Role of bacterial infection in the development and progression of gastric cancers

Abstract

At present, cancer is the second leading cause of death worldwide, accounting for an estimated 9.6 million deaths in 2018.1 This type of diseases elicits from uncontrolled growth and proliferation of malignant cells harboring genetic alterations. These abnormally growing and proliferating cells can have a life-threatening effect when they physically or pathologically affect adjacent healthy cells in a vital organ. Distinct genetic alterations within a cell that result in out of control cell proliferation are responsible for the initiation of cancer formation. In this regard, genetic alterations in proto-oncogenes and tumor suppressor genes are frequently reported in several cancer cell types. Prolonged exposure to various mutagens can be involved in the induction of these genetic alterations in cancerous cells.2 Chronic infection represents a risk factor for cancer development. It has been estimated that up to 20% of the global cancer burden is attributed to infectious agents, especially viruses and bacteria.3,4 The bacterium Helicobacter pylori and viruses Hepatitis B virus, Hepatitis C virus, certain strains of human papillomavirus, Epstein-Barr virus, human immunodeficiency virus type-1, and human T-cell lymphotropic virus type-1 have been identified as major carcinogenic infectious agents by International Agency for Research on Cancer (IARC).3 These infectious agents are highly prevalent in the world. Nevertheless, most infected individuals do not develop cancer, indicating that genetic susceptibility of host and environmental factors may be associated with cancer caused by these infectious agents. Gastrointestinal tract is constantly exposed to many bacterial agents and some of these agents induce chronic inflammation in this organ. On the other hand, chronic inflammation may increase the rate of mutation in epithelial cells leading to cancerous cell formation. As discussed below for gastric cancer, some evidences suggest that specific bacteria can be involved in cancer development or progression. These bacteria can trigger oxidative stress in host cells, activate some intracellular pathways such as nuclear factor-kappa B (NF-κB) pathway, and promote production of various components involved in carcinogenesis. Role of inflammation in induction of oxidative stress and NF-κB pathway activation and cancer development, Phagocytosis of bacteria initiates oxidative stress in the phagocytic cells leading to release of reactive oxygen and nitrogen species such as peroxynitrite, reactive hydroxyl group, and other free radicals. These reactive components produced by inflammatory cells at site of infection affect enzymatic activities and expression of several genes. They can also induce DNA damage and genomic instability. Indeed, nucleotide modifications induced during oxidative stress can lead to mutagenesis. Some critical mutations and genomic instability, if not properly repaired, have the potential to orchestrate events in precancerous cells resulting in resistance to stress and death signals, and induce aberrant cell proliferation. Oxidative stress is linked to NF-κB pathway activation.4,5 Activation of NF-κB is involved in the immediate-early innate immune responses in microbial infections.6 NF-κB exists in the cytoplasm of many different cells and is bound to IkappaB (IκB), which prevents it from entering the nucleus. When cell is stimulated, NF-κB is released from IκB, enters into the nucleus and binds to specific sequences in promoter regions of target genes and upregulates their transcription. Activated NF-κB regulates transcription of several genes encoding growth factors, cytokines, chemokines, cell adhesion molecules, proinflammatory enzymes, angiogenesis factors, and apoptosis-related proteins. Accordingly, NF-κB has important roles in various cell functions such as in cell proliferation by activating growth factors such as IL-2, granulocytemonocyte colony stimulating factor and CD40L,7,8 in cell cycle progression by activating c-myc and cyclin D1,7,9 and in inhibition of apoptosis through regulation of the anti-apoptotic proteins ciAPS, c-FLP and members of the Bcl-2 family.7‒11 Activation of NF-κB also leads to upregulation of vascular endothelial growth factor (VEGF) and matrix metalloproteinase (MMP) that are associated with angiogenesis and cell migration, respectively. Furthermore, NF-κB is involved in overexpression of cyclooxygenase-2 (COX2), an enzyme regulating prostaglandin synthesis,12 which has a role in cell proliferation,13‒15 migration,15 invasion,15 apoptosis, and angiogenesis.14‒18 COX-2 also contributes to immune evasion.19 The