Effects of infections on the pathogenesis of cancer

Epstein–Barr virus (EBV)

EBV was discovered in the cultured cancer cells obtained from a Burkitt lymphoma (BL) biopsy56. EBV is considered, along with other factors, a causal agent for the development of BL, undifferentiated nasopharyngeal carcinoma, immunoblastic lymphomas and lymphoproliferative disorders in immunocompromised patients57. Furthermore, EBV infection represents a risk factor for Hodgkin's disease, non-Hodgkin's lymphoma, thymic lymphoepithelioma, salivary gland and urogenital carcinoma in immunocompetent hosts58 (Fig.1). In patients with autoimmune diseases, with HIV infection or treated with immunosuppressive therapy after an organ transplant, EBV is strongly associated with leiomyomas, leiomyosarcomas and other smooth muscle neoplasms59. A high worldwide prevalence of EBV (around 8.29%) has been reported in patients with gastric adenocarcinoma60. However, it is unclear whether EBV infection is involved in gastric cancer development or is a consequence of gastric inflammation due to immunosuppressive therapies60.

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Fig. 1

Pathogenetic mechanisms of Epstein–Barr virus on carcinogenesis. EBV is associated with different human tumours. EBV may infect B lymphocytes, leading to a malignant transformation into a lymphoma. Also, EBV may transform epithelial cells into epithelial tumours, LMP: EBV latent membrane protein; EBV, Epstein–Barr virus. Source: Ref 56.

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Hepatitis B virus (HBV)

Chronic infections caused by HBV and HCV represent the main risk factor for the development of hepatocellular carcinoma (HCC). HBV is a non-cytopathic, partially double-stranded hepatotropic DNA virus which belongs to Hepadnaviridae family. There are eight HBV genotypes (designated A-H) and four serotypes (adv, ayw, adr and ayr) characterized by different geographic distribution and clinical differences. Studies on HBV infection showed that genetic characteristics, including viral genotypes and specific mutations, may contribute to the development of HCC through direct and indirect pathways61. HBV can integrate its genome into the human genome, leading to alterations of transcription and cell growth. Integrated HBV sequences have been observed in established hepatoma cell lines and in about 80 per cent of human HBV-related HCCs62. The integration of HBV DNA does not play an essential role in viral replication but may cause viral genome persistence and poses high risk for hepatic cancer. The risk for HCC is increased in patients with active hepatitis and in cirrhotic patients, although HBV may cause cancer even in the absence of cirrhosis63. Continuous injury and regeneration of cirrhotic liver may lead to increased liver cells turnover, favouring genome critical mutations, chromosomal rearrangements, activation of oncogenes and inactivation of tumour suppressor genes. The T-cells immune response, elicited to contrast viral infection, contributes to hepatocytes necrosis, inflammation and regeneration64. HBV can replicate within the pancreas, and higher serum and urinary levels of pancreatic enzymes are frequently observed in patients with HBV chronic infection65. A meta-analysis of eight studies showed an association between past exposure to HBV and increased risk for pancreatic cancer development [odds ratio (OR)=1.24] mainly among individuals without natural immunity [anti-hepatitis B core (HBc)-positive/anti-hepatitis B surface antibody (anti-HBs) negative], with an OR of 1.6766. Chronic hepatitis B- and HBsAg-positive patients had a significantly increased risk for pancreatic cancer (OR=1.20); past exposure to HBV with natural immunity (anti-HBc positive/anti-HBs positive) had no association with pancreatic cancer development with an OR=0.98. Anti-HBs-positive patients showed a lower risk of pancreatic cancer compared to anti-HBs-negative patients (OR=0.54)6768. Further research is needed to explain the pathogenetic mechanisms involved in the progression from active hepatitis virus infection to chronic inflammatory response associated to pancreatic carcinogenesis.

