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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Cell Physiol. Author manuscript; available in PMC 2010 April 15.
Published in final edited form as:
PMCID: PMC2855192
NIHMSID: NIHMS187529

The Role of Viral and Bacterial Pathogens in Gastrointestinal Cancer

Abstract

The association of Helicobacter pylori (H. pylori) with gastric cancer is thus far the best understood model to comprehend the causal relationship between a microbial pathogen and cancer in the human gastrointestinal tract. Besides H. pylori, a variety of other pathogens are now being recognized as potential carcinogens in different settings of human cancer. In this context, viral causes of human cancers are central to the issue since these account for 10–20% of cancers worldwide. In the case of H. pylori and gastric cancer, as well as the human papillomavirus and anal cancer, the causal relationship between the infectious agent and the related cancer in the gastrointestinal tract has been clearly confirmed by epidemiological and experimental studies. Similarly, Epstein–Barr virus and the oncogenic JC virus are being suggested as possible causative agents for cancers in the upper and lower gastrointestinal tract. This review discusses various viral and microbial pathogens and their oncogenic properties in the evolution of gastrointestinal carcinogenesis and summarizes the available experimental data make a convincing agreement favoring the associations between infectious agents and specific human cancers.

Viral and bacterial pathogens have been long proposed to play a role in the development of cancer. For the past 20 years the ongoing research has continuously broadened our knowledge about the role of oncogenic infectious agents. Animal and human studies have widely suggested a carcinogenic role of several pathogens. Viruses in particular have been found to play a major role in the tumorigenic process involving several organs: the human papillomavirus (cervical cancer), the herpes viruses (Kaposi sarcoma), human and simian polyomaviruses (mesothelioma, brain tumors), the Epstein–Barr virus (B-cell lymphomas, nasopharyngeal cancer), the human T-cell leukemia virus-1 (T-cell leukemias), and the hepatitis B and C viruses (hepatocellular carcinoma).

An estimated 17.8% or approximately 1.9 million cases of the worldwide incidence of cancer in the year 2002 can be attributed to bacterial or virus induced infections (Parkin, 2006). This underlines the importance to study these specific pathogens and their pathways leading to cancer.

Cancers of the gastrointestinal tract are a major health problem and represent almost 20% of all cancer related deaths in both men and women (Ferlay et al., 2007). While the incidence of gastric cancer has slowly declined in developed countries, the disease is still important in Asia, where possible multiple factors are key players for its pathogenesis. Contrary to gastric cancer, the incidence of colorectal and esophageal cancers is still on the rise. In the US, an estimated 112,340 new cases of colon cancers were expected for 2007 with 52,180 deaths among both sexes (Jemal et al., 2007). The picture regarding esophageal cancer is even more critical with 15,560 new cases and 13,940 deaths.

Although various risk factors may influence an individual’s predisposition to the development of gastrointestinal cancer, it is clear, at least since the discovery of Helicobacter pylori and its role in gastric cancer, that microbial pathogens are critical players in the development of tumors of the gastrointestinal tract. This review focuses on the role of microbial pathogens in the gastrointestinal tract and tries to clarify our understanding on how bacteria and viruses induce cancer in the different segments of the gastrointestinal tract.

The first part of this review introduces the different microbial pathogens and their oncogenic properties, while the second part focuses on the different types of cancers in the gastrointestinal tract and the possible implications of viral and bacterial pathogens in their development.

Oncogenic Viral and Bacterial Pathogens

Epstein–Barr virus (EBV)

EBV is an ubiquitous herpes virus that infects >90% of the world’s adult population and infected individuals remain lifelong carriers of the virus with few, if any, symptoms (Henle and Henle, 1980). However, EBV was the first human virus to be directly implicated in carcinogenesis, when the virus was isolated from biopsy tissue samples of the childhood malignancy Burkitt’s lymphoma (Burkitt, 1958; Epstein et al., 1964). Subsequently, EBV was found to be strongly associated with other malignancies like nasopharyngeal carcinoma (Pathmanathan et al., 1995), post-transplant lymphoma and gastric carcinoma (Shibata and Weiss, 1992).

The oncogenic properties of EBV are mainly due to the expression of the different types of EBV nuclear antigens (EBNAs) and three latent membrane proteins (LMPs). The main transforming protein of EBV is LMP-1 which behaves like a classical oncogene by transforming fibroblasts and B-cells in vitro (Wang et al., 1985; Kaye et al., 1993). LMP-1 resembles CD40, a member of the tumor necrosis factor receptor (TNFR) family and hence mimics the cellular growth and differentiation signals that normally result from the binding of CD40 ligand (Zimber-Strobl et al., 1996; Gires et al., 1997). In addition to these effects, LMP-1 can mediate the activation of NF-κB (Huen et al., 1995) and upregulate bcl-2 and A20b (Fries et al., 1996; Wang et al., 1996), which protects infected cells from p53-mediated apoptosis. On the other hand, the LMP-2 gene of EBV encodes two proteins, LMP-2A and LMP-2B. The structure of these two integral membrane proteins is similar. It is thought that LMP-2 proteins play a role in modifying normal B-cell development and thus prevent activation of the viral replicative cycle to maintain EBV latency. The expression of LMP-2A in many cancers associated with EBV suggests an important function for this protein in carcinogenesis (Tao et al., 2006). A recent work done by Stewart et al. (2004) showed that LMP-2A regulates viral and cellular gene expression by modulating the NF-κB transcription factor pathway suggesting an important role of LMP-2A in the pathogenesis of EBV-associated tumors.

Moreover, EBV encodes a series of EBV-determined nuclear antigens: EBNA-1, EBNA-2, EBNA-3 (A–C) and EBNA-LP. These products are essential for EBV-induced immortalization of the cell, and also promote EBV infection and transformation. For example, EBNA-LP binds to the tumor suppressors p53 and pRb by forming protein–protein complexes (Szekely et al., 1993). EBNA-A2 upregulates several viral and cellular genes. For example, EBNA-A2 interacts with transcription factors involved in the NOTCH signaling pathway that controls cell fate, proliferation and apoptosis (Henkel et al., 1994; Hsieh et al., 1996). Several studies have confirmed the absolute requirements for EBNA-2 and LMP-1 for cellular transformation. An important role for the transformation process has been suggested for EBNA-1, EBNA-LP, EBNA-3A, and EBNA-3C (Kieff and Rickinson, 2001).

Human papillomavirus (HPV)

Papillomaviruses are small non-enveloped DNA viruses with a virion size of ~55 nm that usually cause sexually transmitted benign tumors. However, HPV infection can sometimes progress to the development of malignant lesions (Bosch et al., 2002; Gillison and Shah, 2003; Cogliano et al., 2005). There are over 80 different HPV subtypes, which have been classified into low-risk and high-risk subtypes. The low-risk HPVs (e.g., types 6, 11, and 33) are associated with the growth of warts and benign lesions. High-risk HPVs (such as 16, 18, and 31) have been recognized as causative agents of several cancers like cervical and anal carcinoma (Ho et al., 1998; Cogliano et al., 2005). The high-risk HPVs 16 and −18 encode for at least three transforming oncoproteins: E5, E6, and E7. These proteins display transforming and growth-stimulating properties by inactivating the tumor suppressor functions of the p53 and retinoblastoma proteins (Werness et al., 1990; Heck et al., 1992; Thomas et al., 1999). Furthermore, it has been reported that the integration of HPV-DNA into host genomic DNA is associated with chromosomal instability (CIN; Ueda et al., 2003). DeFilippis et al. (2003) showed, that integration of E6 and E7 into HeLa cervical carcinoma cells inhibits telomerase activity, increases cyclin-dependent kinase activity and induces expression of c-myc, suggesting that E6 and E7 expressions are required for increased cell proliferation and cell survival.

Helicobacter pylori

H. pylori is a gram-negative microaerophilic spiral bacterium, measuring 2–4 µm in length and 05–1 µm in width. The bacterium has 2–6 unipolar, sheathed flagella, which confer motility and allow rapid movement in viscous solutions like the mucus layer overlying gastric epithelial cells. The infection with the bacterium remains the main cause of stomach and duodenal diseases. Large epidemiological studies have provided a convincing evidence that H. pylori is associated with chronic gastritis, peptic ulcer disease, low-grade gastric mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric adenocarcinoma. The infection is usually acquired during childhood, and when left untreated shows a lifelong persistence in the host (Everhart, 2000). Various mechanisms enable the bacterium to colonize the gastric epithelium and to persist in the mucosa for a very long period: ammonia-mediated metabolism and resistance to acid by using urease; use of bacterial virulence factors; change of the host immune response, and induction of signaling pathways.

The infection rate with H. pylori varies among the populations, but remains still high (~40%) in people over 50 years of age in many Western countries. Recent data however demonstrate a lower prevalence (7.1%) in people between 16 and 20 years of age, which most likely will also result in a progressively lower incidence of severe gastroduodenal diseases as future generations age (Malfertheiner et al., 2002, 2004).

JC virus (JCV)

JCV belongs to the polyomavirus family along with the human virus BK (BKV) and the simian virus 40 (SV40).JCV is a 5.13-kb, closed, circular, supercoiled, double-stranded DNA virus that encodes six proteins: Two (alternatively spliced) viral oncoproteins, the T- and t-antigens, three viral capsid proteins—VP1, VP2, and VP3, and the agnoprotein.

JCV infects humans worldwide, and about 90% of the adult population develop antibodies against the virus by age 15 (Major et al., 1992). The initial infection is asymptomatic, but the virus establishes a lifelong persistent infection. However, in patients with impaired cell-mediated immunity, the neurotropic virus may be reactivated and cause a lytic infection of oligodendrocytes, leading to the lethal demyelinating disease progressive multifocal leukoencephalopathy (PML; Padgett et al., 1971). The oncogenic potential of JCV was discovered when the virus was injected into the brain of Syrian hamsters inducing aneuploid tumors (Walker et al., 1973; Reiss and Khalili, 2003). In a broad range of experiments with several animal models, the oncogenic potential of JCV has been further established (London et al., 1978; Ohsumi et al., 1986). Transgenic mice that express JCV T-antigen (T-Ag) can develop tumors of the pituitary gland and malignant peripheral nerve sheath tumors that resemble rare neoplasms that can occur in patients with neurofibromatosis (Gordon et al., 2000; Shollar et al., 2004). Furthermore, the virus has been found in many human brain tumors, most notably medulloblastomas (Rencic et al., 1996; Krynska et al., 1999; Del et al., 2001; White et al., 2005). JCV is oncogenic because of the expression of the highly transforming protein T-Ag.

T-Ag can transform mammalian cells, in part, by binding and inactivating two key tumor suppressor proteins that regulate cell cycle progression: p53 and pRb (Bollag et al., 1989; Dyson et al., 1990; Krynska et al., 1997). Loss of the tumor suppressor protein p53 is observed in approximately 50% of all human cancers. As a G1/S checkpoint protein, p53 regulates the cell cycle and apoptotic events (Levine, 1997; Vogelstein et al., 2000). As a consequence of the binding and inactivation of p53 by T-Ag, JCV prevents the inhibition of cell cycle or apoptosis that would be expected with the onset of CIN. pRb is another inhibitor of cell cycle progression from G1 to S phase, and acts through its ability to interact with the E2F family of transcription factors (Caracciolo et al., 2006). The inactivation of pRb family members by T-Ag binding leads to the release of E2F, and subsequently the expression of E2F–dependent genes such as c-fos and c-myc, leading to increased cellular proliferation. Thus JCV provides for itself an optimal cellular environment for its replication and packaging during a lytic polyomavirus infection, and also facilitates transformation in non-permissive cells.

