni colitis-related colorectal cancer suggests that schistosome infections may induce carcinogenesis by targeting oncogenes (Madbouly et al., 2007Bcl-2 and C-Myc also are relevant in the development of colorectal cancer during schistosomiasis (Zalata et al., 2005S. mansoni infection could result from somatic mutations in oncogenes and in the regulation of immune responses that can activate several host signaling cancer pathways (Fig. 1

2.4. Carcinogenicity of Schistosoma intercalatum and Schistosoma mekongi

Two case reports only have pointed to a possible association of infection with S. intercalatum and S. mekongi with cancer (Cuesta et al., 1992, Muller and van der Werf, 2008S. mekongi infection has been associated with leiomyosarcoma of the small bowel (Cuesta et al., 1992), and intestinal S. intercalatum infection was observed in a patient with rectosigmoid carcinoma (Muller and van der Werf, 2008S. intercalatum and S. mekongi were the causative agents of the observed malignant tumors. To our knowledge, only a single study on an animal model (Cynomolgus monkeys) provides evidence of an association of S. intercalatum infection with urinary bladder cancer (Cheever et al., 1976S. intercalatum may possibly be inferred due to the similarity of S. intercalatum and S. haematobium in both morphology and life cycle of the parasite. However, compelling evidence indicating carcinogenicity of S. intercalatum and S. mekongi is still tenuous.

Go to:

3. Liver Fluke Infections and Cholangiocarcinoma

Opisthorchiasis and clonorchiasis are caused by fish-borne liver flukes of the trematode family Opisthorchiidae. > 45 million people worldwide are infected by these pathogens. Species of opisthorchiid flukes that cause disease in humans are Opisthorchis felineus, Opisthorchis viverrini, and Clonorchis sinensis. The IARC classifies C. sinensis as a Group 1 agent (carcinogenic to humans). O. felineus is endemic in parts of Europe and Russia; C. sinensis in China, the Republic of Korea, and northern Vietnam; while O. viverrini-infections occur in Southeast Asia (Petney et al., 2013Opisthorchis and Clonorchis are highly endemic in Mekong Basin countries such as Laos (50% to 70% of O. viverrini infection), Thailand (16.6% O. viverrini infection in the Northeast region and Nakhon Phanom province reported up to 60%), Cambodia (4% to 27% O. viverrini infection) and Vietnam (15% to 37% O. viverrini infection in southern regions and C. sinensis infection 0.2% to 26% in the north) (Sithithaworn et al., 2012O. viverrini infected animals contributes largely to increased incidences (Forrer et al., 2012, Xayaseng et al., 2013Keiser and Utzinger, 2009Sripa et al., 2012a

Cholangiocarcinoma, or bile duct cancer, is a highly aggressive malignancy with poor prognosis. Cholangiocarcinoma accounts for approximately 20% of all hepatobiliary malignancies and it can be classified as intrahepatic and extrahepatic cholangiocarcinoma (Tyson and El-Serag, 2011Palmer and Patel, 2012, Welzel et al., 2007Brindley et al., 2015, Chaiyadet et al., 2015a, Chaiyadet et al., 2015b) (Fig. 1

3.1. Carcinogenicity of Opisthorchis viverrini

Opisthorchiasis is inarguably associated with cholangiocarcinoma in Southeast Asia (Khuntikeo et al., 2016, Haswell-Elkins et al., 1994) and is classified as Group 1 carcinogen by the IARC (Bouvard et al., 2009, IARC, 2012, de Martel et al., 2012O. viverrini infection, co-factors such as environmental or exotic microbes in the biliary system that resist host inflammatory responses might also contribute to carcinogenesis (Sripa et al., 2007, Plieskatt et al., 2013, Chng et al., 2016O. viverrini infection and bile duct cancer is that parasite-derived molecules can lead to uncontrolled growth of host cells. An animal model has supported this mechanism by showing that the dimethylnitrosamine derived from Opisthorchis can induce cholangiocarcinoma and the levels of precursors of nitroso compounds were elevated in body fluids of O. viverrini infected individuals (Haswell-Elkins et al., 1994Sripa et al., 2012a, Smout et al., 2009, Matchimakul et al., 2015, Smout et al., 2015O. viverrini extract has identified novel oxysterol derivatives in O. viverrini, which are potential carcinogenic compounds (Vale et al., 2013

Long-lasting interactions between O. viverrini and host responses initiate carcinogenesis. O. viverrini extracts could stimulate the production of inflammatory cytokines (Ninlawan et al., 2010) and O. viverrini derived products are internalized by cholangiocytes, which consequently induced cell proliferation and IL-6 production (Chaiyadet et al., 2015aSripa et al., 2009, Sripa et al., 2012bOgorodova et al., 2015O. viverrini infection down-regulates RB1 (retinoblastoma 1) and p16^INK4 (cyclin-dependent kinase inhibitor 2A) expression‎ and up-regulates cyclin D1 and CDK4 (cyclin-dependent kinase 4) expression‎ during cholangiocarcinoma development (Boonmars et al., 2009O. viverrini leads to upregulation of the PI3K/AKT and Wnt/β-catenin signaling pathways involved in tumorgenesis (Yothaisong et al., 2014O. viverrini infection and in early stages of O. viverrini-induced cholangiocarcinoma (Haonon et al., 2015) and in intrahepatic cholangiocarcinoma of patients void of O. viverrini infection (Zhang et al., 2015Tzivion et al., 2006, Wanzel et al., 2005

At the genomic level, analysis of the mutation profiles of 108 cases with O. viverrini-related cholangiocarcinomas and 101 cases with non-O. viverrini infection-related cholangiocarcinomas revealed a significant difference in host genetic mutation patterns (Chan-On et al., 2013p53 and SMAD4 (SMAD family member 4) genes in O. viverrini related cholangiocarcinomas compared to non-O. viverrini related cholangiocarcinomas. Somatic mutations occurring in the BAP1 (BRCA1 associated protein-1), IDH1, and IDH2 (isocitrate dehydrogenases 1 and 2) genes are more common in non-O. viverrini than in O. viverrini related cholangiocarcinomas (Chan-On et al., 2013, Jusakul et al., 2015p53 and SMAD4 directly affect the related cellular signaling pathways p53 and TGF-b, which both are involved in tumorgenesis (Jusakul et al., 2015

3.2. Carcinogenicity of Clonorchis sinensis

The association between infection with C. sinensis and cholangiocarcinoma has been convincingly documented (IARC, 2012, Sripa et al., 2007, Choi et al., 2006), and these helminths have been classified as highly carcinogenic agents (Bouvard et al., 2009, de Martel et al., 2012C. sinensis infection was significantly associated with increased risk of cholangiocarcinoma (OR = 7.3, 95%CI = 3.96–13.3) (Choi et al., 2006C. sinensis infection was associated with a higher incidence of cholangiocarcinoma (Lim et al., 2006C. sinensis contribute to carcinogenesis are not clearly understood, although similar mechanisms to those of O. viverrini-induced carcinogenesis (via inflammation, parasite-derived products and physical damage) may be anticipated. Pancreatic ducts may harbor C. sinensis, which can lead to squamous metaplasia and mucous gland hyperplasia, and a well-differentiated ductal adenocarcinoma of the pancreas (Colquhoun and Visvanathan, 1987C. sinensis-derived excretory-secretory products may promote aggregation and invasion of cholangiocarcinoma cells into the neighboring extracellular matrix (Won et al., 2014C. sinensis could be a risk factor for the initiation and development of cancer (Kim et al., 2012C. sinensis infection, peroxiredoxin 6 (Prdx6) expression‎ was inversely correlated with NF-κB activation due to the response to C. sinensis-derived excretory-secretory products (ESPs) (Pak et al., 2016C. sinensis induces the expressions of various lipid peroxidation products such as 4-hydroxy-2-nonenal (HNE), cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX) and 8-oxo-7.8-dihydro-2′-deoxyguanosine (8-oxodG) and plasma proinflammatory cytokines (TNF-α, ILβ-1 and IL-6). Among various lipid peroxidation products, 8-oxodG formation (a product of DNA lesion) was initially detected in the nucleus of the inflammatory cells and subsequently in the biliary epithelial cells in a C. sinensis mouse model (Maeng et al., 2016C. sinensis demonstrate a strong immunogenic property and robustly induce metabolic oxidative stress.