Human papillomavirus (HPV)

HPV, a virus belonging to the Papovavirus group, is responsible for common infections contracted through sexual, oral and skin contact. It is estimated that over 70 per cent of women contract genital HPV infection during their lives, but a large number of infections disappears spontaneously over a few months due to the activity of immune system69. There are more than 100 types of HPV, and most of these do not cause serious disease; however, about 15 genotypes are known to be carcinogenic principally in the transformation zone between different types of epithelium70. This process has been observed in almost all uterine cervix cancers, in which HPV is able to induce different grades of cervical intraepithelial neoplasia (CIN). HPV-16 and HPV-18, the two most carcinogenic genotypes, are responsible for about 50 per cent of CIN3 and 70 per cent of cervical cancer71 (Fig. 2). The use of prophylactic vaccination against HPV infection is efficient and represents the most useful way of cervical cancer prevention. Other cancers associated with HPV infection, are breast, anus, prostate, penis, vagina, vulva, oropharynx, conjunctiva and non-melanoma skin cancers72. Potential cofactors involved in CIN development may include HIV, Chlamydia trachomatis, herpes simplex virus type 2 and immunosuppression72.

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Fig. 2

Effects of human papillomavirus (HPV) on the development of cervical cancer. The oncogenic proteins E6 and E7 affect control of the cell cycle by their interaction with p53 and retinoblastoma protein. HPV induces cervical intraepithelial neoplasia (CIN), which may develop into cervical cancer through changes in cytokine levels and reduction of apoptosis. CIN, cervical intraepithelial neoplasia; pRB, retinoblastoma protein; IL-10, interleukin 10; IFN-α, interferon alpha; IFN-β, interferon beta. Source: Ref. 71.

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Merkel cell polyomavirus

Merkel cell polyomavirus is found in tumour tissues of Merkel cell carcinoma (MCC). MCC is a rare and aggressive neuroectodermal cancer frequently observed in transplant recipients, immunocompromised those, patients with B-cell lymphoid tumours and patients with acquired immune deficiency syndrome (AIDS)73. Clonal integration of viral DNA into tumour cell genome has been observed in patients with MCC. Treatment protocols include the administration of bleomycin, a drug with direct antiviral effects against HCV and HIV74.

Kaposi's sarcoma-associated human herpes virus (KSHV)

KSHV, also known as human herpes virus 8 (HHV8), is considered the cause of various types of Kaposi's sarcoma (KS), such as AIDS-associated, classic, endemic, African and iatrogenic. HHV8 encodes for homologues of several cytokines and their receptors, but the exact role of virus in cancer induction is not yet clear75. The viral genome of HHV8 has been found in primary effusion lymphoma, multicentric Castleman disease, angioimmunoblastic lymphadenopathy and in some cases of reactive lymphadenopathies. HHV8 is also considered as a cause of body cavity-based lymphomas76.

Parvovirus B19

Parvovirus B19 infection may play a role in the pathogenesis of rheumatic diseases and acute lymphoblastic and myeloblastic leukaemia77. Parvovirus DNA and viral proteins have been detected in neoplastic epithelium of patients with papillary thyroid carcinoma (PTC)78. The possible role of B19 in pathogenesis of thyroid tumours is suggested by the involvement of immune system, NF-κB, IL-6 and viral proteins. The tax- and tat-mediated NF-κB activation plays a crucial role in the HTLV-1-induced acute leukaemia and HIV-induced KS; NF-κB is also significantly increased and co-localized with viral DNA in PTC tissues79. One of the non-structural proteins (NS1) encoded by the viral genome is cytotoxic to the host cells and linked to NF-κB and IL-680. This association is probably due to the fact that non-structural viral proteins resemble tax protein of HTLV-1 and tat protein of type 1-HIV. These all play a part in the viral propagation and activate IL-6 production through the NF-κB-binding site in the IL-6 promoter81. These findings suggested a link between parvovirus B19 and thyroid carcinoma.

Human T-cell leukaemia virus type 1 (HTLV-1)

HTLV-1 is a single-stranded RNA retrovirus predominantly associated to adult T-cell leukaemia (ATL), an aggressive malignancy characterized by uncontrolled growth of CD4+ T-lymphocytes, lymphadenopathy, hypercalcaemia, immunodeficiency and unfavourable prognosis82. HTLV-1 may have a long latent period of several decades after the initial infection. Mechanisms leading to ATL are not well understood; a multi-step leukaemogenic process has been hypothesized, in which the main roles are played by viral genes, their products and host immune status83. High levels of NF-κB, a regulator of immune response against infections, strongly associated with carcinogenesis, have been observed in ATL cells75.