JCV T-Ag also induces karyotypic changes when transfected into diploid cells (Ricciardiello et al., 2003). Several studies have reported CIN in T-Ag positive cells (Hunter and Gurney, 1994; Woods et al., 1994; Kappler et al., 1999). The mechanisms underlying the type of genetic instability induced by T-Ag are only partially understood. Trojanek et al. demonstrated that JCV T-Ag inhibits homologous recombination DNA repair, which is a part of the maintenance system insuring genomic stability. This action of JCV T-Ag is mediated through an interaction with the insulin receptor substrate 1 (IRS-1) (Trojanek et al., 2006). Additionally, the receptor for insulin-like growth factor (IGF-1R) plays a major role in mediating both physiological and pathological responses in the cell. The activation of IGF-1R, together with the interaction between JCV T-Ag and IRS-1, triggers cell proliferation, sends anti-apoptotic signals, and inhibits homologous recombination repair, all of which supports the evolution of CIN and the emergence of cancer (Reiss et al., 2006).

Cancers of the Gastrointestinal Tract

Esophageal cancer

Esophageal cancer is the ninth most common malignancy worldwide with an extremely poor prognosis and an overall 5-year survival rate of less than 10% (Pisani et al., 1993, 2002). Incidence rates of this cancer vary worldwide. The highest rates have been found in Asia, southern and eastern Africa and in these high-risk areas the annual mortality exceeds 100 deaths per 100,000 persons (Stoner and Gupta, 2001). Cancers of the esophagus can be divided into two major types: squamous cell carcinoma and adenocarcinoma. In recent years, esophageal adenocarcinoma has risen sharply in the industrialized countries (Blot and McLaughlin, 1999). This is mainly due to Barrett’s Esophagus (BE), a metaplastic change of the esophageal epithelium in the gastro-esophageal junction, which may be induced by chronic gastro-esophageal reflux (van der Woude et al., 2002). BE has been shown to be responsible for 86% of primary esophageal adenocarcinomas (Haggitt et al., 1978). Other risk factors, which mainly account for squamous cell carcinoma, include alcohol, tobacco, smoked food (content of nitrosamines and nitrites), fungal toxins, and thermal injuries (hot drinks and soups; Cheng et al., 1995; Garidou et al., 1996). In addition to these factors, recent findings suggest a role for viral pathogens, in particular of HPV, EBV and JCV in the development of this disease.

HPV and esophageal cancer

Previous studies showed that many HPV subtypes have been found in esophageal cancer specimens (Sur and Cooper, 1998; Matsha et al., 2002). Although several studies failed to detect HPV in esophageal cancer tissues (Gao et al., 2006), many others showed a possible etiological implication for the virus in this disease (Syrjanen, 2002). In particular, the frequent detection of the high-risk HPV-16 and −18 supports the causal role of HPV in esophageal cancer (Togawa et al., 1994). Indirect evidence has been provided by an in vitro experiment in which the genomes of HPV-16 and −18 without the E1 and E2 proteins were transiently transfected into esophageal cancer cells (Togawa and Rustgi, 1995). The HPV E1 and E2 proteins are involved in viral DNA replication and the regulation of the early transcription. In this study the viral genomes replicated without E1 and E2, which suggests that specific host nuclear factors expressed by esophageal squamous epithelial cells may support HPV replication. Further evidence for the involvement of HPV in esophageal carcinogenesis has resulted from animal experiments. In particular, studies in cattle described a persistent papillomatosis and carcinomas in these animals, which was experimentally reproducible with bovine papillomavirus 4 (BPV4; Campo, 1987). It has been shown that up to 96% of the cancer-bearing animals had concomitant papillomas, and the progression from benign papillomas to carcinomas could be clearly identified (Jarrett et al., 1978; Jarrett, 1987). Recently, Shen et al. (2004) were able to demonstrate the transformation toward malignancy of a human fetal esophageal epithelial cell that was immortalized by gene E6/ E7 of HPV type 18. Furthermore this infection induced telomere length shortening, altered telomerase activity and aneuploidy, as well as the amplification of several oncogenes including c-myc and ras, and different patterns of p53 expression depending on the stage of transformation. Interestingly, with this study the authors demonstrated that HPV-induced carcinogenesis is a multistage dynamic transformation process, which goes through the initial, immortal, premalignant, and malignant transformation.

In conclusion, these studies provide abundant evidence for a causative role of HPV in esophageal carcinogenesis, but several questions need to be answered and more in vivo experiments need to be carried out before HPV can be more clearly implicated in human esophageal cancers.

Epstein–Barr virus, JC virus, and esophageal cancer

Other viruses like Epstein–Barr virus (EBV) and JC virus (JCV) have also been detected in esophageal cancers. Because of the close anatomical proximity of the esophagus to the nasopharynx and the involvement of EBV into nasophayrngeal cancer, EBV was thought to be involved in the esophageal carcinogenesis. However, subsequent studies revealed either a low prevalence, or no detection of, EBV in esophageal cancer (Lam et al., 1995; Jenkins et al., 1996; Yanai et al., 2003). The explanation for the detection of EBV by PCR in some cases might be due to the detection of the virus from stromal lymphocytes. To date, there is no sufficient evidence that EBV is important in the pathogenesis of this disease.

Recently, Del et al. (2005) detected the neurotropic polyomavirus JCV and its potent transforming protein T-antigen in both esophageal adenocarcinomas and squamous cell carcinomas, and suggested a possible role of JCV in the development of both diseases. This is thus far the only report of JCV in the esophageal cancer, and further investigation and confirmation of these findings are required.

Gastric cancer

Despite its decreasing incidence, gastric cancer remains the fifth most common cancer, the fourth leading cause of cancer-related death, and is responsible for the death of more than 100,000 people each year in Europe (Ferlay et al., 2007). Histologically, gastric adenocarcinoma is usually classified according to the Lauren’s classification into well differentiated/ intestinal and diffuse/signet ring cell types (Lauren, 1965). The intestinal type gastric cancer is associated with atrophy, intestinal metaplasia, and corpus-dominant gastritis. On the other hand, the diffuse type typically occurs with pangastritis without atrophy, or arises even within non-inflamed apparently normal gastric mucosa (Cuello et al., 1979). Depending on its location, gastric cancer is suggested to be the consequence of either H. pylori infection or H. pylori independent etiologic factors. Most gastric cancers are located in the distal part of the stomach, and evidence for a causal relationship with H. pylori infection is strong, however there may also be a relationship with proximal gastric cancer.

H. pylori and gastric cancer

H. pylori induces chronic gastric inflammation in all infected individuals that eventually, depending on the individual’s susceptibility, may progress to atrophy, metaplasia, dysplasia, and finally to gastric cancer (Peek and Blaser, 2002).

Because of the strong association between H. pylori-infection and gastric cancer, the WHO has classified H. pylori as a class 1 carcinogen since 1994 (IARC Monographs on the Carcinogenic Risks to Humans, 1994). A malignant complication of H. pylori infection other than gastric cancer is mucosal-associated-lymphoid-type (MALT) lymphoma (Hessey et al., 1990; Marwick, 1990; Stolte, 1992; Suerbaum and Michetti, 2002; Vogiatzi et al., 2007). Most infected individuals fortunately remain asymptomatic and the bacterial infection does not lead to gastric cancer, but H. pylori-infected patients may have a 2- to 20-fold increase in risk of developing gastric cancer compared to uninfected individuals (Huang et al., 1998; Ekstrom et al., 2001). The fact that H. pylori infection leads to gastric cancer in only 0.1–0.5% of the infected subjects underscores the importance of others factors in the development of the cascade leading to cancer. H. pylori-induced gastric carcinogenesis depends on at least three different key factors: H. pylori and its different virulence determinants, a genetically susceptible host, and permissive environmental factors.

Virulence determinants of H. pylori

H. pylori strains are extremely diverse and isolates within an individual can change over time, due to DNA rearrangements, recombination events and endogenous mutations (Salama et al., 2000; Cooke et al., 2005). This diversity makes it difficult to identify bacterial virulence factors responsible for the induction of gastric cancer. Among bacterial factors identified, the cag pathogenicity island, the vacuolating cytotoxin (VacA), and the outer-membrane protein BabA have been identified to be the most critical ones in the association with malignancy (Peek and Crabtree, 2006). These gene products seem to interact with each other and their expression represents an increased risk for the development of gastric cancer.

The cag pathogenicity island (PAI) type IV secretion system (TFSS)

H. pylori cagA+ strains show an association with higher grades of inflammation and a significantly increased risk of developing gastric cancer (Parsonnet et al., 1997; Enroth et al., 2000). CagA+ strains contain a 40-kb region of DNA known as the cag-PAI. The cag-PAI plays an important part in H. pylori pathogenesis, and is not present in all strains. The prevalence of cag-PAI+ strains varies widely between different geographical regions, with the highest prevalence in Asia and Africa (Suerbaum and Josenhans, 2007). The cag-PAI encodes a type IV secretion system that translocates the cagA and other bacterial products (peptidoglycans) into the gastric epithelial cells (Backert et al., 2000; Odenbreit et al., 2000). A recent study by Kwok et al. demonstrated that the H. pylori cagL protein, a specialized adhesion molecule, binds to and activates the integrin α5β1 receptor on gastric epithelial cells. This interaction triggers cagA delivery into target cells as well as activation of focal adhesion kinase and Src (Kwok et al., 2007). Once injected into the host cell, cagA becomes tyrosine phosphorylated at its five amino-acid EPIYA repeat region by host Src kinase (Selbach et al., 2002; Stein et al., 2002). After phosphorylation, cagA binds specifically to, and activates, the oncogenic tyrosine phosphatase Shp-2, leading to the activation of the mitogenic Ras-mitogen-activated protein kinase (MAPK) pathway, involving the Ras-dependent kinases ERK1 and ERK2 (Higashi et al., 2002; Tsutsumi et al., 2003; Hatakeyama, 2004). The activation of this pathway leads to dephosphorylation of host-cell proteins (Asahi et al., 2000; Odenbreit et al., 2000; Stein et al., 2000) and morphological changes in the epithelial cells (Segal et al., 1999).

Previous data from Brandt et al. (2005) indicated that cagA also activates the Ras-Erk pathway in an Shp-2-independent manner. This activation leads to an increased interleukin (IL)-8 release and NF-κB activation. Interleukin (IL)-8 release leads to the recruitment of neutrophils into the gastric mucosa and NF-κB activation is essential in inflammation associated cancer (Brandt et al., 2005).

In addition, independent of its phosphorylation status, cagA disrupts the apical junctional complex of gastric mucosal cells that maintains the epithelial barrier function and regulates the cell–cell contact (Amieva et al., 2003). Interestingly the cagA-Shp-2 complex cannot be detected in the gastric mucosa of patients with intestinal metaplasia or gastric cancer, whereas it is found in chronic atrophic gastritis samples (Yamazaki et al., 2003). These findings suggest that cagA expression may represent an early event in H. pylori-induced carcinogenesis.

The VacA toxin

VacA is an 88 kDa toxin, which is encoded by all H. pylori strains, but there is a considerable genetic diversity among the vac alleles (Atherton et al., 1995, 1997; Cover and Blanke, 2005). Regions of major diversity are localized to the VacA secretion signal sequence (allele types s1 or s2) and the mid-region (m1 and m2). The most extensively studied have been the s1 and m1 vac allele that is strongly correlated with the presence of the cag PAI (Covacci et al., 1993; Tummuru et al., 1993), and is associated with enhanced epithelial cell injury (Ghiara et al., 1995; Atherton et al., 1997) and distal gastric cancer (Van Doorn et al., 1999), compared with VacA m2 strains. As a secreted protein, VacA has the ability to induce the formation of cytoplasmic vacuoles and stimulates epithelial cell apoptosis in several gastric cell lines (Leunk et al., 1988; Rudi et al., 1998; Peek et al., 1999; Galmiche et al., 2000; Kuck et al., 2001). Previous studies suggested that VacA acts as a multifunctional protein that modulates epithelial cell and immune-cell function (Cover and Blanke, 2005). Furthermore, VacA efficiently blocks proliferation of T cells by inducing cell cycle arrest in the G1/S phase, which could explain the persistence of H. pylori infections (Gebert et al., 2003).