3.3. Carcinogenicity of Opisthorchis felineus

The association of infection with O. felineus with cholangiocarcinoma has been proposed (Sripa et al., 2007, Maksimova et al., 2015O. felineus contributes to carcinogenesis are also not clearly understood. Negative correlations between O. felineus and responses to allergens suggest that Opisthorchiidae are able to induce regulatory cells (Ogorodova et al., 2007O. felineus infection has been shown to be a relevant modifier of Th1/Th2-regulating genes as O. felineus antigens were able to modulate expression‎ of specific genes like SOCS5 (suppressor of cytokine signaling 5) and IFNG (interferon gamma) (Saltykova et al., 2014Nomura and Sakaguchi, 2005Saengboonmee et al., 2015), and activities of dicarbonyl stress may also be implicated (Saltykova et al., 2016

Go to:

4. Malaria and Burkitt lymphoma

4.1. Malaria

Five species of the protozoan parasite Plasmodium - Plasmodium falciparum, P. vivax, P. ovale, P. malariae, and P. knowlesi affect humans. P. falciparum is the most virulent and widespread in regions endemic for malaria (Hay et al., 2010WHO, 2014Anopheles mosquitoes. P. falciparum exhibits remarkable biological diversity and the ability to rapidly develop resistance to almost all anti-malarial drugs (Hay et al., 2010

4.2. Burkitt Lymphoma

Burkitt lymphoma is a monoclonal B cells cancer and the fastest growing tumor in humans in malaria endemic areas of sub-Saharan Africa (Molyneux et al., 2012Molyneux et al., 2012, Orem et al., 2007c-Myc oncogene and immunoglobulin (Ig) gene loci that leads to deregulation of c-Myc expression‎ together with p53 gene mutations are known to be most relevant in the pathogenesis of Burkitt lymphoma (Chiarle et al., 2011, Klein et al., 2011, Wilmore et al., 2015, Gutierrez et al., 1997Molyneux et al., 2012, Rochford et al., 2005

4.3. Malaria as Indirect Risk Factor for Burkitt Lymphoma

Although malaria itself is not classified carcinogenic, endemic Burkitt lymphoma in sub-Saharan Africa is geographically associated with holoendemicity of P. falciparum malaria. A plethora of epidemiological, experimental and clinical studies have demonstrated the synergistic effects of host genetic factors and infections such as EBV, P. falciparum and HIV on Burkitt lymphoma development (Molyneux et al., 2012P. falciparum malaria and EBV is the main risk factor for endemic Burkitt lymphoma. In a cohort of 711 Kenyan Burkitt lymphoma cases, the rates were higher in regions with chronic and intense malaria transmission compared to regions with no or sporadic malaria transmission (Rainey et al., 2007P. falciparum parasites compared to non-endemic Burkitt lymphoma-related cancers (Johnston et al., 2014Fig. 2

Open in a separate window

Fig. 2

Proposed mechanisms of induction of Epstein-Barr virus driven Burkitt lymphoma by falciparum malaria.

Plasmodium falciparum infected red blood cells (iRBC) bind to the Epstein-Barr virus (EBV) latently infected B cells through the CIDR1α domain of P. falciparum erythrocyte membrane protein 1 (PfEMP1) that lead to the expansion of the latently infected B cell pool and/or lead to the reactivation of EBV. The interaction between iRBCs and EBV-infected B cells in the germinal center (GC) also results in the increased expression‎ of the Activation-Induced cytidine Deaminase (AID). The AID in turn contributes to break host DNA at the immunoglobulin (Ig) or/and highly transcribed regions, to activate oncogenes (c-Myc) and to induce somatic mutations. The AID also induces the chromosomal rearrangement especially the translocation between Ig regions and c-Myc oncogene. All these processes lead to the genomic instability that can drive the proliferation and differentiation of B cells in GC and subsequently lead to the emergence of a malignant B-cell clone. In addition, the binding of iRBC to the dendritic cells (DCs) could lead to a modification of DC functions that contributes to suppress EBV-specific T-cell immunity (CD8⁺ and CD4⁺ T cells), therefore resulting in the loss of controlling the expansion of EBV-infected B cells including emergent Burkitt lymphoma clones.

4.3.1. Expansion of EBV-Infected B Cells

Interaction of P. falciparum and B cells is considered as a key factor. B cell activation and hyper-gammaglobulinemia in malaria have been well described both experimentally and clinically. A study has shown that P. falciparum-infected erythrocytes directly adhere to and activate B cells through the CIDR1α domain of P. falciparum erythrocyte membrane protein 1 (PfEMP1) (Simone et al., 2011Simone et al., 2011Donati et al., 2004Rochford et al., 2005P. falciparum infection is associated with enhanced proliferation and transformation of EBV-infected cells in both children with acute or asymptomatic malaria (Moormann et al., 2005) (Fig. 2

4.3.2. Suppression of EBV-Specific T Cell Immunity

The fact that P. falciparum can inhibit EBV-specific T cell immunity could explain how EBV and P. falciparum infections are associated with the increased risk of Burkitt lymphoma. Failure of EBV-specific T cells to control EBV-infected cells in malaria patients leads to the expansion and abnormal proliferation of EBV-infected B cells (Whittle et al., 1984Moormann et al., 2007, Chattopadhyay et al., 2013Precopio et al., 2003P. falciparum-infected erythrocytes are able to adhere to dendritic cells and modulate their functions through a TLR9-dependent pathway (Pichyangkul et al., 2004Urban et al., 1999, Ocana-Morgner et al., 2003Urban et al., 2001, Hugosson et al., 2004) (Fig. 2

4.3.3. Reactivation of EBV Viremia Induced by Malaria

The expansion of EBV-infected B cells is associated with higher levels of B cell-carried EBV-DNA and plasma cell-free EBV-DNA (Njie et al., 2009, Rasti et al., 2005Rasti et al., 2005, Daud et al., 2015Moormann et al., 2005, Rasti et al., 2005, Donati et al., 2006, Yone et al., 2006) indicating that P. falciparum infection contributes to reactivate viral replication. Furthermore, elevated plasma EBV viral loads were associated with the development of endemic Burkitt lymphoma (Asito et al., 2010P. falciparum-induced EBV reactivation, a study has uncovered the mechanism that binding between latently EBV-infected B cells and the domain CIDR1α of the PfEMP1 protein directly switches the virus into lytic replication and CIDR1α stimulates EBV production in peripheral blood mononuclear cells (Chene et al., 2007) (Fig. 2

4.3.4. AID-Dependent Genomic Translocation Induced by Plasmodium falciparum

Molecular mechanisms to explain how Plasmodium infection promotes Burkitt lymphomagenesis remain controversial. P. chabaudi was used to establish chronic malaria in an animal model; the infection resulted in an increased and prolonged clonal expansion of B cells in germinal centers and primarily induced expression‎ of AID in Plasmodium-induced germinal center B cells (Robbiani et al., 2015Robbiani et al., 2015P. falciparum extracts were shown to stimulate expression‎ of AID in germinal center B cells in-vitro and in-vivo (Torgbor et al., 2014⁺ memory B cells (Wilmore et al., 2015Plasmodium-induced germinal center B cells and the rearrangements occurred more frequently in genic regions. In a mouse model of chronic malaria, AID induced genomic instability of germinal center B cells, mostly in immunoglobulin (Ig) regions and in highly transcribed genes (Robbiani et al., 2015c-Myc) that lead to c-Myc and IgH translocations (Robbiani et al., 2008Klein et al., 2011Qian et al., 2014, Meng et al., 2014P. falciparum infection rather modifies the lymphoma phenotype to favor more mature B cell lymphomas by stimulating prolonged AID expression‎ in germinal center B cells (Robbiani et al., 2015) (Fig. 2

Go to:

5. Strongyloides stercoralis and Cancer

Strongyloides stercoralis, an intestinal nematode, can cause strongyloidiasis and gastrointestinal ulcer. S. stercoralis infects approximately 50–100 million people in tropical and subtropical regions (Segarra-Newnham, 2007S. stercoralis are asymptomatic while symptomatic forms may lead to severe skin pathology, diarrhea, nausea, and abdominal discomfort. Infection with S. stercoralis may be complicated by autoinfection, which results in a hyperinfection syndrome and is associated with sustained infection, high worm burden and high mortality (Segarra-Newnham, 2007S. stercoralis has been demonstrated to be in part geographically associated with the occurrence of HTLV-1 infections. A recent epidemiological study investigated the association of co-infection with S. stercoralis and HTLV-1 with cancers in a large cohort of 5209 cancer patients and showed that S. stercoralis infection was associated with an increased occurrence of cancers (Tanaka et al., 2016IARC, 2012, Gabet et al., 2000S. stercoralis infection suggesting that S. stercoralis may stimulate HTLV-1 replication (Gabet et al., 2000Satoh et al., 2002S. stercoralis is a cofactor for the development of HTLV-1- induced lymphoid cancers (Table 1

In addition, a case report described a Korean patient presenting with both S. stercoralis infection and early gastric adenocarcinoma. Further analysis revealed that the gastric adenocarcinoma and adenoma tissues were positive for S. stercoralis suggesting a causative effect of S. stercoralis (Seo et al., 2015S. stercoralis infection has also been reported in a Columbian patient (Tomaino et al., 2015S. stercoralis may not only serve as a cofactor for induction of HTLV-1-related lymphoid cancers, but also stimulates induction of colon adenocarcinoma probably by interacting with the host and/or activating the host immune response.

