Parasite Infection, Carcinogenesis and Human Malignancy – PMC

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, 1976). A study from South Africa analyzing primary malignant bladder tumors found that the cancers were frequently squamous cell carcinomas (61%) (Cooppan et al., 1984). In Tanzania, 72% of bladder cancers were squamous cell carcinomas, and 46% of patients with squamous cell carcinomas were positive for S. haematobium eggs in tumor tissues (Kitinya et al., 1986). Another study found that UGS was strongly related to an increased risk of cytological abnormalities in a S. haematobium endemic area of Kenya (Hodder et al., 2000). S. haematobium-associated lesions were also detected in 69% of patients with squamous cell bladder carcinoma in Sudan (Sharfi and el SS, 1992). Case reports also have suggested a possible association of UGS with other malignant neoplasms such as prostatic adenocarcinoma and squamous cell carcinoma of the cervix (Basilio-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. 1). The mechanisms, however, need to be investigated further. Fibrosis induced by Schistosoma 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., 2015). The detection of 8-oxodG indicates the damage of DNA in UGS via 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., 2013). Chromosomal damage and somatic mutations were frequently observed in these oncogenes in invasive squamous cell carcinomas of the bladder during UGS (Rosin et al., 1994). A recent proteomic analysis of urine samples from UGS patients additionally confirms the involvement of oxidative stress and immune responses in the development of S. 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., 2005). A Japanese study found that 19% of patients with chronic liver disease and 51% of patients with hepatocellular carcinoma (HCC) were infected with S. 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., 1999). A matched, case-control study in rural China has indicated that previous infections with S. 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., 1989). An isolated case of cutaneous squamous cell carcinoma associated with sporadic porphyria cutanea tarda due to liver functional disorder after S. japonicum infection was reported (Ohtake et al., 1991). Furthermore, a recent case report described a concomitance of S. japonicum infection with rectal carcinoid tumor in an asymptomatic patient from the Philippines (Zanger et al., 2010). Soluble egg antigen (SEA) from S. japonicum, which has a strong immunogenic activity, may contribute to carcinogenesis through stimulation of chronic inflammation (Ishii et al., 1994). Somatic mutations in the p53 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., 1998). S. 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., 2010). A recent case report from Turkey described the etiological relationship between S. mansoni and bladder cancer (Kiremit et al., 2015). Cell-mediated responses are depressed during intestinal schistosomiasis and the degree of suppression apparently correlates with the development of hepatosplenomegaly. Anti-idiotype antibodies produced during chronic schistosomiasis may modulate immune responses and S. mansoni egg antigens can effectively modify subpopulations of T helper cells (Cheever et al., 2002). Moreover, schistosomal colitis may be associated with earlier onset of multicentric colorectal cancer. Altered expression of the tumor protein 53 (TP53) in patients with S. mansoni colitis-related colorectal cancer suggests that schistosome infections may induce carcinogenesis by targeting oncogenes (Madbouly et al., 2007). Other oncogenes such as Bcl-2 and C-Myc also are relevant in the development of colorectal cancer during schistosomiasis (Zalata et al., 2005). Therefore, cancer induction by S. 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).

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., 2012). Together with O. 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., 2016). A mechanism that can explain the association between O. 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., 1994). The parasite-derived granulin can promote proliferation of biliary cells, and thioredoxin (TRX) and thioredoxin peroxidase (TPX) can prevent apoptosis (Sripa et al., 2012a, Smout et al., 2009, Matchimakul et al., 2015, Smout et al., 2015). In addition, an analysis of O. 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., 2015a). Higher IL-6 levels were observed in infected patients with bile duct cancer compared to those without (Sripa et al., 2009, Sripa et al., 2012b). These data indicate that opisthorchiidae have strong proinflammatory properties, which increase the risk of carcinogenesis (Ogorodova et al., 2015). On the other hand, host immunological factors play also a crucial role in determining the outcome of opisthorchiid infection and in initiation of cholangiocarcinogenesis. In this context, it was shown that O. 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., 2009). These proteins are members of the retinoblastoma protein (RB) pathway, which is strongly involved in cancer development. Moreover, the chronic inflammatory condition caused by O. viverrini leads to upregulation of the PI3K/AKT and Wnt/β-catenin signaling pathways involved in tumorgenesis (Yothaisong et al., 2014). Recently, a proteomic study has indicated that the 14-3-3 eta protein is up-regulated during O. 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., 2015), indicating that the 14-3-3 eta protein is involved in host responses and contributes to carcinogenesis. This is supported by previous findings on the central role of the 14-3-3 eta protein in different controlling processes of cell cycle and in the regulation of various oncogenes and tumor suppressor genes (Tzivion 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., 2013). In particular, somatic mutations occur more frequently in the p53 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., 2015). Mutations in the tumor suppressor genes p53 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., 2012). Indeed, a case-control study from Korea showed that C. sinensis infection was significantly associated with increased risk of cholangiocarcinoma (OR = 7.3, 95%CI = 3.96–13.3) (Choi et al., 2006). An epidemiologic survey performed in 3169 Korean residents also showed that a higher prevalence of C. sinensis infection was associated with a higher incidence of cholangiocarcinoma (Lim et al., 2006). The exact mechanisms by which C. 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, 1987). A study has demonstrated that C. sinensis-derived excretory-secretory products may promote aggregation and invasion of cholangiocarcinoma cells into the neighboring extracellular matrix (Won et al., 2014). Strong stimulation of Th2-associated inflammation by C. sinensis could be a risk factor for the initiation and development of cancer (Kim et al., 2012). During C. 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., 2016). C. 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., 2016). These results indicate that C. sinensis demonstrate a strong immunogenic property and robustly induce metabolic oxidative stress.

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., 2012). Burkitt lymphoma is classified into the clinical types of endemic, sporadic and immunodeficiency-associated Burkitt lymphoma. The annual incidence is approximately 40–50 per one million children, and in high-risk areas, endemic Burkitt lymphoma accounts for half of all childhood cancers and up to 90% of lymphoma diagnoses (Molyneux et al., 2012, Orem et al., 2007). The chromosome translocation between the c-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., 1997). Burkitt lymphoma is clearly associated with EBV infection, and in non-malaria-endemic areas it is associated with HIV/AIDS (Molyneux et al., 2012, Rochford et al., 2005).

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., 1980). A case report described a patient with chagasic megaesophagus who had developed esophageal leiomyosarcoma (Adad et al., 1999). A case-control study has shown that 27% of women with uterine leiomyoma were serologically positive for CD compared to 16% of controls with other benign gynecological alterations (Murta et al., 2002). Other case reports have pointed to an association of chagasic megacolon and development of colon cancer (Adad et al., 2002, Oliveira et al., 1997). One documented mechanism is an increase of gastroesophageal reflux into the megaesophagus (de Oliver et al., 2014). A study examined cytogenetic alterations in patients with chagasic megaesophagus and observed aneuploidies of chromosomes 7, 11, and 17 in 60% and the deletion of the oncogene p53 in 54.5% of 20 study patients; this might increase the risk of tumor development (Manoel-Caetano et al., 2004). While point mutations in exonic regions of p53, 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., 2010). The assumed T. 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).

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), CA164719, CA155297 and AI098639 from National Institutes of Health (NIH). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI, NIAID, or NIH.