The outer-membrane protein BabA

BabA, encoded by the strain-specific gene babA2, is a 78-kDa outer-membrane protein. Depending on the geographic region, 40–95% of H. pylori strains express BabA (Prinz et al., 2003). BabA binds the Lewis b blood group antigen and related ABO antigens on gastric epithelial cells which enables maximal adherence of the bacterium to gastric epithelium (Ilver et al., 1998). Patients infected with BabA positive strains have a higher density of bacterial colonization in the gastric mucosa and higher levels of the proinflammatory cytokine IL-8, which leads to enhanced mucosal inflammation (Rad et al., 2002). H. pylori strains expressing BabA are associated with an increased incidence of gastric adenocarcinoma. More importantly, the presence of BabA is correlated with the presence of cagA and the s1 allele of VacA. It is known that strains possessing all three genes are associated with the highest risk of gastric cancer (Gerhard et al., 1999).

Additional aspects of H. pylori-induced gastric carcinogenesis

The cagPAI+ H. pylori strains clearly have an important role in the induction of gastric cancer. However, the very high frequency (nearly 100%) of cagPAI+ H. pylori strains in countries like Korea and Japan indicates the contribution of additional virulence factors for the cancer development in these populations (Covacci et al., 1993; Shimoyama et al., 1997). Previous studies from Suganuma et al. (2005, 2006) identified tumor necrosis factor-α-inducing protein (Tipα) released from H. pylori as a carcinogenic factor (Kuzuhara et al., 2007). They demonstrated that Tipα induced upregulation of TNF-α in gastric cells, mediated through NF-κB activation, indicating that Tipα acts like an inducer of NF-κB activation. It is well accepted that NF-κB is essential for promoting inflammation-associated cancer (Brandt et al., 2005) and the authors proposed that the activation of NF-κB via Tipα may play an important role in stomach carcinogenesis, which may provide a new model for gastric cancer development.

Recent work in the ongoing research into Helicobacter-induced carcinogenesis has focused on the role of stem cells in cancer. Houghton et al. (2004) showed that chronic infection of C57BL/6 mice with Helicobacter felis, a known carcinogen in animal models, led to the repopulation of the stomach with bone marrow-derived cells (BMDCs). In this study the authors indicated that transdifferentation of BMDCs to gastric epithelial cells would lead to intraepithelial cancer through metaplasia and dysplasia. This work showed that BMDCs might fail to differentiate properly and progress to cancer only in the Helicobacter-infected environment. For a more detailed discussion of this topic, we refer to two recent reviews (Starzynska and Malfertheiner, 2006; Correa and Houghton, 2007).

The role of host genetic factors in gastric cancer

Host genetic factors have a significant impact in the clinical outcome and anatomical distribution of H. pylori infection. Several functional polymorphisms in the host have been previously described, involving interleukin (IL)-1, tumor necrosis factor alpha (TNF-α),and IL-10. These polymorphisms increase the risk of distal gastric cancer.

H. pylori-infected individuals with the IL-1B-31*C or —511*T and IL-1RN2*/*2 are at increased risk of developing hypochlorhydria and gastric atrophy in response to H. pylori infection (El-Omar et al., 2000). This is mainly due to II-Iβ, which is the earliest and most important proinflammatory cytokine in the context of H. pylori infection, and it is also the most powerful known acid inhibitor. Patients carrying these polymorphisms have a two- to three fold increased risk of developing gastric cancer compared with subjects who have the less proinflammatory genotypes (El-Omar et al., 2003).

TNF-α is another powerful proinflammatory cytokine that is produced in the gastric mucosa in response to H. pylori infection (Crabtree et al., 1991). Compared to IL-1β, TNF-α has also an acid inhibitory effect but at a much weaker level. Polymorphisms in this gene are correlated to an increased risk of gastric cancer (Machado et al., 2003). The polymorphism in the IL-10 gene, in association with down-regulation of the proinflammatory cytokine IL-10, results in elevated levels of IL-1β, TNF-α, and interferon-γ. Previous studies focusing on the combination of disease-related polymorphisms led to estimates of a 27-fold increased risk of developing gastric cancer in H. pylori-infected individuals compared to those who were not infected (El-Omar et al., 2003). In addition, ongoing investigations into other genetic polymorphisms have revealed a broad range of new loci associated with an increased risk of gastric cancer, which are presented in Table 1.

TABLE 1
Human genetic polymorphisms, associated with an increased of gastric cancer development

Epstein–Barr virus (EBV), JCV, and gastric cancer

About 6–16% of gastric adenocarcinoma cases worldwide are associated with EBV (Takada, 2000). EBV-positive gastric cancers are more likely to be in male patients (Tokunaga et al., 1993), in the antrum of the stomach (Galetsky et al., 1997) and frequently associated with poorly differentiated tumors (Adachi et al., 1996; Gulley et al., 1996). The virus is found in almost all tumor cells and the viral DNA shows monoclonality in EBV-positive cancers (Fukayama et al., 2001). It has also been demonstrated that EBV-positive gastric carcinomas are associated with the upregulation of the anti-apoptotic protein bcl-2, and down-regulation of E-cadherin which is an integral component of the cell–cell adhesion (Shiozaki et al., 1996; Kume et al., 1999; Wu et al., 2000). Those findings implicate a delayed apoptosis and abnormal cellular differentiation in EBV-positive gastric carcinomas. This suggests that the virus might play a causative role in the development of a subset of gastric cancers. This conclusion is confounded by the lack of expression of the EBV oncogenes in EBV-positive gastric cancers. Of the different types of EBV EBNAs, only EBNA-1 is expressed, and of the three LMPs, only LMP-2A is expressed in some cases (Takada, 2000; Luo et al., 2005).

Kim et al. investigated whether viral microRNAs (miRNAs) were expressed in EBV-associated gastric carcinomas. miRNAs have been proposed to play an important role in the viral cell cycle (Kim et al., 2007). miRNAs may support cell proliferation or suppress apoptosis under certain conditions and might also have a function as tumor suppressors or oncogenes (Bartel, 2004; Cimmino et al., 2005; Esquela-Kerscher and Slack, 2006). In a previous study, Pfeffer et al. (2004) were able to clone five EBV miRNAs, clustered in two genomic regions. One cluster of miRNAs was found in the BHRF gene encoding three miRNAs (miR-BHRF1-1, miR-BHRF1–2, miR-BHRF1–3). The other cluster is located within the BART gene (miR-BART1 and mi-BART2). Kim et al. were able to demonstrate the expression of BART miRNAs in EBV-infected gastric carcinoma cell lines, in an animal model, as well as in human gastric carcinoma tissues. Although they failed to detect the expression of BHRF1 miRNAs, the expression of BART miRNAs might provide new possible insights into EBV-induced epithelial cell transformation.

A recent study by Shin et al. (2006) demonstrated the expression of the oncogenic JCV protein T-Ag in a subset of gastric cancer. These findings were confirmed by Murai et al. (2007) showing a high JCV load in gastric cancer. However, in this study the viral oncoprotein T-Ag was reportedly expressed in only 1 of 23 cancer specimens. Taken together, these studies indicate a possible role for viruses as causative infectious agents for cancers in the proximal stomach.

H. pylori and gastric MALT lymphoma

MALT lymphomas are a unique and distinct form of marginal zone B-cell-non-Hodgkin’s lymphoma. MALT lymphomas account for approximately 7–8%of all non-Hodgkin’s lymphoma and the gastrointestinal tract is the most common site of the disease (The Non-Hodgkin’s Lymphoma Classification Project, 1997). The strongest evidence linking H. pylori to this disease is that 62% of patients with low-grade gastric MALT lymphoma have complete remission within 12 months of H. pylori eradication (Fischbach et al., 2000, 2004). Furthermore, H. pylori is present in the gastric mucosa of 70–90% of patients with gastric MALT lymphoma (Wotherspoon et al., 1991). MALT lymphoma is a good example of the close relationship between chronic inflammation and lymphomagenesis. The hypothesis that MALT lymphoma develops as a consequence of chronic inflammation is supported by the association between low-grade gastric MALT-lymphoma and H. pylori induced gastritis (Eidt et al., 1994). Furthermore, several autoimmune diseases (i.e., Sjogren syndrome, Hashimoto’s thyroiditis) that are associated with a chronic inflammation show an increased risk of developing MALT lymphomas (Royer et al., 1997; Derringer et al., 2000). In vitro experiments indicate the presence of antigen-driven clonal expansion, showing that B-cells from low-grade MALT lymphomas proliferate in co-culture with H. pylori. This stimulation is driven by tumor-infiltrating T-cells activated by H. pylori (Hussell et al., 1993, 1996).

H. pylori has been mainly linked to low-grade MALT lymphomas and even though the exact mechanisms underlying the transition of low-grade to aggressive lymphoma remain unclear, several studies have found genetic alterations associated with this histological transformation, including p53 allelic loss and mutation, hypermethylation of p15 and p16, and chromosomal translocations (Du et al., 1995; Martinez-Delgado et al., 1998; Min et al., 2006). The t(11:18)(q21;q21) chromosomal translocation has been described which results in the fusion of the apoptosis inhibitor-2 gene (API2) on chromosome 11 with the MALT1 gene on chromosome 18 (Zucca et al., 2000; Farinha and Gascoyne, 2005). As a result, the fusion protein API2-MALT1 activates the NF-κB pathway, which plays a central role in the regulation of diverse biological processes, and may promote the survival of B-cell clones via anti-apoptotic effects. The genetic abnormalities, which facilitate the transition of low-grade MALT lymphoma to an aggressive lymphoma have been linked to the presence of H. pylori CagA-positive strains. It has been therefore hypothesized that the release of genotoxic free radicals in the H. pylori-infected environment might play a role in the development of oncogenic genetic alterations (Peng et al., 1998; Ye et al., 2003).

Colorectal cancer

Colorectal cancer (CRC) is the fourth commonest cancer in Western Countries (Jemal et al., 2005) affecting over one million of new cases globally every year with almost 500,000 deaths (Vainio and Miller, 2003). The molecular pathogenesis of this cancer is incompletely understood, but over the last 20 years it has become clear that CRC evolves through multiple pathways (Jass, 2006, 2007). Three molecular features have been identified in CRC: microsatellite instability (MSI), CIN and the CpG island methylator phenotype (CIMP; Jones, 1996; Jones and Laird, 1999; Goel et al., 2003). In about 15% of all colon cancers, MSI is the mutational signature, and the tumors occur as a consequence of the inactivation of the DNA mismatch repair system (MMR). This is either due to germline mutations in an MMR gene, which occurs in Lynch syndrome (Aaltonen et al., 1993; Ionov et al., 1993), or more often, through hypermethylation of the hMLH1 gene promoter, which occurs as an acquired event in sporadic cancers (Kane et al., 1997). CIN is characterized by aneuploidy and frequent loss of heterozygosity (LOH), which facilitates the sequential inactivation of the adenomatous polyposis coli (APC) and p53genes, respectively. CIN is present in more than 50% of CRC (Lengauer et al., 1997). Methylation of cytosine residues at CpG-rich sequences (CpG islands), present in the promoter regions of many tumor suppressor genes, is a feature of about 35–40% of colorectal CRC (Baylin et al., 1998; Goel et al., 2003). The causes and the molecular mechanisms underlying CIN and epigenetic alterations, which occur in approximately 80–85% of all CRCs, are still a matter of controversy. An infection with an oncogenic virus might provide some reasonable explanations for many of these findings.

JCV and colorectal cancer

It has been previously reported that JCV DNA sequences are frequently present in the upper and lower gastrointestinal tract and in CRCs, with >10-fold higher viral loads in cancers than in the adjacent normal colon (Laghi et al., 1999; Ricciardiello et al., 2000; Ricciardiello et al., 2001). In this context, Khalili et al. demonstrated that T-Ag is involved in the Wnt signaling pathway. The authors showed that T-Ag forms a complex with b-catenin, a central component of the Wnt pathway, and this is associated with the translocation of β-catenin to the nucleus, with the consequent transcriptional activation of c-myc and cyclin D1 (Enam et al., 2002). The transcription factor c-myc is commonly deregulated in tumorigenesis, and is overexpressed in nearly 70% of CRCs (Erisman et al., 1985). c-myc was one of the first oncogenes recognized to modulate a broad range of biological activities including cell proliferation, growth and transformation. It has been shown that upregulation of c-myc increases apoptosis, genomic instability and angiogenesis (Ponzielli et al., 2005).