Go to:

6. Paradoxical Dual Impacts of Chagas Disease in Carcinogenesis

Chagas disease (CD), a parasitic disease caused by the flagellated protozoan Trypanosoma cruzi, occurs throughout South and Central America, and affects approximately 15 million people (Coura, 2013T. cruzi primarily occurs through triatomine insects (kissing bugs). People become infected when feces of the kissing bug containing the trypomastigote stage of T. cruzi are deposited on the human skin while the insect feeds on blood; the T. cruzi containing insect feces contaminate mucous membranes, conjunctivae, or skin breaks, and initiate human infection (Stevens et al., 2011

Approximately 40% of persons infected with T. cruzi are asymptomatic or present with indeterminate forms. About 2–5% progress annually to symptomatic forms with irreversible cardiac and/or digestive disorders, mostly presenting as megaorgans (Nunes et al., 2013Nunes et al., 2013

6.1. Chronic Infection with Trypanosoma cruzi as a Risk Factor for Carcinogenesis

An association of CD with gastrointestinal cancer has been proposed (Sacerdote de et al., 1980Adad et al., 1999Murta et al., 2002Adad et al., 2002, Oliveira et al., 1997de Oliver et al., 2014p53 in 54.5% of 20 study patients; this might increase the risk of tumor development (Manoel-Caetano et al., 2004p53, FHIT (fragile histidine triad gene) and CDKN2A (cyclin-dependent kinase Inhibitor 2A) genes or genomic imbalances were not frequent in chagasic megaesophagus, a silent mutation in exon7 of the FHIT gene and copy numbers of the CDKN2A and CEP9 (C-terminally encoded peptide 9) genes might be involved in esophageal carcinogenesis (SM-C et al., 2009, Bellini et al., 2010T. cruzi-related carcinogenesis is most likely due to host genetic factors, and the parasite-host interaction resulting in chronic inflammation in particular tissues (Fig. 3

Open in a separate window

Fig. 3

Paradoxical roles of Chagas disease, infection with Trypanosoma cruzi, in carcinogenesis.

Infection with Trypanosoma cruzi has been proposed in both carcinogenesis and in inhibition of carcinogenesis. T. cruzi has antitumor effects by inducing host immunity against tumor. T. cruzi expresses a calreticulin (T. cruzi calreticulin, TcCRT) that can directly interact with endothelial cells and inhibit their proliferation, migration and capillary morphogenesis as well as inhibit tumor cell growth. The DNA mismatch repair protein (TcMSH2), a central component of the mismatch repair (MMR) machinery in T. cruzi, allows T. cruzi to respond effectively to the oxidative stress during infection. The oxidative stress mediated by alkylating agents and hydrogen peroxide leads to carcinogenesis by damaging DNA. The TcMSH2 protein of T. cruzi may also contribute to protect host chromosomes from oxidative stress during infection, and therefore consequently inhibit tumorigenicity. On the other hand, T. cruzi may also cause cancer by inducing somatic mutation and genomic imbalance during chronic inflammation. However, the molecular details of this latter phenomenon are yet not understood.

6.2. Anticancer Activity of Trypanosoma cruzi

Anticancer properties of T. cruzi were first reported in 1931 and a product of T. brucei, another member of the trypanosome family, has been suggested to exert antitumor properties. A study using a mouse model demonstrated that smaller tumor size was associated with high parasitemia and suggested that surface cellular antigens and an inhibiting or lysing factor of T. cruzi contribute to anticancer activities (Kallinikova et al., 2001Oliveira et al., 2001T. cruzi epimastigote lysate strongly inhibited tumor development in vivo by inducing the activation of both CD4(+) and CD8(+) T cells as well as by increasing numbers of CD11b/c(+) His48(−) MHC II(+) cells, which correspond to macrophages and/or dendritic cells. Antibodies against T. cruzi lysate recognized various rat and human tumor cell types such as colon and human breast cancer cells and thus mediate tumor cell killing through antibody-dependent cellular cytotoxicity (ADCC) (Ubillos et al., 2016T. cruzi calreticulin (TcCRT) (Aguillon et al., 2000) and demonstrated its potent antiangiogenic and antitumor effects both in-vitro and in-vivo. TcCRT is able to directly interact with human endothelial cells through a receptor-dependent mechanism and to inhibit their proliferation, migration and capillary morphogenesis. In an in vitro experiment, TcCRT was capable to inhibit growth of murine mammary tumor cells (Lopez et al., 2010, Ramirez et al., 2011aC1), mannose-binding lectin (MBL), and ficolins to inhibit activation of the complement system that leads to increased infectivity of the parasite (Lopez et al., 2010, Ramirez et al., 2011b, Sosoniuk et al., 2014Sanchez-Valdez et al., 2014T. cruzi strains are able to respond to oxidative stress caused by DNA damaging agents (Campos et al., 2011, Grazielle-Silva et al., 2015T. cruzi was mediated via the TcMSH2 protein, which is the central component of the mismatch repair (MMR) machinery in T. cruzi (Campos et al., 2011, Augusto-Pinto et al., 2001T. cruzi in the host is most likely granted through protection from oxidative stress by the effective DNA repairing pathway. In addition, MMR deficiency is significantly associated with predisposition to cancer (Bridge et al., 2014T. cruzi may also be of importance in protection of host chromosomes during chronic inflammation and, thus, in reduced cancer development.

Further to the anticancer properties, T. cruzi is an effective cancer antigen delivery vector (Junqueira et al., 2011T. cruzi CL-14 clone to express exogenously a cancer testis antigen (NY-ESO-1) and showed that T. cruzi parasites expressing NY-ESO-1 were able to induce strong NY-ESO-1 specific immune responses both in-vitro and in-vivo. Interestingly, immunization with T. cruzi parasites expressing NY-ESO-1 would lead to an effective immune response to kill tumor cells and to inhibit tumor development (Junqueira et al., 2011T. cruzi may exert both carcinogenic and antitumor effects (Fig. 3

Go to:

7. Conclusions and Perspectives

The associations between infections with parasites and human cancers are well-evidenced. S. haematobium, O. viverrini, and C. sinensis are highly carcinogenic while other infectious species of the genera Opisthorchis (O. felineus) and Schistosoma (S. japonicum and S. mansoni) demonstrate their carcinogenic potential in humans (Table 1Fig. 1

In malaria-related endemic Burkitt lymphoma, the AID protein appears to be an important factor that contribute to control chronic malaria and to induce human genomic instability (Fig. 2Plasmodium infection and in its interaction with host chromosomes during B cell differentiation needs to be studied. In addition, the mechanisms by which S. stercoralis can induce malignancy together with HTLV-1 and/or directly induce carcinogenesis require further studies. While the carcinogenic role and mechanism of T. cruzi are not understood, anticancer properties of T. cruzi are mediated via the TcCRT and probably due to an effective response to oxidative stress (Fig. 3T. cruzi including studies of TcCRT and other molecules, which are potentially involved.

Go to:

Contributors

HVT conceived this review, did the literature search, data extraction, interpretation of information, prepared the figures, drafted and revised the review. PJB, CGM and VTP provided critical reviews, developed and revised the manuscript. All authors read and approved the final version of the manuscript.

Go to:

Declaration of Interests

The authors declare that there are no conflicts of interest.