Human immunodeficiency virus (HIV)

HIV is a RNA virus of the Lentivirus genus divided into two strains: HIV-1 and HIV-2. The viral infection is responsible for the AIDS, a disease defined as a set of clinical manifestations due to the depletion of T lymphocyte. HIV is also able to infect other cell types such as lymphocytes, macrophages, microglia and dendritic cells. Patients with HIV showed an increased risk to develop cancers such as KS, non-Hodgkin's lymphoma B-cell, primitive brain lymphoma B-cells and invasive carcinoma of the uterine cervix84. Other HIV/AIDS-related cancers include Hodgkin's disease and cancers of the lung, mouth and digestive system85. Opportunistic infections caused by viruses, bacteria, fungi and parasites are the leading causes of deaths in patients with AIDS (Table IV). The higher risk of developing opportunistic infections, as well as the increased incidence of cancer in HIV-infected patients, is mainly associated with immunosuppression88. The use of highly active antiretroviral therapy (HAART) has led to an increase of life expectancy, progressively transforming HIV into a chronically manageable infection. However, patients treated with HAART showed an increased risk of cancer such as lung, digestive system and liver cancers not necessarily associated with HIV infection89.

Hepatitis C virus (HCV)

HCV is a non-cytopathic RNA virus of the family Flaviviridae, and is an important risk factor for HCC development in Western countries. To date, at least six major genotypes of HCV have been identified90. HCV is not able to integrate its genome into host cells because of the absence of reverse transcriptase activity and may cause HCC by indirect pathways such as severe chronic hepatitis, cell death and proliferation which usually progress towards cirrhosis. Furthermore, HCV can evade host immune responses to cause a persistent infection in the liver91. Continuous cycles of death and regeneration in hepatocytes may favour the accumulation of mutations. HCV-infected patients have a higher risk of developing HCC compared with HCV-negative individuals, also depending on the degree of fibrosis and duration of viral infection92.

Helicobacter pylori (HP)

Although gastric malignancies may have multifactorial causes (e.g., use of tobacco, low vegetable intake, high dietary salt and nitrate intake), but HP plays a main role in the carcinogenesis as shown by the increased risk of developing gastric cancer in infected individuals106. In 1994, the International Association for Research on Cancer classified HP as Group 1 carcinogen107. The duration of infection and the type of bacterial strain may influence the risk of cancer, and the presence of cagA-positive strains of HP is associated with an increased risk of gastric carcinoma. The cagA gene encodes for one of the major HP virulence proteins, and infection from cagA-positive strains is characterized by increased virulence and inflammation108. The combination of environmental factors, bacterial factors and host immune response may drive the initiation and progression of carcinogenesis (Fig. 3). The precancerous cascade is a progressive process that usually lasts for several decades, but the mechanisms underlying initial DNA damage are still not known. The most plausible hypothesis is that cancer onset could be the result of oxidative stress, as represented by inducible NOS expression due to HP infection109. A reduction in the incidence of gastric cancer and a regression of precancerous lesions have been observed in patients with HP infection after treatment with antioxidant supplements (such as β-carotene, vitamin E and C and selenium)110. Other antioxidants showed protective effects on cancer inhibiting reactive oxygen species production and MAPK signal transduction pathways111112.

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Fig. 3

Role of Helicobacter pylori in the pathogenesis of gastric cancer. H. pylori infection may cause a number of diseases, ranging from superficial gastritis to gastric carcinoma. The progression to gastric cancer is mediated by cytokines, genetic polymorphisms, oxidative stress, gastric commensal organisms and alteration of epithelial cells response to acid. Source: Ref 91.