Furthermore, Ricciardiello et al. (2003) demonstrated that JCV T-Ag directly induces CIN in human colonic cells and that interaction of JCV T-Ag with β-catenin and p53 causes morphological changes and loss of cell–cell contact. In addition, Goel et al. (2006) demonstrated a significant association between T-Ag expression and CIN in human CRCs. Another important point of this study was that it revealed a strong association between T-Ag expression and the methylator phenotype in CRC. Aberrant methylation in connection to JCV may play a role in early stages of carcinogenesis. Taken together, these results indicate that JCV may be involved in two of the principal molecular mechanisms of carcinogenesis in the colon and rectum: abnormal DNA methylation and CIN.

Anal cancer

Anal cancer is a rare tumor that accounts for 1.5% of cases of the gastrointestinal tract cancers in the USA. In 2007, 4,650 men and women were estimated to develop anal cancer with estimated deaths in 690 individuals (Jemal et al., 2007). Over the last two decades there has been a rising incidence of anal cancer and studies have identified several risk factors for anal cancer: persistent infection with high-risk genotype human papillomaviruses (HPV), cervical dysplasia or cancer, HIV seropositivity, low CD4 count, cigarette smoking, receptive anal intercourse, and immunosuppression after organ transplant (Daling et al., 2004).

HPV, human deficiency virus (HIV), and anal cancer

Several studies analyzing European, Asian and United States populations detected HPV DNA in 70–100% of anal cancer biopsy specimens (Williams et al., 1996; Frisch et al., 1999; Daling et al., 2004). The HPV genotypes detected were mainly the high-risk HPVs 16 and −18 (Frisch et al., 1997; Carter et al., 2001; Munger and Howley, 2002), which implicate this virus as an etiologic agent for the development of squamous cell carcinoma of the anorectal region. The high-risk HPVs 16 and −18 encode the transforming oncoproteins E6 and E7, which inactivate the tumor suppressor functions of p53 and Rb. There is an association between the expression of E6 and an increased risk of high-grade anal neoplasia (Da Costa et al., 2002).

There is a well-documented association between HIV infection, HPV, and cancer. The risk for the development of anal cancer is 37-fold higher in HIV-positive men compared to the general population (Frisch et al., 1997). The risk of anal cancers in HIV-positive women is nearly sevenfold higher over the general population. Furthermore anal cancer occurs almost two decades earlier in both HIV-positive women and men (Frisch et al., 2000). These findings support the hypothesis that HIV infection interacts with HPV, and has a major impact on the etiology of anal cancer. There are several possible mechanisms that may provide a reasonable explanation for these findings: the impact of the immunological changes in the HIV-infected population, direct interactions between HIV and HPV, and direct effects of HIV triggering anal carcinogenesis.

The immune response to HPV plays a critical role in controlling the HPV infection. In general, women become HPV negative after age 30, and only a small proportion of infected healthy individuals develop lesions. Even a smaller percentage acquire high grade dysplasia or cancer (Schiffman, 1992). However, HIV-positive patients have a substantially higher risk of anal cancer and the risk is inversely proportional to the CD4 count (Critchlow et al., 1995; Palefsky et al., 1998).

Several studies have indicated that the local immune response to HPV is altered in HIV-positive individuals (Sobhani et al., 2004). Dendritic Langerhans cells seem to play an important role in the local immune response to HPV infection. Levi et al. (2005) reported that HIV viremia is associated with a decreased number of dendritic cells, suggesting an impaired local immune response to a HPV infection.

Other mechanistic factors contributing to this may be the down-regulation of regulatory cytokines. Kobayashi et al. (2004) demonstrated the down-regulation of regulatory cytokines and a decrease in immune cell densities in cervical intraepithelial neoplasia of HIV-positive women, indicating that both pro- and anti-inflammatory responses are suppressed in HIV-positive women.

Previous in vitro studies have suggested a direct interaction between HIV and HPV at a molecular level. The HIV-1 tat protein transactivates the HPV long control region, and in vitro data suggest that HIV can modulate HPV gene expression (Vernon et al., 1993). However the HIV-1 tat protein has never been found in HPV-infected epithelium in vivo and so it remains speculative if the two viruses interact directly and influence anal carcinogenesis.

Another interesting point of anal carcinogenesis is found in the genetic and epigenetic changes of HIV-positive individuals. Allelic loss is a key feature of CIN, and certain loci are targets in many gastrointestinal cancers. Gervaz et al. (2004) demonstrated that CIN, and specifically allelic losses at 18q (DCC and the SMAD genes), 17p (p53) and 5q (APC) are relatively uncommon in the anal cancers of HIV-positive patients, whereas in HIV-negative patients the allelic losses at these loci were significantly more frequent. Therefore these authors suggested that CIN is part of the mutational signature of anal cancer in HIV-negative patients, but that and that the immunosuppression in the HIV population triggers an alternative pathway of carcinogenesis.

It is possible that MSI plays a role in the putative alternative pathway. In cervical and lung cancers, MSI has been reported to occur more frequently in HIV-positive patients than in the HIV-negative population (Wistuba et al., 1998, 1999). In those two studies, the frequency of microsatellite alterations in the HIV-positive group was six fold greater than in the negative group, suggesting that MSI may be important in HIV-associated tumors. Thus, there is a need for additional investigation to determine the interactions between HIV and HPV in anal cancer, and to define their exact role in anal carcinogenesis.

Conclusion

Research over the last 20 years has shown that viruses and bacterial pathogens are either definitive causative agents or play at least a major role in the etiology of many gastrointestinal cancers (Table 2). Improved abilities to detect and analyze microbial gene products will make it ever more likely to implicate novel microbial pathogens in human cancers in the future. In particular, the era of AIDS and the increased number of organ transplantations will highlight the role of immunosuppression in carcinogenesis, leading to an increasing appreciation of virus related cancers, much in the way Kaposi sarcoma has been elucidated. On the other hand, life style changes and the introduction of new, powerful biological therapeutic agents may relate new viruses and bacteria to human cancers.

TABLE 2
Viruses and microbes in gastrointestinal cancers

The increasing number of studies indicating that viruses might represent a key factor in cancer development and progression open new perspectives on how to tackle each disease and, more importantly, to prevent or treat them. However, the immense challenge for the future research on pathogens and their role in gastrointestinal cancers will be to translate all the in vitro findings into in vivo results. The in vivo proof is critical and will allow us to test new potential drugs or to develop effective vaccines against viral and bacterial pathogens. However, while this has been achieved with the model of H. pylori and gastric cancer, it still represents a big challenge for viral-associated gastrointestinal cancers, in particular for the lack of viable animal models. The example of cervical cancer and the effective vaccination against HPV has proven that the incidence of a life threatening cancer can be reduced by tackling a viral pathogen (Koutsky et al., 2002). The fact that H. pylori eradication has the potential to reduce the risk of gastric cancer development, is an indication of how basic research can be translated into medical practice, and this has major implications for the future directions of public health (Roderick et al., 2003; Ford et al., 2005; Malfertheiner et al., 2005; Fry et al., 2007). Thus, the future challenge will be to clearly demonstrate a causative role of viral pathogens in gastrointestinal cancers and eventually to design appropriate vaccines and antiviral agents.

Acknowledgments

This study was supported from the National Cancer Institute of the NIH (R01 CA72851 and R01 CA98572 to CRB), and funds from the Baylor Research Institute.

Contract grant sponsor: National Cancer Institute of the NIH

Contract grant numbers: R01 CA72851, R01 CA98572

Contract grant sponsor: Baylor Research Institute.