Go to:

Acknowledgements

PJB gratefully acknowledges support from awards R01CA155297 and R01CA164719 from the National Cancer Institute (NCI), P50AI098639 from the National Institute of Allergy and Infectious Diseases (NIAID), {"type":"entrez-nucleotide","attrs":{"text":"CA164719","term_id":"35082413","term_text":"CA164719"}}CA164719, {"type":"entrez-nucleotide","attrs":{"text":"CA155297","term_id":"35063267","term_text":"CA155297"}}CA155297 and {"type":"entrez-nucleotide","attrs":{"text":"AI098639","term_id":"3448164","term_text":"AI098639"}}AI098639

Go to:

References

• Abd El-Aal A.A., Bayoumy I.R., Basyoni M.M., Abd El-Aal A.A., Emran A.M., Abd El-Tawab M.S. Genomic instability in complicated and uncomplicated Egyptian schistosomiasis haematobium patients. Mol. Cytogenet. 2015;8(1):1. [PMC free article] [PubMed] [Google Scholar]
• Adad S.J., Etchebehere R.M., Hayashi E.M., Asai R.K., de Souza F.P., Macedo C.F. Leiomyosarcoma of the esophagus in a patient with chagasic megaesophagus: case report and literature review. Am.J.Trop. Med. Hyg. 1999;60(5):879–881. (May) [PubMed] [Google Scholar]
• Adad S.J., Etchebehere R.M., Araujo J.R., Madureira A.B., Lima V.G., Silva A.A. Association of chagasic megacolon and cancer of the colon: case report and review of the literature. Rev. Soc. Bras. Med. Trop. 2002;35(1):63–68. (January) [PubMed] [Google Scholar]
• Aguillon J.C., Ferreira L., Perez C., Colombo A., Molina M.C., Wallace A. Tc45, a dimorphic Trypanosoma cruzi immunogen with variable chromosomal localization, is calreticulin. Am.J.Trop. Med. Hyg. 2000;63(5–6):306–312. (November) [PubMed] [Google Scholar]
• Asito A.S., Piriou E., Odada P.S., Fiore N., Middeldorp J.M., Long C. Elevated anti-Zta IgG levels and EBV viral load are associated with site of tumor presentation in endemic Burkitt's lymphoma patients: a case control study. Infect Agent Cancer. 2010;5:13. [PMC free article] [PubMed] [Google Scholar]
• Augusto-Pinto L., Bartholomeu D.C., Teixeira S.M., Pena S.D., Machado C.R. Molecular cloning and characterization of the DNA mismatch repair gene class 2 from the Trypanosoma cruzi. Gene. 2001;272(1–2):323–333. (July 11) [PubMed] [Google Scholar]
• Basilio-de-Oliveira C.A., Aquino A., Simon E.F., Eyer-Silva W.A. Concomitant prostatic schistosomiasis and adenocarcinoma: case report and review. Braz. J. Infect. Dis. 2002;6(1):45–49. (February) [PubMed] [Google Scholar]
• Bellini M.F., Manzato A.J., Silva A.E., Varella-Garcia M. Chromosomal imbalances are uncommon in chagasic megaesophagus. BMC Gastroenterol. 2010;10:20. [PMC free article] [PubMed] [Google Scholar]
• Bernardo C., Cunha M.C., Santos J.H., da Costa J.M., Brindley P.J., Lopes C. Insight into the molecular basis of Schistosoma haematobium-induced bladder cancer through urine proteomics. Tumour Biol. 2016;37(8):11279–11287. (August) [PubMed] [Google Scholar]
• Bhagwandeen S.B. Schistosomiasis and carcinoma of the bladder in Zambia. S. Afr. Med. J. 1976;50(41):1616–1620. (September 25) [PubMed] [Google Scholar]
• Boonmars T., Wu Z., Boonjaruspinyo S., Pinlaor S., Nagano I., Takahashi Y. Alterations of gene expression‎ of RB pathway in Opisthorchis viverrini infection-induced cholangiocarcinoma. Parasitol. Res. 2009;105(5):1273–1281. (October) [PubMed] [Google Scholar]
• Botelho M.C., Veiga I., Oliveira P.A., Lopes C., Teixeira M., da Costa J.M. Carcinogenic ability of Schistosoma haematobium possibly through oncogenic mutation of KRAS gene. Adv. Cancer Res. Treat. 2013;28:2013. (April) [PMC free article] [PubMed] [Google Scholar]
• Bouvard V., Baan R., Straif K., Grosse Y., Secretan B., El G.F. A review of human carcinogens–part B: biological agents. Lancet Oncol. 2009;10(4):321–322. (April) [PubMed] [Google Scholar]
• Bridge G., Rashid S., Martin S.A. DNA mismatch repair and oxidative DNA damage: implications for cancer biology and treatment. Cancers (Basel) 2014;6(3):1597–1614. [PMC free article] [PubMed] [Google Scholar]
• Brindley P.J., da Costa J.M., Sripa B. Why does infection with some helminths cause cancer? Trends Cancer. 2015;1(3):174–182. (November 1) [PMC free article] [PubMed] [Google Scholar]
• Campos P.C., Silva V.G., Furtado C., Machado-Silva A., DaRocha W.D., Peloso E.F. Trypanosoma cruzi MSH2: functional analyses on different parasite strains provide evidences for a role on the oxidative stress response. Mol. Biochem. Parasitol. 2011 March;176(1):8–16. [PMC free article] [PubMed] [Google Scholar]
• Chaiyadet S., Smout M., Johnson M., Whitchurch C., Turnbull L., Kaewkes S. Excretory/secretory products of the carcinogenic liver fluke are endocytosed by human cholangiocytes and drive cell proliferation and IL6 production. Int. J. Parasitol. 2015;45(12):773–781. (October) [PMC free article] [PubMed] [Google Scholar]
• Chaiyadet S., Sotillo J., Smout M., Cantacessi C., Jones M.K., Johnson M.S. Carcinogenic liver fluke secretes extracellular vesicles that promote cholangiocytes to adopt a tumorigenic phenotype. J. Infect. Dis. 2015;212(10):1636–1645. (November 15) [PMC free article] [PubMed] [Google Scholar]
• Chan-On W., Nairismagi M.L., Ong C.K., Lim W.K., Dima S., Pairojkul C. Exome sequencing identifies distinct mutational patterns in liver fluke-related and non-infection-related bile duct cancers. Nat. Genet. 2013;45(12):1474–1478. (December) [PubMed] [Google Scholar]
• Chattopadhyay P.K., Chelimo K., Embury P.B., Mulama D.H., Sumba P.O., Gostick E. Holoendemic malaria exposure is associated with altered Epstein-Barr virus-specific CD8(+) T-cell differentiation. J. Virol. 2013;87(3):1779–1788. (February) [PMC free article] [PubMed] [Google Scholar]
• Cheever A.W., Kuntz R.E., Moore J.A., Huang T.C. Proliferative epithelial lesions of the urinary bladder in cynomolgus monkeys (Macaca fascicularis) infected with Schistosoma intercalatum. Cancer Res. 1976;36(8):2928–2931. (August) [PubMed] [Google Scholar]
• Cheever A.W., Lenzi J.A., Lenzi H.L., Andrade Z.A. Experimental models of Schistosoma mansoni infection. Mem. Inst. Oswaldo Cruz. 2002;97(7):917–940. (October) [PubMed] [Google Scholar]
• Chen M.G. Assessment of morbidity due to Schistosoma japonicum infection in China. Infect. Dis. Poverty. 2014;3(1):6. [PMC free article] [PubMed] [Google Scholar]
• Chene A., Donati D., Guerreiro-Cacais A.O., Levitsky V., Chen Q., Falk K.I. A molecular link between malaria and Epstein-Barr virus reactivation. PLoS Pathog. 2007;3(6) (June) [PMC free article] [PubMed] [Google Scholar]
• Chiarle R., Zhang Y., Frock R.L., Lewis S.M., Molinie B., Ho Y.J. Genome-wide translocation sequencing reveals mechanisms of chromosome breaks and rearrangements in B cells. Cell. 2011;147(1):107–119. (September 30) [PMC free article] [PubMed] [Google Scholar]
• Chng K.R., Chan S.H., Ng A.H., Li C., Jusakul A., Bertrand D. Tissue microbiome profiling identifies an enrichment of specific enteric bacteria in Opisthorchis viverrini associated cholangiocarcinoma. EBioMedicine. 2016;8:195–202. (June) [PMC free article] [PubMed] [Google Scholar]
• Choi D., Lim J.H., Lee K.T., Lee J.K., Choi S.H., Heo J.S. Cholangiocarcinoma and Clonorchis sinensis infection: a case-control study in Korea. J. Hepatol. 2006;44(6):1066–1073. (June) [PubMed] [Google Scholar]
