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.

Table 2 Bacterial toxins and their possible roles in carcinogenesis

Toxin	Source	Activity and outcome
Potential genotoxins
CDT (three subunits: CdtB is a functional unit, while CdtA and CdtC serve as accessory units for delivery into target cells)	Haemophilus ducreyi, Helicobacter hepaticus, Salmonella typhi. Actinobacillus actinomycetemcomitans	DNAase; DNA damage and cell cycle inhibitor[56,57]
Cytolethal distending toxin B	Salmonella typhi	DNAase activity, genotoxic by creating DNA lesions[58]
Colibactin	Escherichia coli	Mechanism unknown[59]
Potential pro-carcinogenic toxins
Pasturella multocida toxin	Pasturella multocida	Modifies Gq proliferation[60]
CagA	Helicobacter pylori	Binds to SHP2 and c- Met cells scattering[61]
Vacuolating cytotoxin A	Helicobacter pylori	Upregulation of VEGF expression (seems to depend on the activation of EGFR, MAP kinase and COX-2 mediated)
Bacteroides fragilis toxin	Bacteroides fragilis	Cleaves E- cadherin proliferation[62]
Cytotoxic necrotizing factor-1	Escherichia coli, Shigella dysenteriae, Campylobacter jejuni and Salmonella typhi, Helicobacter hepaticus, Actinobacillus actinomycetemcomitans	Modifies Rho family proteins, inflammation and inhibition of cell cycle, blocks cytokines[39]
Cycle inhibiting factor	Escherichia coli	Inhibit cell cycle at G2-M transition[63]
MAP	Citrobacter rodentium	Multifunctional effectors protein that target host cell mitochondria implicated in the disruption of epithelial barrier function both in vitro and in vivo[64]
VEGF	Bartonella species	Angiogenesis and proliferation[65]

MAP: Mitochondrial associated protein; VEGF: Vascular endothelial growth factor; EGFR: Epidermal growth factor receptor.

Table 3 Spectrum of bacteria isolated from bile (Brook et al[73])

Organism	No. of isolates	%
Aerobic bacteria
Escherichia coli	71	32.9
Group D streptococci	42	19.4
Klebsiella species	29	15.3
Enterobacter species	26	12.5
Proteus species	15	6.9
α-haemolytic streptococci	11	5.1
Citrobacter species	8	3.6
Staphylococcus species	7	3.2
γ-haemolytic streptococci	5	2.3
Pseudomonas species	2	0.9
Anaerobic bacteria
Clostridium perfringens	23	29.9
Bacteroides fragilis	9	11.7
Other Bacteroides species	5	6.5
B. thetaiotamicron	4	5.2
B. ovatus	2	5.2
B. distasonis	2	2.6
Propionibacterium acne	7	9.1