Literature Cited

  • Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J, Hamilton SR. Clues to the pathogenesis of familial colorectal cancer. Science. 1993;260:812–816. [PubMed]
  • Adachi Y, Yoh R, Konishi J, Iso Y, Matsumata T, Kasai T, Hashimoto H. Epstein-Barr virus-associated gastric carcinoma. J Clin Gastroenterol. 1996;23:207–210. [PubMed]
  • Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 2003;300:1430–1434. [PMC free article] [PubMed]
  • Asahi M, Azuma T, Ito S, Ito Y, Suto H, Nagai Y, Tsubokawa M, Tohyama Y, Maeda S, Omata M, Suzuki T, Sasakawa C. Helicobacter pylori CagA protein can be tyrosine phosphorylated in gastric epithelial cells. J Exp Med. 2000;191:593–602. [PMC free article] [PubMed]
  • Atherton JC, Cao P, Peek RM, Jr, Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem. 1995;270:17771–17777. [PubMed]
  • Atherton JC, Peek RM, Jr, Tham KT, Cover TL, Blaser MJ. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology. 1997;112:92–99. [PubMed]
  • Backert S, Ziska E, Brinkmann V, Zimny-Arndt U, Fauconnier A, Jungblut PR, Naumann M, Meyer TF. Translocation of the Helicobacter pylori CagA protein in gastric epithelial cells by a type IV secretion apparatus. Cell Microbiol. 2000;2:155–164. [PubMed]
  • Bartel DP. MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 2004;116:281–297. [PubMed]
  • Baylin SB, Herman JG, Graff JR, Vertino PM, Issa JP. Alterations in DNA methylation: A fundamental aspect of neoplasia. Adv Cancer Res. 1998;72:141–196. [PubMed]
  • Blot WJ, McLaughlin JK. The changing epidemiology of esophageal cancer. Semin Oncol. 1999;26:2–8. [PubMed]
  • Bollag B, Chuke WF, Frisque RJ. Hybrid genomes of the polyomaviruses JC virus, BK virus, and simian virus 40: Identification of sequences important for efficient transformation. J Virol. 1989;63:863–872. [PMC free article] [PubMed]
  • Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV. The causal relation between human papillomavirus and cervical cancer. J Clin Pathol. 2002;55:244–265. [PMC free article] [PubMed]
  • Brandt S, Kwok T, Hartig R, Konig W, Backert S. NF-kappaB activation and potentiation of proinflammatory responses by the Helicobacter pylori CagA protein. Proc Natl Acad Sci USA. 2005;102:9300–9305. [PubMed]
  • Burkitt D. A sarcoma involving the jaws in African children. Br J Surg. 1958;46:218–223. [PubMed]
  • Campo MS. Papillomas and cancer in cattle. Cancer Surv. 1987;6:39–54. [PubMed]
  • Caracciolo V, Reiss K, Khalili K, De FG, Giordano A. Role of the interaction between large T antigen and Rb family members in the oncogenicity of JC virus. Oncogene. 2006;25:5294–5301. [PubMed]
  • Carter JJ, Madeleine MM, Shera K, Schwartz SM, Cushing-Haugen KL, Wipf GC, Porter P, Daling JR, McDougall JK, Galloway DA. Human papillomavirus 16 and 18 L1 serology compared across anogenital cancer sites. Cancer Res. 2001;61:1934–1940. [PubMed]
  • Cheng KK, Duffy SW, Day NE, Lam TH. Oesophageal cancer in never-smokers and never-drinkers. Int J Cancer. 1995;60:820–822. [PubMed]
  • Cimmino A, Calin GA, Fabbri M, Iorio MV, Ferracin M, Shimizu M, Wojcik SE, Aqeilan RI, Zupo S, Dono M, Rassenti L, Alder H, Volinia S, Liu CG, Kipps TJ, Negrini M, Croce CM. miR-15 and miR-16 induce apoptosis by targeting B CL2. Proc Natl Acad Sci USA. 2005;102:13944–13949. [PubMed]
  • Cogliano V, Baan R, Straif K, Grosse Y, Secretan B, El GF. Carcinogenicity of human papillomaviruses. Lancet Oncol. 2005;6:204. [PubMed]
  • Cooke CL, Huff JL, Solnick JV. The role of genome diversity and immune evasion in persistent infection with Helicobacter pylori. FEMS Immunol Med Microbiol. 2005;45:11–23. [PubMed]
  • Correa P, Houghton J. Carcinogenesis of Helicobacter pylori. Gastroenterology. 2007;133:659–672. [PubMed]
  • Covacci A, Censini S, Bugnoli M, Petracca R, Burroni D, Macchia G, Massone A, Papini E, Xiang Z, Figura N. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci USA. 1993;90:5791–5795. [PubMed]
  • Cover TL, Blanke SR. Helicobacter pylori VacA, a paradigm for toxin multifunctionality. Nat Rev Microbiol. 2005;3:320–332. [PubMed]
  • Crabtree JE, Shallcross TM, Heatley RV, Wyatt JI. Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis. Gut. 1991;32:1473–1477. [PMC free article] [PubMed]
  • Critchlow CW, Surawicz CM, Holmes KK, Kuypers J, Daling JR, Hawes SE, Goldbaum GM, Sayer J, Hurt C, Dunphy C. Prospective study of high grade anal squamous intraepithelial neoplasia in a cohort of homosexual men: Influence of HIV infection, immunosuppression and human papillomavirus infection. AIDS. 1995;9:1255–1262. [PubMed]
  • Cuello C, Lopez J, Correa P, Murray J, Zarama G, Gordillo G. Histopathology of gastric dysplasias: Correlations with gastric juice chemistry. Am J Surg Pathol. 1979;3:491–500. [PubMed]
  • Da Costa MM, Hogeboom CJ, Holly EA, Palefsky JM. Increased risk of high-grade anal neoplasia associated with a human papillomavirus type 16 E6 sequence variant. J Infect Dis. 2002;185:1229–1237. [PubMed]
  • Daling JR, Madeleine MM, Johnson LG, Schwartz SM, Shera KA, Wurscher MA, Carter JJ, Porter PL, Galloway DA, McDougall JK. Human papillomavirus, smoking, and sexual practices in the etiology of anal cancer. Cancer. 2004;101:270–280. [PubMed]
  • DeFilippis RA, Goodwin EC, Wu L, DiMaio D. Endogenous human papillomavirus E6 and E7 proteins differentially regulate proliferation, senescence, and apoptosis in HeLa cervical carcinoma cells. J Virol. 2003;77:1551–1563. [PMC free article] [PubMed]
  • Del VL, Baehring J, Lorenzana C, Giordano A, Khalili K, Croul S. Expression of a human polyomavirus oncoprotein and tumour suppressor proteins in medulloblastomas. Mol Pathol. 2001;54:331–337. [PMC free article] [PubMed]
  • Del VL, White MK, Enam S, Oviedo SP, Bromer MQ, Thomas RM, Parkman HP, Khalili K. Detection of JC virus DNA sequences and expression of viral T antigen and agnoprotein in esophageal carcinoma. Cancer. 2005;103:516–527. [PubMed]
  • Derringer GA, Thompson LD, Frommelt RA, Bijwaard KE, Heffess CS, Abbondanzo SL. Malignant lymphoma of the thyroid gland: A clinicopathologic study of 108 cases. Am J Surg Pathol. 2000;24:623–639. [PubMed]
  • Du M, Peng H, Singh N, Isaacson PG, Pan L. The accumulation of p53 abnormalities is associated with progression of mucosa-associated lymphoid tissue lymphoma. Blood. 1995;86:4587–4593. [PubMed]
  • Dyson N, Bernards R, Friend SH, Gooding LR, Hassell JA, Major EO, Pipas JM, Vandyke T, Harlow E. Large T antigens of many polyomaviruses are able to form complexes with the retinoblastoma protein. J Virol. 1990;64:1353–1356. [PMC free article] [PubMed]
  • Eidt S, Stolte M, Fischer R. Helicobacter pylori gastritis and primary gastric non-Hodgkin’s lymphomas. J Clin Pathol. 1994;47:436–439. [PMC free article] [PubMed]
  • Ekstrom AM, Held M, Hansson LE, Engstrand L, Nyren O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection. Gastroenterology. 2001;121:784–791. [PubMed]
  • El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, Herrera J, Lissowska J, Yuan CC, Rothman N, Lanyon G, Martin M, Fraumeni JF, Jr, Rabkin CS. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000;404:398–402. [PubMed]
  • El-Omar EM, Rabkin CS, Gammon MD, Vaughan TL, Risch HA, Schoenberg JB, Stanford JL, Mayne ST, Goedert J, Blot WJ, Fraumeni JF, Jr, Chow WH. Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms. Gastroenterology. 2003;124:1193–1201. [PubMed]
  • Enam S, Del VL, Lara C, Gan DD, Ortiz-Hidalgo C, Palazzo JP, Khalili K. Association of human polyomavirus JCV with colon cancer: Evidence for interaction of viral T-antigen and beta-catenin. Cancer Res. 2002;62:7093–7101. [PubMed]
  • Enroth H, Kraaz W, Engstrand L, Nyren O, Rohan T. Helicobacter pylori strain types and risk of gastric cancer: A case-control study. Cancer Epidemiol Biomarkers Prev. 2000;9:981–985. [PubMed]
  • Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet. 1964;1:702–703. [PubMed]
  • Erisman MD, Rothberg PG, Diehl RE, Morse CC, Spandorfer JM, Astrin SM. Deregulation of c-myc gene expression in human colon carcinoma is not accompanied by amplification or rearrangement of the gene. Mol Cell Biol. 1985;5:1969–1976. [PMC free article] [PubMed]
  • Esquela-Kerscher A, Slack FJ. Oncomirs—MicroRNAs with a role in cancer. Nat Rev Cancer. 2006;6:259–269. [PubMed]
  • Everhart JE. Recent developments in the epidemiology of Helicobacter pylori. Gastroenterol Clin North Am. 2000;29:559–578. [PubMed]
  • Farinha P, Gascoyne RD. Molecular pathogenesis of mucosa-associated lymphoid tissue lymphoma. J Clin Oncol. 2005;23:6370–6378. [PubMed]
  • Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol. 2007;18:581–592. [PubMed]
  • Fischbach W, Dragosics B, Kolve-Goebeler ME, Ohmann C, Greiner A, Yang Q, Bohm S, Verreet P, Horstmann O, Busch M, Duhmke E, Muller-Hermelink HK, Wilms K, Allinger S, Bauer P, Bauer S, Bender A, Brandstatter G, Chott A, Dittrich C, Erhart K, Eysselt D, Ellersdorfer H, Ferlitsch A, Fridrik MA, Gartner A, Hausmaninger M, Hinterberger W, Hugel K, Ilsinger P, Jonaus K, Judmaier G, Karner J, Kerstan E, Knoflach P, Lenz K, Kandutsch A, Lobmeyer M, Michlmeier H, Mach H, Marosi C, Ohlinger W, Oprean H, Pointer H, Pont J, Salabon H, Samec HJ, Ulsperger A, Wimmer A, Wewalka F. Primary gastric B-cell lymphoma: Results of a prospective multicenter study. The German-Austrian Gastrointestinal Lymphoma Study Group. Gastroenterology. 2000;119:1191–1202. [PubMed]
  • Fischbach W, Goebeler-Kolve ME, Dragosics B, Greiner A, Stolte M. Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication therapy: Experience from a large prospective series. Gut. 2004;53:34–37. [PMC free article] [PubMed]
  • Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P. A community screening program for Helicobacter pylori saves money: 10-year follow-up of a randomized controlled trial. Gastroenterology. 2005;129:1910–1917. [PubMed]
  • Fries KL, Miller WE, Raab-Traub N. Epstein-Barr virus latent membrane protein 1 blocks p53-mediated apoptosis through the induction of the A20 gene. J Virol. 1996;70:8653–8659. [PMC free article] [PubMed]
  • Frisch M, Glimelius B, van den Brule AJ, Wohlfahrt J, Meijer CJ, Walboomers JM, Goldman S, Svensson C, Adami HO, Melbye M. Sexually transmitted infection as a cause of anal cancer. N Engl J Med. 1997;337:1350–1358. [PubMed]
  • Frisch M, Fenger C, van den Brule AJ, Sorensen P, Meijer CJ, Walboomers JM, Adami HO, Melbye M, Glimelius B. Variants of squamous cell carcinoma of the anal canal and perianal skin and their relation to human papillomaviruses. Cancer Res. 1999;59:753–757. [PubMed]
  • Frisch M, Biggar RJ, Goedert JJ. Human papillomavirus-associated cancers in patients with human immunodeficiency virus infection and acquired immunodeficiency syndrome. J Natl Cancer Inst. 2000;92:1500–1510. [PubMed]