• Colquhoun B.P., Visvanathan K. Adenocarcinoma of the pancreas associated with Clonorchis sinensis infection. CMAJ. 1987;136(2):153–154. (January 15) [PMC free article] [PubMed] [Google Scholar]
• Cooppan R.M., Bhoola K.D., Mayet F.G. Schistosomiasis and bladder carcinoma in Natal. S. Afr. Med. J. 1984;66(22):841–843. (December 1) [PubMed] [Google Scholar]
• Coura J.R. Chagas disease: control, elimination and eradication. Is it possible? Mem. Inst. Oswaldo Cruz. 2013;108(8):962–967. (December) [PMC free article] [PubMed] [Google Scholar]
• Cuesta R.A., Kaw Y.T., Duwaji M.S. Schistosoma mekongi infection in a leiomyosarcoma of the small bowel: a case report. Hum. Pathol. 1992;23(4):471–473. (April) [PubMed] [Google Scholar]
• Daud I.I., Ogolla S., Amolo A.S., Namuyenga E., Simbiri K., Bukusi E.A. Plasmodium falciparum infection is associated with Epstein-Barr virus reactivation in pregnant women living in malaria holoendemic area of Western Kenya. Matern. Child Health J. 2015;19(3):606–614. (March) [PMC free article] [PubMed] [Google Scholar]
• de Martel C., Ferlay J., Franceschi S., Vignat J., Bray F., Forman D. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012;13(6):607–615. (June) [PubMed] [Google Scholar]
• de Oliver V.M., Mendes L.M., Almeida D.J., Hoelz L.V.B., Torres P.H.M., Pascutti P.G. New treatments for Chagas disease and the relationship between chagasic patients and cancers. Can. Respir. J. 2014;2(6–1):11–29. (December 26) [Google Scholar]
• Donati D., Zhang L.P., Chene A., Chen Q., Flick K., Nystrom M. Identification of a polyclonal B-cell activator in Plasmodium falciparum. Infect. Immun. 2004;72(9):5412–5418. (September) [PMC free article] [PubMed] [Google Scholar]
• Donati D., Espmark E., Kironde F., Mbidde E.K., Kamya M., Lundkvist A. Clearance of circulating Epstein-Barr virus DNA in children with acute malaria after antimalaria treatment. J. Infect. Dis. 2006;193(7):971–977. (April 1) [PubMed] [Google Scholar]
• Ferlay J., Shin H.R., Bray F., Forman D., Mathers C., Parkin D.M. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int. J. Cancer. 2010;127(12):2893–2917. (December 15) [PubMed] [Google Scholar]
• Forrer A., Sayasone S., Vounatsou P., Vonghachack Y., Bouakhasith D., Vogt S. Spatial distribution of, and risk factors for, Opisthorchis viverrini infection in southern Lao PDR. PLoS Negl. Trop. Dis. 2012;6(2) [PMC free article] [PubMed] [Google Scholar]
• Gabet A.S., Mortreux F., Talarmin A., Plumelle Y., Leclercq I., Leroy A. High circulating proviral load with oligoclonal expansion of HTLV-1 bearing T cells in HTLV-1 carriers with strongyloidiasis. Oncogene. 2000;19(43):4954–4960. (October 12) [PubMed] [Google Scholar]
• Gouveia M.J., Santos J., Brindley P.J., Rinaldi G., Lopes C., Santos L.L. Estrogen-like metabolites and DNA-adducts in urogenital schistosomiasis-associated bladder cancer. Cancer Lett. 2015;359(2):226–232. (April 10) [PubMed] [Google Scholar]
• Grazielle-Silva V., Zeb T.F., Bolderson J., Campos P.C., Miranda J.B., Alves C.L. Distinct phenotypes caused by mutation of MSH2 in trypanosome insect and mammalian life cycle forms are associated with parasite adaptation to oxidative stress. PLoS Negl. Trop. Dis. 2015;9(6) (June) [PMC free article] [PubMed] [Google Scholar]
• Gutierrez M.I., Bhatia K., Cherney B., Capello D., Gaidano G., Magrath I. Intraclonal molecular heterogeneity suggests a hierarchy of pathogenetic events in Burkitt's lymphoma. Ann. Oncol. 1997;8(10):987–994. (October) [PubMed] [Google Scholar]
• Haonon O., Rucksaken R., Pinlaor P., Pairojkul C., Chamgramol Y., Intuyod K. Upregulation of 14-3-3 eta in chronic liver fluke infection is a potential diagnostic marker of cholangiocarcinoma. Proteomics Clin. Appl. 2015;5 (October) [PubMed] [Google Scholar]
• Haswell-Elkins M.R., Satarug S., Tsuda M., Mairiang E., Esumi H., Sithithaworn P. Liver fluke infection and cholangiocarcinoma: model of endogenous nitric oxide and extragastric nitrosation in human carcinogenesis. Mutat. Res. 1994;305(2):241–252. (March 1) [PubMed] [Google Scholar]
• Hay S.I., Okiro E.A., Gething P.W., Patil A.P., Tatem A.J., Guerra C.A. Estimating the global clinical burden of Plasmodium falciparum malaria in 2007. PLoS Med. 2010;7(6) (June) [PMC free article] [PubMed] [Google Scholar]
• Helling-Giese G., Sjaastad A., Poggensee G., Kjetland E.F., Richter J., Chitsulo L. Female genital schistosomiasis (FGS): relationship between gynecological and histopathological findings. Acta Trop. 1996;62(4):257–267. (December 30) [PubMed] [Google Scholar]
• Hodder S.L., Mahmoud A.A., Sorenson K., Weinert D.M., Stein R.L., Ouma J.H. Predisposition to urinary tract epithelial metaplasia in Schistosoma haematobium infection. Am.J.Trop. Med. Hyg. 2000;63(3–4):133–138. (September) [PubMed] [Google Scholar]
• Honeycutt J., Hammam O., Fu C.L., Hsieh M.H. Controversies and challenges in research on urogenital schistosomiasis-associated bladder cancer. Trends Parasitol. 2014;30(7):324–332. (July) [PMC free article] [PubMed] [Google Scholar]
• Honeycutt J., Hammam O., Hsieh M.H. Schistosoma haematobium egg-induced bladder urothelial abnormalities dependent on p53 are modulated by host sex. Exp. Parasitol. 2015;6 (July) [PMC free article] [PubMed] [Google Scholar]
• HS O.E., Hamid H.K., Mekki S.O., Suleiman S.H., Ibrahim S.Z. Colorectal carcinoma associated with schistosomiasis: a possible causal relationship. World J. Surg. Oncol. 2010;8:68. [PMC free article] [PubMed] [Google Scholar]
• Hugosson E., Montgomery S.M., Premji Z., Troye-Blomberg M., Bjorkman A. Higher IL-10 levels are associated with less effective clearance of Plasmodium falciparum parasites. Parasite Immunol. 2004;26(3):111–117. (March) [PubMed] [Google Scholar]
• IARC Schistosomes, liver flukes and helicobacter pylori. IARC working group on the eval‎uation of carcinogenic risks to humans. Lyon, 7-14 June 1994. IARC Monogr. Eval‎. Carcinog. Risks Hum. 1994;61:1–241. [PubMed] [Google Scholar]
• IARC Biological agents. Volume 100 B. A review of human carcinogens. IARC Monogr. Eval‎. Carcinog. Risks Hum. 2012;100(Pt B):1–441. [PMC free article] [PubMed] [Google Scholar]
• Iida F., Iida R., Kamijo H., Takaso K., Miyazaki Y., Funabashi W. Chronic Japanese schistosomiasis and hepatocellular carcinoma: ten years of follow-up in Yamanashi prefecture, Japan. Bull. World Health Organ. 1999;77(7):573–581. [PMC free article] [PubMed] [Google Scholar]
• Ishii A., Matsuoka H., Aji T., Ohta N., Arimoto S., Wataya Y. Parasite infection and cancer: with special emphasis on Schistosoma japonicum infections (Trematoda). A review. Mutat. Res. 1994;305(2):273–281. (March 1) [PubMed] [Google Scholar]
• Johnston W.T., Mutalima N., Sun D., Emmanuel B., Bhatia K., Aka P. Relationship between Plasmodium falciparum malaria preval‎ence, genetic diversity and endemic Burkitt lymphoma in Malawi. Sci. Rep. 2014;4:3741. [PMC free article] [PubMed] [Google Scholar]
• Junqueira C., Santos L.I., Galvao-Filho B., Teixeira S.M., Rodrigues F.G., DaRocha W.D. Trypanosoma cruzi as an effective cancer antigen delivery vector. Proc. Natl. Acad. Sci. U. S. A. 2011;108(49):19695–19700. (December 6) [PMC free article] [PubMed] [Google Scholar]
