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Table 1: Gastrointestinal malignancies linked to chronic infl ammation
Organ Tumor type Chronic infl ammation
Esophagus Squamous cell carcinoma Cigarette smoking, alcohol and hot beverages
Adenocarcinoma GERD
Stomach Adenocarcinoma H. pylori, autoimmune
MALT lymphoma H. pylori, HCV
Colorectal Colorectal cancer Ulcerative colitis, Crohn’s disease
Liver Hepatocellular carcinoma HBV, HCV and cirrhosis (alcohol, NAFLD)
Pancreas Pancreatic ductal adenocarcinoma Chronic pancreatitis
Biliary system Gallbladder carcinoma Chronic cholecystitis
Cholangiocarcinoma PSC, chronic cholangitis and liver cirrhosis
GERD: Gastroesophageal reflux disease; H. pylori: Helicobacter pylori; HBV: Hepatitis B virus; HCV: Hepatitis C virus;
NAFLD: Non-alcoholic fatty liver disease; PSC: Primary sclerosing cholangitis; MALT: Mucosa-associated lymphoid tissue

[2]
macrophages are one of the key players. Recent studies cancers (CRCs). Several mechanisms of COX-2-
showed that tumor-associated macrophages (TAMs) mediated intestinal carcinogenesis have been elucidated.
were dispersed throughout tumor lesions and contributed These include inhibition of apoptosis, modulation
to tumor growth, invasion and metastasis by producing of cellular adhesion and motility, promotion of
various mediators. [4,5] In general, TAMs are found angiogenesis and immunosuppression. [14-16] Among
within and surrounding most tumor cells and can, the most potent inducers of COX-2, there are key
when activated, release numerous factors to infl uence pro-infl ammatory cytokines, IL-1α, IL-1β and TNF-α.
the behavior of tumor cells and the local tissue COX-2 is signifi cantly overexpressed in malignancies,
microenvironment. Interferon (IFN)-γ induces “classical” and non-steroidal anti-infl ammatory drugs are associated
activation of macrophages, while anti-infl ammatory with a reduction in the incidence of a variety of GI
mediators such as interleukin (IL)-10, IL-4 and IL-13 cancers. [17,18]
provoke “alternative’’ activation of macrophages, which Nuclear factor-κB
are referred as M1 and M2 macrophages respectively. [6,7]
M2 macrophages are oriented toward promoting tumor Infl ammatory responses contribute to carcinogenesis
progression, tissue repair and angiogenesis as well as through multiple mechanisms. As mentioned above,
suppressing adaptive immunity in tumors, whereas M1 reactive oxygen species, COX-2 and some cytokines
macrophages, as classically or alternatively activated interact with each other in a complex manner during
macrophages, are activated by lipopolysaccharides and development and progression of an infl ammatory
IFN-γ, and can secrete high levels of IL-12 and low environment. One such mediator is the transcription factor
levels of IL-10. [4,8-10] nuclear factor-κB (NF-κB), which is a key mediator of
infl ammation and involved in the regulation of apoptotic
Reactive oxygen species, nitric oxide and and oncogenic gene expression and activation. NF-κB
[19]
cyclooxygenase-2 has often been described as the central mediator of the
Chronic infl ammation creates a microenvironment immune response and as being critically involved in
locally to induce genomic instability in cells. At cancer-associated infl ammation and the tissue repair
the site of chronic infl ammation, cells are exposed response. [2,20] Aberrant activation of NF-κB protein was
to oxygen and nitrogen radicals from mononuclear associated with infl ammation and cancer in mouse models
phagocytes and leukocytes. These radicals can cause and in human GI cancers. [21-23] Activation of NF-κB plays
DNA damage. For example, nitric oxide and its products an important role in integrating multiple stress stimuli and
may exert oncogenic effects via several mechanisms, regulating immune responses. [23,24] Bile acids, particularly
including inhibition of DNA mismatch repair, protein deoxycholic acid, have been shown to activate the NF-κB
[25]
damage, induction of hypermethylation, inhibition of pathway. NF-κB activation through phosphorylation
apoptosis, mutation of DNA and disruption of cellular leads to translocation into the nucleus, and in turn
repair functions such as those involving the p53 regulates the transcription of several pro-infl ammatory
pathway. [11-13] Release of reactive oxygen and nitrogen cytokines such as TNF-α, IL-1β, IL-6, IL-8, and
species is enhanced by pro-infl ammatory cytokines such chemokines such as CXCL-1 and CXCL-2. [24,26]
as tumor necrosis factor (TNF), IL-1β and IFN-α. Thus, chronic infl ammation could lead to carcinogenesis
Another inducible enzyme with carcinogenic properties by sustaining pro-infl ammatory oncogenic signaling,
that is active in infl amed and malignant tissues is angiogenesis and immune suppression.
cyclooxygenase-2 (COX-2). Strong epidemiological
evidence implicates that COX-2 plays a role in the Esophageal Cancer
pathogenesis of a number of epithelial malignancies, There are two major histological subtypes of esophageal
including esophageal, gastric and colorectal cancer, that is, esophageal squamous cell carcinoma

Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 139