  • Fry LC, Monkemuller K, Malfertheiner P. Prevention of gastric cancer: A challenging but feasible task. Acta Gastroenterol Latinoam. 2007;37:110–117. [PubMed]
  • Fukayama M, Chong JM, Uozaki H. Pathology and molecular pathology of Epstein-Barr virus-associated gastric carcinoma. Curr Top Microbiol Immunol. 2001;258:91–102. [PubMed]
  • Galetsky SA, Tsvetnov VV, Land CE, Afanasieva TA, Petrovichev NN, Gurtsevitch VE, Tokunaga M. Epstein-Barr-virus-associated gastric cancer in Russia. Int J Cancer. 1997;73:786–789. [PubMed]
  • Galmiche A, Rassow J, Doye A, Cagnol S, Chambard JC, Contamin S, de Thillot V, Just I, Ricci V, Solcia E, Van OE, Boquet P. The N-terminal 34 kDa fragment of Helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release. EMBO J. 2000;19:6361–6370. [PubMed]
  • Gao GF, Roth MJ, Wei WQ, Abnet CC, Chen F, Lu N, Zhao FH, Li XQ, Wang GQ, Taylor PR, Pan QJ, Chen W, Dawsey SM, Qiao YL. No association between HPV infection and the neoplastic progression of esophageal squamous cell carcinoma: Result from a cross-sectional study in a high-risk region of China. Int J Cancer. 2006;119:1354–1359. [PubMed]
  • Garidou A, Tzonou A, Lipworth L, Signorello LB, Kalapothaki V, Trichopoulos D. Lifestyle factors and medical conditions in relation to esophageal cancer by histologic type in a low-risk population. Int J Cancer. 1996;68:295–299. [PubMed]
  • Gebert B, Fischer W, Weiss E, Hoffmann R, Haas R. Helicobacter pylori vacuolating cytotoxin inhibits T lymphocyte activation. Science. 2003;301:1099–1102. [PubMed]
  • Gerhard M, Lehn N, Neumayer N, Boren T, Rad R, Schepp W, Miehlke S, Classen M, Prinz C. Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc Natl Acad Sci USA. 1999;96:12778–12783. [PubMed]
  • Gervaz P, Hahnloser D, Wolff BG, Anderson SA, Cunningham J, Beart RW, Jr, Klipfel A, Burgart L, Thibodeau SN. Molecular biology of squamous cell carcinoma of the anus: A comparison of HIV-positive and HIV-negative patients. J Gastrointest Surg. 2004;8:1024–1030. [PubMed]
  • Ghiara P, Marchetti M, Blaser MJ, Tummuru MK, Cover TL, Segal ED, Tompkins LS, Rappuoli R. Role of the Helicobacter pylori virulence factors vacuolating cytotoxin, CagA, and urease in a mouse model of disease. Infect Immun. 1995;63:4154–4160. [PMC free article] [PubMed]
  • Gillison ML, Shah KV. Role of mucosal human papillomavirus in nongenital cancers. J Natl Cancer Inst Monogr. 2003;31:57–65. [PubMed]
  • Gires O, Zimber-Strobl U, Gonnella R, Ueffing M, Marschall G, Zeidler R, Pich D, Hammerschmidt W. Latent membrane protein 1 of Epstein-Barr virus mimics a constitutively active receptor molecule. EMBO J. 1997;16:6131–6140. [PubMed]
  • Goel A, Arnold CN, Niedzwiecki D, Chang DK, Ricciardiello L, Carethers JM, Dowell JM, Wasserman L, Compton C, Mayer RJ, Bertagnolli MM, Boland CR. Characterization of sporadic colon cancer by patterns of genomic instability. Cancer Res. 2003;63:1608–1614. [PubMed]
  • Goel A, Li MS, Nagasaka T, Shin SK, Fuerst F, Ricciardiello L, Wasserman L, Boland CR. Association of JC virus T-antigen expression with the methylator phenotype in sporadic colorectal cancers. Gastroenterology. 2006;130:1950–1961. [PubMed]
  • Gordon J, Del VL, Otte J, Khalili K. Pituitary neoplasia induced by expression of human neurotropic polyomavirus, JCV, early genome in transgenic mice. Oncogene. 2000;19:4840–4846. [PubMed]
  • Gulley ML, Pulitzer DR, Eagan PA, Schneider BG. Epstein-Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation. Hum Pathol. 1996;27:20–27. [PubMed]
  • Haggitt RC, Tryzelaar J, Ellis FH, Colcher H. Adenocarcinoma complicating columnar epithelium-lined (Barrett’s) esophagus. Am J Clin Pathol. 1978;70:1–5. [PubMed]
  • Hatakeyama M. Oncogenic mechanisms of the Helicobacter pylori CagA protein. Nat Rev Cancer. 2004;4:688–694. [PubMed]
  • Heck DV, Yee CL, Howley PM, Munger K. Efficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses. Proc Natl Acad Sci USA. 1992;89:4442–4446. [PubMed]
  • Henkel T, Ling PD, Hayward SD, Peterson MG. Mediation of Epstein-Barr virus EBNA2 transactivation by recombination signal-binding protein J kappa. Science. 1994;265:92–95. [PubMed]
  • Henle W, Henle G. Epidemiologic aspects of Epstein-Barr virus (EBV)-associated diseases. Ann NY Acad Sci. 1980;354:326–331. [PubMed]
  • Hessey SJ, Spencer J, Wyatt JI, Sobala G, Rathbone BJ, Axon AT, Dixon MF. Bacterial adhesion and disease activity in Helicobacter associated chronic gastritis. Gut. 1990;31:134–138. [PMC free article] [PubMed]
  • Higashi H, Tsutsumi R, Muto S, Sugiyama T, Azuma T, Asaka M, Hatakeyama M. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science. 2002;295:683–686. [PubMed]
  • Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998;338:423–428. [PubMed]
  • Hold GL, Rabkin CS, Chow WH, Smith MG, Gammon MD, Risch HA, Vaughan TL, McColl KE, Lissowska J, Zatonski W, Schoenberg JB, Blot WJ, Mowat NA, Fraumeni JF, Jr, El-Omar EM. A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors. Gastroenterology. 2007;132:905–912. [PubMed]
  • Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, Fox JG, Goldenring JR, Wang TC. Gastric cancer originating from bone marrow-derived cells. Science. 2004;306:1568–1571. [PubMed]
  • Hsieh JJ, Henkel T, Salmon P, Robey E, Peterson MG, Hayward SD. Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EB NA2. Mol Cell Biol. 1996;16:952–959. [PMC free article] [PubMed]
  • Huang JQ, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the relationship between Helicobacter pylori seropositivity and gastric cancer. Gastroenterology. 1998;114:1169–1179. [PubMed]
  • Huen DS, Henderson SA, Croom-Carter D, Rowe M. The Epstein-Barr virus latent membrane protein-1 (LMP1) mediates activation of NF-kappa B and cell surface phenotype via two effector regions in its carboxy-terminal cytoplasmic domain. Oncogene. 1995;10:549–560. [PubMed]
  • Hunter DJ, Gurney EG. The genomic instability associated with integrated simian virus 40 DNA is dependent on the origin of replication and early control region. J Virol. 1994;68:787–796. [PMC free article] [PubMed]
  • Hussell T, Isaacson PG, Spencer J. Proliferation and differentiation of tumour cells from B-cell lymphoma of mucosa-associated lymphoid tissue in vitro. J Pathol. 1993;169:221–227. [PubMed]
  • Hussell T, Isaacson PG, Crabtree JE, Spencer J. Helicobacter pylori-specific tumour-infiltrating T cells provide contact dependent help for the growth of malignant B cells in low-grade gastric lymphoma of mucosa-associated lymphoid tissue. J Pathol. 1996;178:122–127. [PubMed]
  • IARC Monographs on the Carcinogenic Risks to Humans. Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. 1994;61:1–241. [PubMed]
  • Ilver D, Arnqvist A, Ogren J, Frick IM, Kersulyte D, Incecik ET, Berg DE, Covacci A, Engstrand L, Boren T. Helicobacter pylori adhesin binding fucosylated histo-blood group antigens revealed by retagging. Science. 1998;279:373–377. [PubMed]
  • Ionov Y, Peinado MA, Malkhosyan S, Shibata D, Perucho M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature. 1993;363:558–561. [PubMed]
  • Jarrett WF. The Leeuwenhoek lecture, 1986. Environmental carcinogens and papillomaviruses in the pathogenesis of cancer. Proc R Soc Lond B Biol Sci. 1987;231:1–11. [PubMed]
  • Jarrett WF, McNeil PE, Grimshaw WT, Selman IE, McIntyre WI. High incidence area of cattle cancer with a possible interaction between an environmental carcinogen and a papilloma virus. Nature. 1978;274:215–217. [PubMed]
  • Jass JR. Colorectal cancer: A multipathway disease. Crit Rev Oncog. 2006;12:273–287. [PubMed]
  • Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology. 2007;50:113–130. [PubMed]
  • Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ. Cancer statistics, 2005. CA Cancer J Clin. 2005;55:10–30. [PubMed]
  • Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43–66. [PubMed]
  • Jenkins TD, Nakagawa H, Rustgi AK. The association of Epstein-Barr virus DNA with esophageal squamous cell carcinoma. Oncogene. 1996;13:1809–1813. [PubMed]
  • Jones PA. DNA methylation errors and cancer. Cancer Res. 1996;56:2463–2467. [PubMed]
  • Jones PA, Laird PW. Cancer epigenetics comes of age. Nat Genet. 1999;21:163–167. [PubMed]
  • Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM, Kolodner R. Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res. 1997;57:808–811. [PubMed]
  • Kappler R, Pietsch T, Weggen S, Wiestler OD, Scherthan H. Chromosomal imbalances and DNA amplifications in SV40 large T antigen-induced primitive neuroectodermal tumor cell lines of the rat. Carcinogenesis. 1999;20:1433–1438. [PubMed]
  • Kaye KM, Izumi KM, Kieff E. Epstein-Barr virus latent membrane protein 1 is essential for B-lymphocyte growth transformation. Proc Natl Acad Sci USA. 1993;90:9150–9154. [PubMed]
  • Kieff E, Rickinson AB. Fields virology. Philadelphia: Lippincott Williams and Wilkins; 2001. pp. 2511–2574.
  • Kim DN, Chae HS, Oh ST, Kang JH, Park CH, Park WS, Takada K, Lee JM, Lee WK, Lee SK. Expression of viral microRNAs in Epstein-Barr virus-associated gastric carcinoma. J Virol. 2007;81:1033–1036. [PMC free article] [PubMed]
  • Kobayashi A, Greenblatt RM, Anastos K, Minkoff H, Massad LS, Young M, Levine AM, Darragh TM, Weinberg V, Smith-McCune KK. Functional attributes of mucosal immunity in cervical intraepithelial neoplasia and effects of HIV infection. Cancer Res. 2004;64:6766–6774. [PubMed]
  • Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, Chiacchierini LM, Jansen KU. A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med. 2002;347:1645–1651. [PubMed]
  • Krynska B, Gordon J, Otte J, Franks R, Knobler R, DeLuca A, Giordano A, Khalili K. Role of cell cycle regulators in tumor formation in transgenic mice expressing the human neurotropic virus, JCV, early protein. J Cell Biochem. 1997;67:223–230. [PubMed]
  • Krynska B, Del VL, Croul S, Gordon J, Katsetos CD, Carbone M, Giordano A, Khalili K. Detection of human neurotropic JC virus DNA sequence and expression of the viral oncogenic protein in pediatric medulloblastomas. Proc Natl Acad Sci USA. 1999;96:11519–11524. [PubMed]
  • Kubben FJ, Sier CF, Meijer MJ, van den BM, van der Reijden JJ, Griffioen G, Van DV, Lamers CB, Verspaget HW. Clinical impact of MMP and TIMP gene polymorphisms in gastric cancer. Br J Cancer. 2006;95:744–751. [PMC free article] [PubMed]
  • Kuck D, Kolmerer B, Iking-Konert C, Krammer PH, Stremmel W, Rudi J. Vacuolating cytotoxin of Helicobacter pylori induces apoptosis in the human gastric epithelial cell line AGS. Infect Immun. 2001;69:5080–5087. [PMC free article] [PubMed]
  • Kume T, Oshima K, Shinohara T, Takeo H, Yamashita Y, Shirakusa T, Kikuchi M. Low rate of apoptosis and overexpression of bcl-2 in Epstein-Barr virus-associated gastric carcinoma. Histopathology. 1999;34:502–509. [PubMed]
  • Kuzuhara T, Suganuma M, Kurusu M, Fujiki H. Helicobacter pylori-secreting protein Tipalpha is a potent inducer of chemokine gene expressions in stomach cancer cells. J Cancer Res Clin Oncol. 2007;133:287–296. [PubMed]