• Jusakul A., Kongpetch S., Teh B.T. Genetics of Opisthorchis viverrini-related cholangiocarcinoma. Curr. Opin. Gastroenterol. 2015;31(3):258–263. (May) [PubMed] [Google Scholar]
• Kallinikova V.D., Matekin P.V., Ogloblina T.A., Leikina M.I., Kononenko A.F., Sokolova N.M. Anticancer properties of flagellate protozoan Trypanosoma cruzi Chagas, 1909. Izv. Akad. Nauk Ser. Biol. 2001;3:299–311. (May) [PubMed] [Google Scholar]
• Keiser J., Utzinger J. Food-borne trematodiases. Clin. Microbiol. Rev. 2009;22(3):466–483. (July) [PMC free article] [PubMed] [Google Scholar]
• Khuntikeo N., Loilome W., Thinkhamrop B., Chamadol N., Yongvanit P. A comprehensive public health conceptual framework and strategy to effectively combat cholangiocarcinoma in Thailand. PLoS Negl. Trop. Dis. 2016;10(1) (January) [PMC free article] [PubMed] [Google Scholar]
• Kim E.M., Bae Y.M., Choi M.H., Hong S.T. Cyst formation, increased anti-inflammatory cytokines and expression‎ of chemokines support for Clonorchis sinensis infection in FVB mice. Parasitol. Int. 2012;61(1):124–129. (March) [PubMed] [Google Scholar]
• Kiremit M.C., Cakir A., Arslan F., Ormeci T., Erkurt B., Albayrak S. The bladder carcinoma secondary to Schistosoma mansoni infection: a case report with review of the literature. Int. J. Surg. Case Rep. 2015;13:76–78. [PMC free article] [PubMed] [Google Scholar]
• Kitinya J.N., Lauren P.A., Eshleman L.J., Paljarvi L., Tanaka K. The incidence of squamous and transitional cell carcinomas of the urinary bladder in northern Tanzania in areas of high and low levels of endemic Schistosoma haematobium infection. Trans. R. Soc. Trop. Med. Hyg. 1986;80(6):935–939. [PubMed] [Google Scholar]
• Klein I.A., Resch W., Jankovic M., Oliveira T., Yamane A., Nakahashi H. Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell. 2011;147(1):95–106. (September 30) [PMC free article] [PubMed] [Google Scholar]
• Knowles M.A., Hurst C.D. Molecular biology of bladder cancer: new insights into pathogenesis and clinical diversity. Nat. Rev. Cancer. 2015;15(1):25–41. (January) [PubMed] [Google Scholar]
• Krementsov N. Trypanosoma cruzi, cancer and the cold war. Hist Cienc Saude Manguinhos. 2009;16(Suppl. 1):75–94. (July) [PubMed] [Google Scholar]
• Lim M.K., Ju Y.H., Franceschi S., Oh J.K., Kong H.J., Hwang S.S. Clonorchis sinensis infection and increasing risk of cholangiocarcinoma in the Republic of Korea. Am.J.Trop. Med. Hyg. 2006;75(1):93–96. (July) [PubMed] [Google Scholar]
• Lopez N.C., Valck C., Ramirez G., Rodriguez M., Ribeiro C., Orellana J. Antiangiogenic and antitumor effects of Trypanosoma cruzi calreticulin. PLoS Negl. Trop. Dis. 2010;4(7) [PMC free article] [PubMed] [Google Scholar]
• Machicado C., Marcos L.A. Carcinogenesis associated with parasites other than Schistosoma, Opisthorchis and Clonorchis: a systematic review. Int. J. Cancer. 2016 (February 3) [PubMed] [Google Scholar]
• Madbouly K.M., Senagore A.J., Mukerjee A., Hussien A.M., Shehata M.A., Navine P. Colorectal cancer in a population with endemic Schistosoma mansoni: is this an at-risk population? Int. J. Color. Dis. 2007;22(2):175–181. (February) [PubMed] [Google Scholar]
• Maeng S, Lee HW, Bashir Q, Kim TI, Hong SJ, Lee TJ et al. Oxidative stress-mediated mouse liver lesions caused by Clonorchis sinensis infection. Int. J. Parasitol. 2016;46(3):195–204 (March). [PubMed]
• Maksimova G.A., Zhukova N.A., Kashina E.V., Lvova M.N., Katokhin A.V., Tolstikova T.G. Role of opisthorchis felineus on induction of bile duct cancer. Parazitologiia. 2015;49(1):3–11. (January) [PubMed] [Google Scholar]
• Manoel-Caetano F.S., Borim A.A., Caetano A., Cury P.M., Silva A.E. Cytogenetic alterations in chagasic achalasia compared to esophageal carcinoma. Cancer Genet. Cytogenet. 2004;149(1):17–22. (February) [PubMed] [Google Scholar]
• Matchimakul P., Rinaldi G., Suttiprapa S., Mann V.H., Popratiloff A., Laha T. Apoptosis of cholangiocytes modulated by thioredoxin of carcinogenic liver fluke. Int. J. Biochem. Cell Biol. 2015;65:72–80. (August) [PMC free article] [PubMed] [Google Scholar]
• Matsuda K., Masaki T., Ishii S., Yamashita H., Watanabe T., Nagawa H. Possible associations of rectal carcinoma with Schistosoma japonicum infection and membranous nephropathy: a case report with a review. Jpn. J. Clin. Oncol. 1999;29(11):576–581. (November) [PubMed] [Google Scholar]
• Meng F.L., Du Z., Federation A., Hu J., Wang Q., Kieffer-Kwon K.R. Convergent transcription at intragenic super-enhancers targets AID-initiated genomic instability. Cell. 2014;159(7):1538–1548. (December 18) [PMC free article] [PubMed] [Google Scholar]
• Molyneux E.M., Rochford R., Griffin B., Newton R., Jackson G., Menon G. Burkitt's lymphoma. Lancet. 2012;379(9822):1234–1244. (March 31) [PubMed] [Google Scholar]
• Moormann A.M., Chelimo K., Sumba O.P., Lutzke M.L., Ploutz-Snyder R., Newton D. Exposure to holoendemic malaria results in elevated Epstein-Barr virus loads in children. J. Infect. Dis. 2005;191(8):1233–1238. (April 15) [PubMed] [Google Scholar]
• Moormann A.M., Chelimo K., Sumba P.O., Tisch D.J., Rochford R., Kazura J.W. Exposure to holoendemic malaria results in suppression of Epstein-Barr virus-specific T cell immunosurveillance in Kenyan children. J. Infect. Dis. 2007;195(6):799–808. (March 15) [PubMed] [Google Scholar]
• Muller M.C., van der Werf S.D. A young woman from Cameroon with rectal blood loss, intestinal schistosomiasis and rectosigmoid carcinoma. Ned. Tijdschr. Geneeskd. 2008;152(16):951–955. (April 19) [PubMed] [Google Scholar]
• Murta E.F., Oliveira G.P., Prado F.O., De Souza M.A., Tavares Murta B.M., Adad S.J. Association of uterine leiomyoma and Chagas' disease. Am.J.Trop. Med. Hyg. 2002;66(3):321–324. (March) [PubMed] [Google Scholar]
• Ninlawan K., O'Hara S.P., Splinter P.L., Yongvanit P., Kaewkes S., Surapaitoon A. Opisthorchis viverrini excretory/secretory products induce toll-like receptor 4 upregulation and production of interleukin 6 and 8 in cholangiocyte. Parasitol. Int. 2010;59(4):616–621. (December) [PMC free article] [PubMed] [Google Scholar]
• Njie R., Bell A.I., Jia H., Croom-Carter D., Chaganti S., Hislop A.D. The effects of acute malaria on Epstein-Barr virus (EBV) load and EBV-specific T cell immunity in Gambian children. J. Infect. Dis. 2009;199(1):31–38. (January 1) [PubMed] [Google Scholar]
• Nomura T., Sakaguchi S. Naturally arising CD25 + CD4 + regulatory T cells in tumor immunity. Curr. Top. Microbiol. Immunol. 2005;293:287–302. [PubMed] [Google Scholar]
• Nunes M.C., Dones W., Morillo C.A., Encina J.J., Ribeiro A.L. Chagas disease: an overview of clinical and epidemiological aspects. J. Am. Coll. Cardiol. 2013;62(9):767–776. (August 27) [PubMed] [Google Scholar]
• Ocana-Morgner C., Mota M.M., Rodriguez A. Malaria blood stage suppression of liver stage immunity by dendritic cells. J. Exp. Med. 2003;197(2):143–151. (January 20) [PMC free article] [PubMed] [Google Scholar]
