Pathogens and Carcinogenesis: a Review
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biology Review Pathogens and Carcinogenesis: A Review Muhammad Nur Adam Hatta , Ezanee Azlina Mohamad Hanif , Siok-Fong Chin and Hui-min Neoh * UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Jalan Ya’acob Latiff, Cheras, Kuala Lumpur 56000, Malaysia; [email protected] (M.N.A.H.); [email protected] (E.A.M.H.); [email protected] (S.-F.C.) * Correspondence: [email protected]; Tel.: +60-391459074 Simple Summary: An increasing number of cancer cases has been reported throughout the years. Most cancers are linked to unhealthy lifestyles and genetic inheritance. Nevertheless, unknown to many, infection from microorganisms (bacteria, viruses, fungi) and sometimes, parasites, can also lead to cancer development. For these cancers, the infection may inflict mechanical injury on host cells, whilst gene products or protein secretion from the microorganism further alters host cell activity, leading to abnormal cell development and growth. Due to the cancer-causing characteristic of these microorganisms, they have been classified as definite biological agents that cause cancer. This review describes the cancer development process caused by some of these microorganisms and highlights strategies to prevent or treat the associated cancers. Abstract: Cancer is a global health problem associated with genetics and unhealthy lifestyles. In- creasingly, pathogenic infections have also been identified as contributors to human cancer initiation and progression. Most pathogens (bacteria, viruses, fungi, and parasites) associated with human cancers are categorized as Group I human carcinogens by the International Agency for Research on Cancer, IARC. These pathogens cause carcinogenesis via three known mechanisms: persistent Citation: Hatta, M.N.A.; Mohamad Hanif, E.A.; Chin, S.-F.; Neoh, H.-m. infection that cause inflammation and DNA damage, initiation of oncogene expression, and im- Pathogens and Carcinogenesis: A munosuppression activity of the host. In this review, we discuss the carcinogenesis mechanism of Review. Biology 2021, 10, 533. ten pathogens, their implications, and some future considerations for better management of the https://doi.org/10.3390/ disease. The pathogens and cancers described are Helicobacter pylori (gastric cancer), Epstein-Barr biology10060533 virus (gastric cancer and lymphoma), Hepatitis B and C viruses (liver cancer), Aspergillus spp. (liver cancer), Opisthorchis viverrine (bile duct cancer), Clonorchis sinensis (bile duct cancer), Fusobacterium Academic Editor: nucleatum (colorectal cancer), Schistosoma haematobium (bladder cancer); Human Papillomavirus Vincent Sanchis-Borja (cervical cancer), and Kaposi’s Sarcoma Herpes Virus (Kaposi’s sarcoma). Received: 6 May 2021 Keywords: infections; pathogens; carcinogenesis Accepted: 2 June 2021 Published: 15 June 2021 Publisher’s Note: MDPI stays neutral 1. Introduction with regard to jurisdictional claims in published maps and institutional affil- Cancer is a disease in which cells divide in an uncontrolled manner and have the iations. ability to invade nearby tissues. The disease is a significant cause of morbidity and mortality. From the latest annual cancer case report of 2020, the World Health Organization (WHO) estimated more than 19.2 million new cases being diagnosed and 9.9 million mortalities from cancer [1]. Carcinogenesis and the progression of cancer are usually undetectable externally; many cancers, such as pancreatic and colorectal cancers (CRC) Copyright: © 2021 by the authors. are undiagnosed until they reach a later stage [2,3]. Risk factors associated with lifestyle, Licensee MDPI, Basel, Switzerland. This article is an open access article diet, and genetic predisposition have been identified to contribute to carcinogenesis [4]. distributed under the terms and Increasingly, infections caused by pathogenic microorganisms and parasites have also been conditions of the Creative Commons linked to cancer [5–9]. Attribution (CC BY) license (https:// Microorganisms have been primarily studied for their roles in causing infection. creativecommons.org/licenses/by/ However, since the early 20th century, the association of some infectious agents with 4.0/). cancer has been reported [10]. Beginning in the 1900s with a report by Askanazy, the link Biology 2021, 10, 533. https://doi.org/10.3390/biology10060533 https://www.mdpi.com/journal/biology Biology 2021, 10, x FOR PEER REVIEW 2 of 23 Biology 2021, 10, 533 Microorganisms have been primarily studied for their roles in causing infection.2 of 22 However, since the early 20th century, the association of some infectious agents with can- cer has been reported [10]. Beginning in the 1900s with a report by Askanazy, the link betweenbetween OpisthorchisOpisthorchis felineusfelineus infectioninfection andand liverliver cancer,cancer, ininaddition addition toto the the discovery discovery of of bladderbladder cancer-causingcancer-causing BilharziaBilharzia infectionsinfections (schistosomiasis),(schistosomiasis), havehave beenbeen highlightedhighlighted [[11].11]. Subsequently,Subsequently, the the remarkable remarkable finding finding of of oncolytic oncolytic viruses viruses was was reported reported by by Peyton Peyton Rous Rous inin 1911 1911 in in an an avian avian model model [ 12[12].]