  • Kwok T, Zabler D, Urman S, Rohde M, Hartig R, Wessler S, Misselwitz R, Berger J, Sewald N, Konig W, Backert S. Helicobacter exploits integrin for type IV secretion and kinase activation. Nature. 2007;449:862–866. [PubMed]
  • Laghi L, Randolph AE, Chauhan DP, Marra G, Major EO, Neel JV, Boland CR. JC virus DNA is present in the mucosa of the human colon and in colorectal cancers. Proc Natl Acad Sci USA. 1999;96:7484–7489. [PubMed]
  • Lam KY, Srivastava G, Leung ML, Ma L. Absence of Epstein-Barr virus in oesophageal squamous cell carcinoma. Clin Mol Pathol. 1995;48:M188–M190. [PMC free article] [PubMed]
  • Lauren P. The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand. 1965;64:31–49. [PubMed]
  • Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature. 1997;386:623–627. [PubMed]
  • Leunk RD, Johnson PT, David BC, Kraft WG, Morgan DR. Cytotoxic activity in broth-culture filtrates of Campylobacter pylori. J Med Microbiol. 1988;26:93–99. [PubMed]
  • Levi G, Feldman J, Holman S, Salarieh A, Strickler HD, Alter S, Minkoff H. Relationship between HIV viral load and Langerhans cells of the cervical epithelium. J Obstet Gynaecol Res. 2005;31:178–184. [PubMed]
  • Levine AJ. p53, the cellular gatekeeper for growth and division. Cell. 1997;88:323–331. [PubMed]
  • Liu F, Pan K, Zhang X, Zhang Y, Zhang L, Ma J, Dong C, Shen L, Li J, Deng D, Lin D, You W. Genetic variants in cyclooxygenase-2: Expression and risk of gastric cancer and its precursors in a Chinese population. Gastroenterology. 2006;130:1975–1984. [PubMed]
  • London WT, Houff SA, Madden DL, Fuccillo DA, Gravell M, Wallen WC, Palmer AE, Sever JL, Padgett BL, Walker DL, ZuRhein GM, Ohashi T. Brain tumors in owl monkeys inoculated with a human polyomavirus (JC virus) Science. 1978;201:1246–1249. [PubMed]
  • Luo B, Wang Y, Wang XF, Liang H, Yan LP, Huang BH, Zhao P. Expression of Epstein-Barr virus genes in EBV-associated gastric carcinomas. World J Gastroenterol. 2005;11:629–633. [PubMed]
  • Machado JC, Figueiredo C, Canedo P, Pharoah P, Carvalho R, Nabais S, Castro AC, Campos ML, Van Doorn LJ, Caldas C, Seruca R, Carneiro F, Sobrinho-Simoes M. A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology. 2003;125:364–371. [PubMed]
  • Magnusson PKE, Enroth H, Eriksson I, Held M, Nyren O, Engstrand L, Hansson LE, Gyllensten UB. Gastric cancer and human leukocyte antigen: Distinct DQ and DR alleles are associated with development of gastric cancer and infection by Helicobacter pylori. Cancer Res. 2001;61:2684–2689. [PubMed]
  • Major EO, Amemiya K, Tornatore CS, Houff SA, Berger JR. Pathogenesis and molecular biology of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain. Clin Microbiol Rev. 1992;5:49–73. [PMC free article] [PubMed]
  • Malfertheiner P, Peitz U, Wolle K, Treiber G. Helicobacter pylori infection—An update for 2004. Dtsch Med Wochenschr. 2004;129:1821–1826. [PubMed]
  • Malfertheiner P, Sipponen P, Naumann M, Moayyedi P, Megraud F, Xiao SD, Sugano K, Nyren O. Helicobacter pylori eradication has the potential to prevent gastric cancer: A state-of-the-art critique. Am J Gastroenterol. 2005;100:2100–2115. [PubMed]
  • Malfertheiner P, Megraud F, O’Morain C, Bazzoli F, El-Omar E, Graham D, Hunt R, Rokkas T, Vakil N, Kuipers EJ. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut. 2007;56:772–781. [PMC free article] [PubMed]
  • Martinez-Delgado B, Robledo M, Arranz E, Osorio A, Garcia MJ, Echezarreta G, Rivas C, Benitez J. Hypermethylation of p15/ink4b/MTS2 gene is differentially implicated among non-Hodgkin’s lymphomas. Leukemia. 1998;12:937–941. [PubMed]
  • Marwick C. Helicobacter: New name, new hypothesis involving type of gastric cancer. JAMA. 2002;264:2724–2727. [PubMed]
  • Matsha T, Erasmus R, Kafuko AB, Mugwanya D, Stepien A, Parker MI. Human papillomavirus associated with oesophageal cancer. J Clin Pathol. 2002;55:587–590. [PMC free article] [PubMed]
  • Min KO, Seo EJ, Kwon HJ, Lee EJ, Kim WI, Kang CS, Kim KM. Methylation of p16(INK4A) and p57(KIP2) are involved in the development and progression of gastric MALT lymphomas. Mod Pathol. 2006;19:141–148. [PubMed]
  • Munger K, Howley PM. Human papillomavirus immortalization and transformation functions. Virus Res. 2002;89:213–228. [PubMed]
  • Murai Y, Zheng HC, bdel Aziz HO, Mei H, Kutsuna T, Nakanishi Y, Tsuneyama K, Takano Y. High JC virus load in gastric cancer and adjacent non-cancerous mucosa. Cancer Sci. 2007;98:25–31. [PubMed]
  • Odenbreit S, Puls J, Sedlmaier B, Gerland E, Fischer W, Haas R. Translocation of Helicobacter pylori CagA into gastric epithelial cells by type IV secretion. Science. 2000;287:1497–1500. [PubMed]
  • Ohsumi S, Motoi M, Ogawa K. Induction of undifferentiated tumors by JC virus in the cerebrum of rats. Acta Pathol Jpn. 1986;36:815–825. [PubMed]
  • Ohyauchi M, Imatani A, Yonechi M, Asano N, Miura A, Iijima K, Koike T, Sekine H, Ohara S, Shimosegawa T. The polymorphism interleukin 8–251A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. Gut. 2005;54:330–335. [PMC free article] [PubMed]
  • Padgett BL, Walker DL, ZuRhein GM, Eckroade RJ, Dessel BH. Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy. Lancet. 1971;1:1257–1260. [PubMed]
  • Palefsky JM, Holly EA, Ralston ML, Jay N, Berry JM, Darragh TM. High incidence of anal high-grade squamous intra-epithelial lesions among HIV-positive and HIV-negative homosexual and bisexual men. AIDS. 1998;12:495–503. [PubMed]
  • Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int.J Cancer. 2006;118:3030–3044. [PubMed]
  • Parsonnet J, Friedman GD, Orentreich N, Vogelman H. Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. Gut. 1997;40:297–301. [PMC free article] [PubMed]
  • Pathmanathan R, Prasad U, Chandrika G, Sadler R, Flynn K, Raab-Traub N. Undifferentiated, nonkeratinizing, and squamous cell carcinoma of the nasopharynx. Variants of Epstein-Barr virus-infected neoplasia. Am J Pathol. 2002;146:1355–1367. [PubMed]
  • Peek RM, Jr, Blaser MJ. Helicobacter pylori and gastrointestinal tract adenocarcinomas. Nat Rev Cancer. 2002;2:28–37. [PubMed]
  • Peek RM, Jr, Crabtree JE. Helicobacter infection and gastric neoplasia. J Pathol. 2006;208:233–248. [PubMed]
  • Peek RM, Jr, Blaser MJ, Mays DJ, Forsyth MH, Cover TL, Song SY, Krishna U, Pietenpol JA. Helicobacter pylori strain-specific genotypes and modulation of the gastric epithelial cell cycle. Cancer Res. 1999;59:6124–6131. [PubMed]
  • Peng H, Ranaldi R, Diss TC, Isaacson PG, Bearzi I, Pan L. High frequency of CagA+ Helicobacter pylori infection in high-grade gastric MALT B-cell lymphomas. J Pathol. 1998;185:409–412. [PubMed]
  • Pfeffer S, Zavolan M, Grasser FA, Chien M, Russo JJ, Ju J, John B, Enright AJ, Marks D, Sander C, Tuschl T. Identification of virus-encoded microRNAs. Science. 2004;304:734–736. [PubMed]
  • Pisani P, Parkin DM, Ferlay J. Estimates of the worldwide mortality from eighteen major cancers in 1985. Implications for prevention and projections of future burden. Int J Cancer. 1993;55:891–903. [PubMed]
  • Pisani P, Bray F, Parkin DM. Estimates of the world-wide prevalence of cancer for 25 sites in the adult population. Int J Cancer. 2002;97:72–81. [PubMed]
  • Ponzielli R, Katz S, Barsyte-Lovejoy D, Penn LZ. Cancer therapeutics: Targeting the dark side of Myc. Eur J Cancer. 2005;41:2485–2501. [PubMed]
  • Prinz C, Hafsi N, Voland P. Helicobacter pylori virulence factors and the host immune response: Implications for therapeutic vaccination. Trends Microbiol. 2003;11:134–138. [PubMed]
  • Rad R, Gerhard M, Lang R, Schoniger M, Rosch T, Schepp W, Becker I, Wagner H, Prinz C. The Helicobacter pylori blood group antigen-binding adhesin facilitates bacterial colonization and augments a nonspecific immune response. J Immunol. 2002;168:3033–3041. [PubMed]
  • Reiss K, Khalili K. Viruses and cancer: Lessons from the human polyomavirus, JCV. Oncogene. 2003;22:6517–6523. [PubMed]
  • Reiss K, Khalili K, Giordano A, Trojanek J. JC virus large T-antigen and IGF-I signaling system merge to affect DNA repair and genomic integrity. J Cell Physiol. 2006;206:295–300. [PubMed]
  • Rencic A, Gordon J, Otte J, Curtis M, Kovatich A, Zoltick P, Khalili K, Andrews D. Detection of JC virus DNA sequence and expression of the viral oncoprotein, tumor antigen, in brain of immunocompetent patient with oligoastrocytoma. Proc Natl Acad Sci USA. 1996;93:7352–7357. [PubMed]
  • Ricciardiello L, Laghi L, Ramamirtham P, Chang CL, Chang DK, Randolph AE, Boland CR. JC virus DNA sequences are frequently present in the human upper and lower gastrointestinal tract. Gastroenterology. 2000;119:1228–1235. [PubMed]
  • Ricciardiello L, Chang DK, Laghi L, Goel A, Chang CL, Boland CR. Mad-1 is the exclusive JC virus strain present in the human colon, and its transcriptional control region has a deleted 98-base-pair sequence in colon cancer tissues. J Virol. 2001;75:1996–2001. [PMC free article] [PubMed]
  • Ricciardiello L, Baglioni M, Giovannini C, Pariali M, Cenacchi G, Ripalti A, Landini MP, Sawa H, Nagashima K, Frisque RJ, Goel A, Boland CR, Tognon M, Roda E, Bazzoli F. Induction of chromosomal instability in colonic cells by the human polyomavirus JC virus. Cancer Res. 2003;63:7256–7262. [PubMed]
  • Roderick P, Davies R, Raftery J, Crabbe D, Pearce R, Patel P, Bhandari P. Cost-effectiveness of population screening for Helicobacter pylori in preventing gastric cancer and peptic ulcer disease, using simulation. J Med Screen. 2003;10:148–156. [PubMed]
  • Rosenstiel P, Hellmig S, Hampe J, Ott S, Till A, Fischbach W, Sahly H, Lucius R, Folsch UR, Philpott D, Schreiber S. Influence of polymorphisms in the NOD1/CARD4 and NOD2/CARD15 genes on the clinical outcome of Helicobacter pylori infection. Cell Microbiol. 2006;8:1188–1198. [PubMed]
  • Royer B, Cazals-Hatem D, Sibilia J, Agbalika F, Cayuela JM, Soussi T, Maloisel F, Clauvel JP, Brouet JC, Mariette X. Lymphomas in patients with Sjogren’s syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses. Blood. 1997;90:766–775. [PubMed]
  • Rudi J, Kuck D, Strand S, von HA, Mariani SM, Krammer PH, Galle PR, Stremmel W. Involvement of the CD95 (APO-1/Fas) receptor and ligand system in Helicobacter pylori-induced gastric epithelial apoptosis. J Clin Invest. 1998;102:1506–1514. [PMC free article] [PubMed]
  • Salama N, Guillemin K, McDaniel TK, Sherlock G, Tompkins L, Falkow S. A whole-genome microarray reveals genetic diversity among Helicobacter pylori strains. Proc Natl Acad Sci USA. 2000;97:14668–14673. [PubMed]
  • Schiffman MH. Recent progress in defining the epidemiology of human papillomavirus infection and cervical neoplasia. J Natl Cancer Inst. 1992;84:394–398. [PubMed]
