Role of bacteria in carcinogenesis, with special reference to carcinoma of the gallbladder

Table 1 Chronic inflammatory mechanisms involved in carcinogenesis

Signaling	Sub categories	Role in inflammation assumed cancer
Pro-inflammatory cytokines and immunosuppressant cytokines	ILS: Pro-inflammatory (IL-1, IL-6, IL-8, IL-17); immunosuppressor (IL-10); TNF-α plays dual role in carcinogenesis, usually it is tumor promoter	Over expressed in inflamed and hyperplastic, metaplastic tissues and adenocarcinoma; Induce DNA damage; Pro-angiogenic molecule such as VEGF, VEGFR, IL-8, NO, ICAM-1 VCAM-1; Activation of pro-inflammatory signals mediated via JAK-STAT and NF-κB; Maintain inflammatory tumor microenvironment; Stimulate cell proliferation and inhibit apoptosis
Chemokines	Four major groups: CXC, CC, XC, CX3C (primary function is to recruit leucocytes at the site of inflammation)	Responsible for attraction to inflammatory and immune cells to tumor microenvironment; Promotion of tumor cell migration, facilitation of invasion and metastasis; Stimulation of inflammatory angiogenesis
COX-2 and prostaglandins	An inducible form of cyclooxygenase, serves as interface between inflammation and cancer[41-44]	Causes promotion of : cellular proliferation, suppression of apoptosis, enhancement of invasiveness, angiogenesis
iNOS	Expression of iNOS is elevated in various precancerous lesions and carcinomas[45]	Elevated in precancerous and cancerous lesions and cause: DNA damage by nitrosation/oxidative pathways; Produce proinflammatory mediators like NO by catalyzing Arginin metabolism; Acts as a downstream effector of NF-κB and inflammatory cytokines mediated signaling
NO	Elevated in precancerous and cancerous lesions[46]	Selects mutant p53 cells and contribute to tumorigenesis by upregulating VEGF; DNA damaged by nitrosation of nucleotide bases
NF-κB (The NF-κB/Rel family of proteins includes CRel, RelA (p65), RelB, NF-κB1 (p50/100), NF-κB2 (p52/p100)[47]	One of the DNA binding proteins that are aberrantly activated in response to inflammatory stimuli leading to induction of transcription of various proinflammatory genes in tumor cells[48]	Enhances expression/production of proinflammatory mediators: Amplifies inflammation signal transduction; Increased expression of anti-apoptotic protein; Help transformed cells to escape apoptosis
ErbB2 (a receptor strongly involved in carcinogenesis)	Inflammation induces the expression[49-50]	Binding of ErbB1 and ErbB2 to ligands results in prolong activation of intrinsic protein kinase activity, leading to activation of a biochemical cascade responsible for mitogenic cell signal transduction

ILS: Interleukins; IL: Interleukin; TNF: Tumor necrosis factor; CC: Chemotactic cytokine; NF-κB: Nuclear factor-κB; VEGFR: Vascular endothelial growth factor receptor; iNOS: Inducible nitric oxide synthetase; NO: Nitric oxide; VCAM-1: Vascular cell adhesion molecule 1; ICAM-1: Inter-cellular adhesion molecule 1.