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COX-2 is a regulator in immune response and it is often over-expressed in many cancers, especially in colorectal cancer. Chronic induction of COX-2 could favour the survival of transformed cells that otherwise would become apoptotic and die. Therefore, cancer invasiveness could be reduced by inhibition of COX-2 activity113. The use of non-steroidal anti-inflammatory drugs (NSAIDs) is associated with a reduced risk of gastric cancer, through both inhibition of COX-2 and NF-κB activity. These findings underlined the role of NF-κB activation as a crucial component in bacteria-associated cancer formation114. Treatment of HP infection may reduce mucosal inflammation, DNA damage and cell turnover and improve gastric acid secretion in patients with previous hypochloridia115. The detection of high levels of HP DNA in liver biopsies of patients with liver chronic diseases, such as HCC, biliary cirrhosis and sclerosing cholangitis, suggested a promoting role of HP in hepatic carcinogenesis116.

Streptococcus infantarius (formerly S. bovis II/1)

Streptococcus infantarius is commonly reported in infections of the central nervous system, osteomyelitis, endocarditis and colon cancer117. However, the link between S. infantarius and cancer is still not clear; the bacterium is occasionally detectable in the normal colonic bacterial flora, but it is increased in faecal material of patients with colorectal cancer. A high percentage of patients with S. infantarius infection also show colorectal adenomatous polyps or carcinoma118. IL-8, a neutrophil and T-cells chemoattractant cytokine, plays a key role in the immune response to S. infantarius and other bacteria. IL-8 can lead to mucosal damage through the production of free radicals and proteolytic enzymes from neutrophils119. S. infantarius infection could be involved in the development of many cancers such as metastatic melanoma lymphoma, pancreas, endometrium, oesophagus, stomach and colon cancer117. However, further research is needed to clarify the link between S. infantarius infection and carcinogenesis.

Chlamydia trachomatis

The consequences of genital C. trachomatis infection are generally represented by urethritis, cervicitis, ectopic pregnancy, infertility, pelvic inflammation, epididymitis, prostatitis and increased risk of HIV infection120. Chlamydial infection causes chronic inflammation with epithelial damage, cytologic cervical atypia and consequent metaplasia, which in turn can increase the risk of cervical cancer121. Invasive squamous cervical cancer has been shown to be associated with serum detection of chlamydial antibodies121.

Chlamydia pneumoniae

Infection with C. pneumoniae, a Gram-negative bacillus, has been associated with an increased risk of lung carcinoma122. A case–control study of chronic C. pneumoniae infection as lung cancer risk factor in smokers showed a significant difference between male patients and their controls for specific C. pneumoniae antibodies, but there were no significant differences between female patients and their control groups123. Chronic C. pneumoniae infection was significantly higher among male patients with lung carcinoma below age 55 than controls, and even in this case, there were no age-related variations to the female sex123. Impairment of lung and bronchial immunity, increased levels of IL-4 and suppression of cellular immunity could facilitate C. pneumoniae lung localization and invasion in smoking subjects. IL-8, also produced by smokers, along with IL-1β and TNF-α, may cause genetic damage124.

Salmonella Typhi

Chronic Salmonella Typhi infection has been found to be strongly associated with gallbladder cancer. Lazcano-Ponce et al125 observed that individuals who became carriers of S. Typhi showed more than eight-fold increased risk of developing gallbladder carcinoma as compared to those who had acute typhoid and cleared the infection. Strom et al126 reported a 12-fold increase in risk of gallbladder cancer in patients with a history of typhoid fever (CI 95% 1.5-598), which unfortunately could not be supported with serological assays. Data from the epidemics of typhus in 1922 in New York and in 1964 in Aberdeen showed that people who contracted typhoid, but did not become carrier, were at lower risk for cancer and chronic typhoid carriers died of hepatobiliary cancer six times more often than the matched controls127.

Strongyloides stercoralis

Strongyloides stercoralis infection is estimated to affect around 100 million people per year worldwide and remains often neglected135. A case–control study showed a high prevalence of S. stercoralis infection in the patients with biliary tract cancer compared to controls136. The presence of S. stercoralis in the duodenum, including the duodenal papilla, may induce various patterns of inflammation, while chronic inflammation of the biliary tract is associated with invading larvae137.