  • Segal ED, Cha J, Lo J, Falkow S, Tompkins LS. Altered states: Involvement of phosphorylated CagA in the induction of host cellular growth changes by Helicobacter pylori. Proc Natl Acad Sci USA. 1999;96:14559–14564. [PubMed]
  • Selbach M, Moese S, Hauck CR, Meyer TF, Backert S. Src is the kinase of the Helicobacter pylori CagA protein in vitro and in vivo. J Biol Chem. 2002;277:6775–6778. [PubMed]
  • Shen ZY, Xu LY, Li EM, Cai WJ, Shen J, Chen MH, Cen S, Tsao SW, Zeng Y. The multistage process of carcinogenesis in human esophageal epithelial cells induced by human papillomavirus. Oncol Rep. 2004;11:647–654. [PubMed]
  • Shibata D, Weiss LM. Epstein-Barr virus-associated gastric adenocarcinoma. Am J Pathol. 1992;140:769–774. [PubMed]
  • Shimoyama T, Fukuda S, Tanaka M, Mikami T, Saito Y, Munakata A. High prevalence of the CagA-positive Helicobacter pylori strains in Japanese asymptomatic patients and gastric cancer patients. Scand J Gastroenterol. 1997;32:465–468. [PubMed]
  • Shin SK, Li MS, Fuerst F, Hotchkiss E, Meyer R, Kim IT, Goel A, Boland CR. Oncogenic T-antigen of JC virus is present frequently in human gastric cancers. Cancer. 2006;107:481–488. [PubMed]
  • Shiozaki H, Oka H, Inoue M, Tamura S, Monden M. E-cadherin mediated adhesion system in cancer cells. Cancer. 1996;77:1605–1613. [PubMed]
  • Shollar D, Del VL, Khalili K, Otte J, Gordon J. JCV T-antigen interacts with the neurofibromatosis type 2 gene product in a transgenic mouse model of malignant peripheral nerve sheath tumors. Oncogene. 2004;23:5459–5467. [PubMed]
  • Sobhani I, Walker F, Roudot-Thoraval F, Abramowitz L, Johanet H, Henin D, Delchier JC, Soule JC. Anal carcinoma: Incidence and effect of cumulative infections. AIDS. 2004;18:1561–1569. [PubMed]
  • Starzynska T, Malfertheiner P. Helicobacter and digestive malignancies. Helicobacter. 2006;11:32–35. [PubMed]
  • Stein M, Rappuoli R, Covacci A. Tyrosine phosphorylation of the Helicobacter pylori CagA antigen after cag-driven host cell translocation. Proc Natl Acad Sci USA. 2000;97:1263–1268. [PubMed]
  • Stein M, Bagnoli F, Halenbeck R, Rappuoli R, Fantl WJ, Covacci A. c-Src/Lyn kinases activate Helicobacter pylori CagA through tyrosine phosphorylation of the EPIYA motifs. Mol Microbiol. 2002;43:971–980. [PubMed]
  • Stewart S, Dawson CW, Takada K, Curnow J, Moody CA, Sixbey JW, Young LS. Epstein-Barr virus-encoded LMP2A regulates viral and cellular gene expression by modulation of the NF-kappaB transcription factor pathway. Proc Natl Acad Sci USA. 2004;101:15730–15735. [PubMed]
  • Stolte M. Helicobacter pylori gastritis and gastric MALT-lymphoma. Lancet. 1992;339:745–746. [PubMed]
  • Stoner GD, Gupta A. Etiology and chemoprevention of esophageal squamous cell carcinoma. Carcinogenesis. 2001;22:1737–1746. [PubMed]
  • Suerbaum S, Josenhans C. Helicobacter pylori evolution and phenotypic diversification in a changing host. Nat Rev Microbiol. 2007;5:441–452. [PubMed]
  • Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347:1175–1186. [PubMed]
  • Suganuma M, Kurusu M, Suzuki K, Nishizono A, Murakami K, Fujioka T, Fujiki H. New tumor necrosis factor-alpha-inducing protein released from Helicobacter pylori for gastric cancer progression. J Cancer Res Clin Oncol. 2005;131:305–313. [PubMed]
  • Suganuma M, Kuzuhara T, Yamaguchi K, Fujiki H. Carcinogenic role of tumor necrosis factor-alpha inducing protein of Helicobacter pylori in human stomach. J Biochem Mol Biol. 2006;39:1–8. [PubMed]
  • Sugimoto M, Furuta T, Shirai N, Kodaira C, Nishino M, Ikuma M, Sugimura H, Hishida A. Role of angiotensinogen gene polymorphism on Helicobacter pylori infection-related gastric cancer risk in Japanese. Carcinogenesis. 2007;28:2036–2040. [PubMed]
  • Sur M, Cooper K. The role of the human papilloma virus in esophageal cancer. Pathology. 1998;30:348–354. [PubMed]
  • Syrjanen KJ. HPV infections and oesophageal cancer. J Clin Pathol. 2002;55:721–728. [PMC free article] [PubMed]
  • Szekely L, Selivanova G, Magnusson KP, Klein G, Wiman KG. EBNA-5, an Epstein-Barr virus-encoded nuclear antigen, binds to the retinoblastoma and p53 proteins. Proc Natl Acad Sci USA. 1993;90:5455–5459. [PubMed]
  • Takada K. Epstein-Barr virus and gastric carcinoma. Mol Pathol. 2000;53:255–261. [PMC free article] [PubMed]
  • Tao Q, Young LS, Woodman CB, Murray PG. Epstein-Barr virus (EBV) and its associated human cancers—Genetics, epigenetics, pathobiology and novel therapeutics. Front Biosci. 2006;11:2672–2713. [PubMed]
  • The Non-Hodgkin’s Lymphoma Classification Project. A Clinical Evaluation of the International Lymphoma Study Group Classification of Non-Hodgkin’s Lymphoma. Blood. 1997;89:3909–3918. [PubMed]
  • Thomas M, Pim D, Banks L. The role of the E6-p53 interaction in the molecular pathogenesis of HPV. Oncogene. 1999;18:7690–7700. [PubMed]
  • Togawa K, Rustgi AK. Human papillomavirus-16 and −18 replication in esophagus squamous cancer cell lines does not require heterologous E1 and E2 proteins. J Med Virol. 1995;45:435–438. [PubMed]
  • Togawa K, Jaskiewicz K, Takahashi H, Meltzer SJ, Rustgi AK. Human papillomavirus DNA sequences in esophagus squamous cell carcinoma. Gastroenterology. 1994;107:128–136. [PubMed]
  • Tokunaga M, Land CE, Uemura Y, Tokudome T, Tanaka S, Sato E. Epstein-Barr virus in gastric carcinoma. Am J Pathol. 1993;143:1250–1254. [PubMed]
  • Trojanek J, Croul S, Ho T, Wang JY, Darbinyan A, Nowicki M, Valle LD, Skorski T, Khalili K, Reiss K. T-antigen of the human polyomavirus JC attenuates faithful DNA repair by forcing nuclear interaction between IRS-1 and Rad51. J Cell Physiol. 2006;206:35–46. [PubMed]
  • Tsutsumi R, Higashi H, Higuchi M, Okada M, Hatakeyama M. Attenuation of Helicobacter pylori CagA × SHP-2 signaling by interaction between CagA and C-terminal Src kinase. J Biol Chem. 2003;278:3664–3670. [PubMed]
  • Tummuru MK, Cover TL, Blaser MJ. Cloning and expression of a high-molecular-mass major antigen of Helicobacter pylori: Evidence of linkage to cytotoxin production. Infect Immun. 1993;61:1799–1809. [PMC free article] [PubMed]
  • Ueda Y, Enomoto T, Miyatake T, Ozaki K, Yoshizaki T, Kanao H, Ueno Y, Nakashima R, Shroyer KR, Murata Y. Monoclonal expansion with integration of high-risk type human papillomaviruses is an initial step for cervical carcinogenesis: Association of clonal status and human papillomavirus infection with clinical outcome in cervical intraepithelial neoplasia. Lab Invest. 2003;83:1517–1527. [PubMed]
  • Vainio H, Miller AB. Primary and secondary prevention in colorectal cancer. Acta Oncol. 2003;42:809–815. [PubMed]
  • van der Woude CJ, Jansen PL, Tiebosch AT, Beuving A, Homan M, Kleibeuker JH, Moshage H. Expression of apoptosis-related proteins in Barrett’s metaplasia-dysplasia-carcinoma sequence: A switch to a more resistant phenotype. Hum Pathol. 2002;33:686–692. [PubMed]
  • Van Doorn LJ, Figueiredo C, Megraud F, Pena S, Midolo P, Queiroz DM, Carneiro F, Vanderborght B, Pegado MD, Sanna R, De BW, Schneeberger PM, Correa P, Ng EK, Atherton J, Blaser MJ, Quint WG. Geographic distribution of vacA allelic types of Helicobacter pylori. Gastroenterology. 1999;116:823–830. [PubMed]
  • Vernon SD, Hart CE, Reeves WC, Icenogle JP. The HIV-1 tat protein enhances E2-dependent human papillomavirus 16 transcription. Virus Res. 1993;27:133–145. [PubMed]
  • Vogelstein B, Lane D, Levine AJ. Surfing the p53 network. Nature. 2000;408:307–310. [PubMed]
  • Vogiatzi P, Cassone M, Luzzi I, Lucchetti C, Otvos L, Jr, Giordano A. Helicobacter pylori as a class I carcinogen: Physiopathology and management strategies. J Cell Biochem. 2007;102:264–273. [PubMed]
  • Walker DL, Padgett BL, ZuRhein GM, Albert AE, Marsh RF. Human papovavirus (JC): Induction of brain tumors in hamsters. Science. 1973;181:674–676. [PubMed]
  • Wang D, Liebowitz D, Kieff E. An EBV membrane protein expressed in immortalized lymphocytes transforms established rodent cells. Cell. 1985;43:831–840. [PubMed]
  • Wang S, Rowe M, Lundgren E. Expression of the Epstein Barr virus transforming protein LMP1 causes a rapid and transient stimulation of the Bcl-2 homologue Mcl-1 levels in B-cell lines. Cancer Res. 1996;56:4610–4613. [PubMed]
  • Werness BA, Levine AJ, Howley PM. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science. 1990;248:76–79. [PubMed]
  • White MK, Gordon J, Reiss K, Del VL, Croul S, Giordano A, Darbinyan A, Khalili K. Human polyomaviruses and brain tumors. Brain Res Brain Res Rev. 2005;50:69–85. [PubMed]
  • Williams GR, Lu QL, Love SB, Talbot IC, Northover JM. Properties of HPV-positive and HPV-negative anal carcinomas. J Pathol. 1996;180:378–382. [PubMed]
  • Wistuba II, Behrens C, Milchgrub S, Virmani AK, Jagirdar J, Thomas B, Ioachim HL, Litzky LA, Brambilla EM, Minna JD, Gazdar AF. Comparison of molecular changes in lung cancers in HIV-positive and HIV-indeterminate subjects. JAMA. 1998;279:1554–1559. [PubMed]
  • Wistuba II, Syed S, Behrens C, Duong M, Milchgrub S, Muller CY, Jagirdar J, Gazdar AF. Comparison of molecular changes in cervical intraepithelial neoplasia in HIV-positive and HIV-indeterminate subjects. Gynecol Oncol. 1999;74:519–526. [PubMed]
  • Woods C, LeFeuvre C, Stewart N, Bacchetti S. Induction of genomic instability in SV40 transformed human cells: Sufficiency of the N-terminal 147 amino acids of large T antigen and role of pRB and p53. Oncogene. 1994;9:2943–2950. [PubMed]
  • Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 1991;338:1175–1176. [PubMed]
  • Wu MS, Shun CT, Wu CC, Hsu TY, Lin MT, Chang MC, Wang HP, Lin JT. Epstein-Barr virus-associated gastric carcinomas: Relation to H. pylori infection and genetic alterations. Gastroenterology. 2000;118:1031–1038. [PubMed]
  • Yamazaki S, Yamakawa A, Ito Y, Ohtani M, Higashi H, Hatakeyama M, Azuma T. The CagA protein of Helicobacter pylori is translocated into epithelial cells and binds to SHP-2 in human gastric mucosa. J Infect Dis. 2003;187:334–337. [PubMed]
  • Yanai H, Hirano A, Matsusaki K, Kawano T, Miura O, Yoshida T, Okita K, Shimizu N. Epstein-Barr virus association is rare in esophageal squamous cell carcinoma. Int J Gastrointest Cancer. 2003;33:165–170. [PubMed]
  • Ye H, Liu H, Attygalle A, Wotherspoon AC, Nicholson AG, Charlotte F, Leblond V, Speight P, Goodlad J, Lavergne-Slove A, Martin-Subero JI, Siebert R, Dogan A, Isaacson PG, Du MQ. Variable frequencies of t(11;18)(q21;q21) in MALT lymphomas of different sites: Significant association with CagA strains of H pylori in gastric MALT lymphoma. Blood. 2003;102:1012–1018. [PubMed]
  • Zimber-Strobl U, Kempkes B, Marschall G, Zeidler R, Van KC, Banchereau J, Bornkamm GW, Hammerschmidt W. Epstein-Barr virus latent membrane protein (LMP1) is not sufficient to maintain proliferation of B cells but both it and activated CD40 can prolong their survival. EMBO J. 1996;15:7070–7078. [PubMed]
  • Zucca E, Bertoni F, Roggero E, Cavalli F. The gastric marginal zone B-cell lymphoma of MALT type. Blood. 2000;96:410–419. [PubMed]