• Ogorodova L.M., Freidin M.B., Sazonov A.E., Fedorova O.S., Gerbek I.E., Cherevko N.A. A pilot screening of preval‎ence of atopic states and opisthorchosis and their relationship in people of Tomsk Oblast. Parasitol. Res. 2007;101(4):1165–1168. (September) [PubMed] [Google Scholar]
• Ogorodova L.M., Fedorova O.S., Sripa B., Mordvinov V.A., Katokhin A.V., Keiser J. Opisthorchiasis: an overlooked danger. PLoS Negl. Trop. Dis. 2015;9(4) (April) [PMC free article] [PubMed] [Google Scholar]
• Ohtake N., Takayama O., Uno A., Kubota Y., Shimada S., Tamaki K. A case of cutaneous squamous cell carcinoma associated with sporadic porphyria cutanea tarda due to liver disorder after Schistosoma japonicum infection. J. Dermatol. 1991;18(4):240–244. (April) [PubMed] [Google Scholar]
• Oliveira E.C., Lette M.S., Ostermayer A.L., Almeida A.C., Moreira H. Chagasic megacolon associated with colon cancer. Am.J.Trop. Med. Hyg. 1997;56(6):596–598. (June) [PubMed] [Google Scholar]
• Oliveira E.C., Leite M.S., Miranda J.A., Andrade A.L., Garcia S.B., Luquetti A.O. Chronic Trypanosoma cruzi infection associated with low incidence of 1.2-dimethylhydrazine-induced colon cancer in rats. Carcinogenesis. 2001;22(5):737–740. (May) [PubMed] [Google Scholar]
• Orem J., Mbidde E.K., Lambert B., de SS W.E. Burkitt's lymphoma in Africa, a review of the epidemiology and etiology. Afr. Health Sci. 2007;7(3):166–175. (September) [PMC free article] [PubMed] [Google Scholar]
• Pak J.H., Son W.C., Seo S.B., Hong S.J., Sohn W.M., Na B.K. Peroxiredoxin 6 expression‎ is inversely correlated with nuclear factor-kappaB activation during Clonorchis sinensis infestation. Free Radic. Biol. Med. 2016;99:273–285. (August 20) [PubMed] [Google Scholar]
• Pakharukova M.Y., Mordvinov V.A. The liver fluke Opisthorchis felineus: biology, epidemiology and carcinogenic potential. Trans. R. Soc. Trop. Med. Hyg. 2016;110(1):28–36. (January) [PubMed] [Google Scholar]
• Palmer W.C., Patel T. Are common factors involved in the pathogenesis of primary liver cancers? A meta-analysis of risk factors for intrahepatic cholangiocarcinoma. J. Hepatol. 2012;57(1):69–76. (July) [PMC free article] [PubMed] [Google Scholar]
• Petney T.N., Andrews R.H., Saijuntha W., Wenz-Mucke A., Sithithaworn P. The zoonotic, fish-borne liver flukes Clonorchis sinensis, Opisthorchis felineus and Opisthorchis viverrini. Int. J. Parasitol. 2013;43(12–13):1031–1046. (November) [PubMed] [Google Scholar]
• Pichyangkul S., Yongvanitchit K., Kum-arb U., Hemmi H., Akira S., Krieg A.M. Malaria blood stage parasites activate human plasmacytoid dendritic cells and murine dendritic cells through a Toll-like receptor 9-dependent pathway. J. Immunol. 2004;172(8):4926–4933. (April 15) [PubMed] [Google Scholar]
• Plieskatt J.L., Deenonpoe R., Mulvenna J.P., Krause L., Sripa B., Bethony J.M. Infection with the carcinogenic liver fluke Opisthorchis viverrini modifies intestinal and biliary microbiome. FASEB J. 2013;27(11):4572–4584. (November) [PMC free article] [PubMed] [Google Scholar]
• Precopio M.L., Sullivan J.L., Willard C., Somasundaran M., Luzuriaga K. Differential kinetics and specificity of EBV-specific CD4 + and CD8 + T cells during primary infection. J. Immunol. 2003;170(5):2590–2598. (March 1) [PubMed] [Google Scholar]
• Qian J., Wang Q., Dose M., Pruett N., Kieffer-Kwon K.R., Resch W. B cell super-enhancers and regulatory clusters recruit AID tumorigenic activity. Cell. 2014;159(7):1524–1537. (December 18) [PMC free article] [PubMed] [Google Scholar]
• Qiu D.C., Hubbard A.E., Zhong B., Zhang Y., Spear R.C. A matched, case-control study of the association between Schistosoma japonicum and liver and colon cancers, in rural China. Ann. Trop. Med. Parasitol. 2005;99(1):47–52. (January) [PubMed] [Google Scholar]
• Rainey J.J., Mwanda W.O., Wairiumu P., Moormann A.M., Wilson M.L., Rochford R. Spatial distribution of Burkitt's lymphoma in Kenya and association with malaria risk. Tropical Med. Int. Health. 2007;12(8):936–943. (August) [PubMed] [Google Scholar]
• Ramirez G., Valck C., Ferreira V.P., Lopez N., Ferreira A. Extracellular Trypanosoma cruzi calreticulin in the host-parasite interplay. Trends Parasitol. 2011;27(3):115–122. (March) [PubMed] [Google Scholar]
• Ramirez G., Valck C., Molina M.C., Ribeiro C.H., Lopez N., Sanchez G. Trypanosoma cruzi calreticulin: a novel virulence factor that binds complement C1 on the parasite surface and promotes infectivity. Immunobiology. 2011;216(1–2):265–273. (January) [PubMed] [Google Scholar]
• Rasti N., Falk K.I., Donati D., Gyan B.A., Goka B.Q., Troye-Blomberg M. Circulating epstein-barr virus in children living in malaria-endemic areas. Scand. J. Immunol. 2005;61(5):461–465. (May) [PubMed] [Google Scholar]
• Robbiani D.F., Bothmer A., Callen E., Reina-San-Martin B., Dorsett Y., Difilippantonio S. AID is required for the chromosomal breaks in c-myc that lead to c-myc/IgH translocations. Cell. 2008;135(6):1028–1038. (December 12) [PMC free article] [PubMed] [Google Scholar]
• Robbiani D.F., Deroubaix S., Feldhahn N., Oliveira T.Y., Callen E., Wang Q. Plasmodium infection promotes genomic instability and AID-dependent B cell lymphoma. Cell. 2015;162(4):727–737. (August 13) [PMC free article] [PubMed] [Google Scholar]
• Rochford R., Cannon M.J., Moormann A.M. Endemic Burkitt's lymphoma: a polymicrobial disease? Nat. Rev. Microbiol. 2005;3(2):182–187. (February) [PubMed] [Google Scholar]
• Rosin M.P., Saad el Din Z.S., Ward A.J., Anwar W.A. Involvement of inflammatory reactions and elevated cell proliferation in the development of bladder cancer in schistosomiasis patients. Mutat. Res. 1994;305(2):283–292. (March 1) [PubMed] [Google Scholar]
• Sacerdote de L.E., Puricelli L., Bal E., Lansetti J.C. Association of Chagas disease and cancer. Medicina (B Aires) 1980;40(1):43–46. (January) [PubMed] [Google Scholar]
• Saengboonmee C., Seubwai W., Wongkham C., Wongkham S. Diabetes mellitus: possible risk and promoting factors of cholangiocarcinoma: association of diabetes mellitus and cholangiocarcinoma. Cancer Epidemiol. 2015;39(3):274–278. (June) [PubMed] [Google Scholar]
• Saltykova I.V., Ogorodova L.M., Bragina E.Y., Puzyrev V.P., Freidin M.B. Opisthorchis felineus liver fluke invasion is an environmental factor modifying genetic risk of atopic bronchial asthma. Acta Trop. 2014;139:53–56. (November) [PubMed] [Google Scholar]
• Saltykova I.V., Ogorodova L.M., Ivanov V.V., Bogdanov A.O., Gereng E.A., Perina E.A. Carbonyl stress phenomena during chronic infection with Opisthorchis felineus. Parasitol. Int. 2016 (January 8) [PMC free article] [PubMed] [Google Scholar]
• Sanchez-Valdez F.J., Perez B.C., Ramirez G., Uncos A.D., Zago M.P., Cimino R.O. A monoallelic deletion of the TcCRT gene increases the attenuation of a cultured Trypanosoma cruzi strain, protecting against an in vivo virulent challenge. PLoS Negl. Trop. Dis. 2014;8(2) (February) [PMC free article] [PubMed] [Google Scholar]
• Santos J., Fernandes E., Ferreira J.A., Lima L., Tavares A., Peixoto A. P53 and cancer-associated sialylated glycans are surrogate markers of cancerization of the bladder associated with Schistosoma haematobium infection. PLoS Negl. Trop. Dis. 2014;8(12) (December) [PMC free article] [PubMed] [Google Scholar]