. Fifty Fifty years years later, later, Anthony Anthony Epstein Epstein proposed proposed and and proved proved thethe association association of of the the Epstein-Barr Epstein-Barr virus virus (EBV (EBV with with Burkitt Burkitt lymphoma lymphoma [ 13[13,14]).,14]). Infectious Infectious agentsagents cause cause carcinogenesis carcinogenesis largely largely via via three three mechanisms mechanisms [ 15[15].]. The The first first mechanism mechanism is is via via persistentpersistent infection infection which which gives gives rise rise to to inflammation inflammation and and cell cell damage, damage, where where accumulative accumula- celltive damage cell damage leads leads to mutations to mutations and carcinogenesis. and carcinogenesis. Alternatively, Alternatively, infectious infectious agents mightagents causemight the cause expression the expression of oncogenic of oncogenic genes genes of their of their host host and and lead lead to cancer.to cancer. In In the the third third scenario,scenario, immunosuppressionimmunosuppression causedcaused byby infectiousinfectious agentsagents leadsleads to to carcinogenesis carcinogenesis in in the the hosthost viavia immunologic immunologic recognition recognition disruption disruption [ 15[15].]. Carcinogenesis Carcinogenesis tropism tropism is is observed observed in in cancerscancers caused caused by by infectious infectious agents, agents, whereby whereb differenty different agents agents are are associated associated with with different differ- typesent types of cancer of cancer (Figure (Figure1). This 1). review This review will describe will describe ten infectious ten infectious agents agents whose whose roles have roles beenhave confirmed been confirmed in carcinogenesis. in carcinogenesis. FigureFigure 1. 1.Tropism Tropism of of pathogens pathogens associated associated with with human human cancer cancer development development described described in this in review.this re- view. 2. Gastric Cancer 2. GastricGastric Cancer cancer (GC) ranked fifth in worldwide cancer incidence (1,089,103 new cases) and thirdGastric in cancer-related cancer (GC) ranked mortality fifth (768,793 in worldw mortalities)ide cancer in incidence the year 2020(1,089,103 [1]. Risk new factors cases) forand GC third include in cancer-related lifestyle modifiers mortality such (768,793 as dietary mortalities) habits in and the smoking,year 2020 family[1]. Risk history, factors andfor GC socioeconomic include lifestyle status modifiers [16–18]. such In addition, as dietary infection habits and with smoking,Helicobacter family pylori history,and EBV and havesocioeconomic also been reported status [16–18]. to be risk In addition, factors for infection the occurrence with Helicobacter of GC [19 ].pyloriH. pylori and EBVinfection have isalso attributed been reported to almost to allbe GCrisk cases; factors EBV for contributes the occurrence to less of than GC 10%[19]. ofH. incidences pylori infection [20,21 ].is attributed to almost all GC cases; EBV contributes to less than 10% of incidences [20,21]. 2.1. Helicobacter pylori Helicobacter pylori is a Gram-negative microaerophilic bacterium that could be isolated from the upper gastrointestinal tract of more than 50% of the population [22]. It can be transmitted through saliva, vomit material, and feces [23]. The bacteria’s chemotaxis Biology 2021, 10, 533 3 of 22 properties allow it to detect pH changes in the stomach and subsequently burrow into the epithelial layer to escape the acidic mucosal lining [24]. In addition, H. pylori secrete urease which breaks down gastric urea to produce carbon dioxide and ammonia, neutralizing the acidic pH of the environment [25]. While these properties allow the bacteria to survive in the stomach and duodenum, the production of ammonia is toxic to host epithelial cells, whereby long-term colonization of H. pylori causes inflammation and results in chronic gastritis [26,27]. For hosts who carry the cag pathogenicity island (PAI)-positive H. pylori, secreted CagA disrupts cellular processes and host cell gene transcription via tyrosine phosphoryla- tion of SHP-2 and kinases, causing neoplastic morphological changes and cell prolifera- tion [28–30]. At the