• Satoh M., Toma H., Sugahara K., Etoh K., Shiroma Y., Kiyuna S. Involvement of IL-2/IL-2R system activation by parasite antigen in polyclonal expansion of CD4(+)25(+) HTLV-1-infected T-cells in human carriers of both HTLV-1 and S. stercoralis. Oncogene. 2002;21(16):2466–2475. (April 11) [PubMed] [Google Scholar]
• Segarra-Newnham M. Manifestations, diagnosis, and treatment of Strongyloides stercoralis infection. Ann. Pharmacother. 2007;41(12):1992–2001. (December) [PubMed] [Google Scholar]
• Sekiguchi A., Shindo G., Okabe H., Aoyanagi N., Furuse A., Oka T. A case of metastatic lung tumor of the colon cancer with ova of schistosoma japonicum in the resected lung specimen. Kyobu Geka. 1989;42(12):1025–1028. (November) [PubMed] [Google Scholar]
• Seo A.N., Goo Y.K., Chung D.I., Hong Y., Kwon O., Bae H.I. Comorbid gastric adenocarcinoma and gastric and duodenal Strongyloides stercoralis infection: a case report. Korean J. Parasitol. 2015;53(1):95–99. (February) [PMC free article] [PubMed] [Google Scholar]
• Sharfi A.R., el SS B.O. Squamous cell carcinoma of the urinary bladder. Br. J. Urol. 1992;69(4):369–371. (April) [PubMed] [Google Scholar]
• Simone O., Bejarano M.T., Pierce S.K., Antonaci S., Wahlgren M., Troye-Blomberg M. TLRs innate immunereceptors and plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1) CIDR1alpha-driven human polyclonal B-cell activation. Acta Trop. 2011;119(2–3):144–150. (August) [PMC free article] [PubMed] [Google Scholar]
• Sithithaworn P., Andrews R.H., Nguyen V.D., Wongsaroj T., Sinuon M., Odermatt P. The current status of opisthorchiasis and clonorchiasis in the Mekong Basin. Parasitol. Int. 2012;61(1):10–16. (March) [PMC free article] [PubMed] [Google Scholar]
• SM-C D.A., Silveira A.F., Silva A.E. Gene mutations in esophageal mucosa of chagas disease patients. Anticancer Res. 2009;29(4):1243–1247. (April) [PubMed] [Google Scholar]
• Smout M.J., Laha T., Mulvenna J., Sripa B., Suttiprapa S., Jones A. A granulin-like growth factor secreted by the carcinogenic liver fluke, Opisthorchis viverrini, promotes proliferation of host cells. PLoS Pathog. 2009;5(10) (October) [PMC free article] [PubMed] [Google Scholar]
• Smout M.J., Sotillo J., Laha T., Papatpremsiri A., Rinaldi G., Pimenta R.N. Carcinogenic parasite secretes growth factor that accelerates wound healing and potentially promotes neoplasia. PLoS Pathog. 2015;11(10) (October) [PMC free article] [PubMed] [Google Scholar]
• Sosoniuk E., Vallejos G., Kenawy H., Gaboriaud C., Thielens N., Fujita T. Trypanosoma cruzi calreticulin inhibits the complement lectin pathway activation by direct interaction with l-Ficolin. Mol. Immunol. 2014;60(1):80–85. (July) [PubMed] [Google Scholar]
• Sripa B., Kaewkes S., Sithithaworn P., Mairiang E., Laha T., Smout M. Liver fluke induces cholangiocarcinoma. PLoS Med. 2007;4(7) (July) [PMC free article] [PubMed] [Google Scholar]
• Sripa B., Mairiang E., Thinkhamrop B., Laha T., Kaewkes S., Sithithaworn P. Advanced periductal fibrosis from infection with the carcinogenic human liver fluke Opisthorchis viverrini correlates with elevated levels of interleukin-6. Hepatology. 2009;50(4):1273–1281. (October) [PMC free article] [PubMed] [Google Scholar]
• Sripa B., Brindley P.J., Mulvenna J., Laha T., Smout M.J., Mairiang E. The tumorigenic liver fluke Opisthorchis viverrini–multiple pathways to cancer. Trends Parasitol. 2012;28(10):395–407. (October) [PMC free article] [PubMed] [Google Scholar]
• Sripa B., Thinkhamrop B., Mairiang E., Laha T., Kaewkes S., Sithithaworn P. Elevated plasma IL-6 associates with increased risk of advanced fibrosis and cholangiocarcinoma in individuals infected by Opisthorchis viverrini. PLoS Negl. Trop. Dis. 2012;6(5) [PMC free article] [PubMed] [Google Scholar]
• Steinmann P., Keiser J., Bos R., Tanner M., Utzinger J. Schistosomiasis and water resources development: systematic review, meta-analysis, and estimates of people at risk. Lancet Infect. Dis. 2006;6(7):411–425. (July) [PubMed] [Google Scholar]
• Stevens L., Dorn P.L., Schmidt J.O., Klotz J.H., Lucero D., Klotz S.A. Kissing bugs. The vectors of Chagas. Adv. Parasitol. 2011;75:169–192. [PubMed] [Google Scholar]
• Tanaka T., Hirata T., Parrott G., Higashiarakawa M., Kinjo T., Kinjo T. Relationship among strongyloides stercoralis infection, human T-cell lymphotropic virus type 1 infection, and cancer: a 24-year cohort inpatient study in Okinawa, Japan. Am.J.Trop. Med. Hyg. 2016;94(2):365–370. (February 3) [PMC free article] [PubMed] [Google Scholar]
• Tomaino C, Catalano C, Tiba M, Aron J. Su2012: a first case report of colorectal cancer associated with chronic strongyloides stercoralis colitis and the complex management decisions that follow. Gastroenterology 2015; 148(4):Suppl.1-S575.
• Torgbor C., Awuah P., Deitsch K., Kalantari P., Duca K.A., Thorley-Lawson D.A. A multifactorial role for P. falciparum malaria in endemic Burkitt's lymphoma pathogenesis. PLoS Pathog. 2014;10(5) (May) [PMC free article] [PubMed] [Google Scholar]
• Tyson G.L., El-Serag H.B. Risk factors for cholangiocarcinoma. Hepatology. 2011;54(1):173–184. (July) [PMC free article] [PubMed] [Google Scholar]
• Tzivion G., Gupta V.S., Kaplun L., Balan V. 14-3-3 proteins as potential oncogenes. Semin. Cancer Biol. 2006;16(3):203–213. (June) [PubMed] [Google Scholar]
• Ubillos L., Freire T., Berriel E., Chiribao M.L., Chiale C., Festari M.F. Trypanosoma cruzi extracts elicit protective immune response against chemically induced colon and mammary cancers. Int. J. Cancer. 2016;138(7):1719–1731. (April 1) [PubMed] [Google Scholar]
• Urban B.C., Ferguson D.J., Pain A., Willcox N., Plebanski M., Austyn J.M. Plasmodium falciparum-infected erythrocytes modulate the maturation of dendritic cells. Nature. 1999;400(6739):73–77. (July 1) [PubMed] [Google Scholar]
• Urban B.C., Mwangi T., Ross A., Kinyanjui S., Mosobo M., Kai O. Peripheral blood dendritic cells in children with acute Plasmodium falciparum malaria. Blood. 2001;98(9):2859–2861. (November 1) [PubMed] [Google Scholar]
• Vale N., Gouveia M.J., Botelho M., Sripa B., Suttiprapa S., Rinaldi G. Carcinogenic liver fluke Opisthorchis viverrini oxysterols detected by LC-MS/MS survey of soluble fraction parasite extract. Parasitol. Int. 2013;62(6):535–542. (December) [PMC free article] [PubMed] [Google Scholar]
• Wanzel M., Kleine-Kohlbrecher D., Herold S., Hock A., Berns K., Park J. Akt and 14-3-3eta regulate Miz1 to control cell-cycle arrest after DNA damage. Nat. Cell Biol. 2005;7(1):30–41. (January) [PubMed] [Google Scholar]
• Welzel T.M., Mellemkjaer L., Gloria G., Sakoda L.C., Hsing A.W., El G.L. Risk factors for intrahepatic cholangiocarcinoma in a low-risk population: a nationwide case-control study. Int. J. Cancer. 2007;120(3):638–641. (February 1) [PubMed] [Google Scholar]
• Whittle H.C., Brown J., Marsh K., Greenwood B.M., Seidelin P., Tighe H. T-cell control of Epstein-Barr virus-infected B cells is lost during P. falciparum malaria. Nature. 1984;312(5993):449–450. (November 29) [PubMed] [Google Scholar]
• WHO . Report No.: December. 2014. Factsheet on the World Malaria Report 2014. [Google Scholar]