The inflammatory inception of gallbladder cancer

Abstract

Gallbladder cancer is a lethal disease with notable geographical variations worldwide and a predilection towards women. Its main risk factor is prolonged exposure to gallstones, although bacterial infections and other inflammatory conditions are also associated. The recurrent cycles of gallbladder epithelium damage and repair enable a chronic inflammatory environment that promotes progressive morphological impairment through a metaplasia–dysplasia–carcinoma, along with cumulative genome instability. Inactivation of TP53, which is mutated in over 50% of GBC cases, seems to be the earliest and one of the most important carcinogenic pathways involved. Increased cell turnover and oxidative stress promote early alteration of TP53, cell cycle deregulation, apoptosis and replicative senescence. In this review, we will discuss evidence for the role of inflammation in gallbladder carcinogenesis obtained through epidemiological studies, genome-wide association studies, experimental carcinogenesis, morphogenetic studies and comparative studies with other inflammation-driven malignancies. The evidence strongly supports chronic, unresolved inflammation as the main carcinogenic mechanism of gallbladder cancer, regardless of the initial etiologic trigger. Given this central role of inflammation, evaluation of the potential for GBC prevention removing causes of inflammation or using anti-inflammatory drugs in high-risk populations may be warranted.

Association of Aflatoxin and Gallbladder Cancer

“…However, 17 somatic mutations in TP53 were identified in 16 different tumor samples, consistent with previous studies finding TP53 as the most commonly mutated gene in GBC. 30 …”

“…In addition, the study had high GBC and gallstone patient ascertainment and participation, minimizing the potential for selection bias. By comparing patients with GBC to patients with gallstones, we were also able to focus on the key transition in gallbladder carcinogenesis from gallbladder inflammation, usually precipitated by gallstones, 30 to the development of cancer.…”

Cancer of the gallbladder—Chilean statistics

“…The high prevalence of gallstones among non-obese young Mapuche people and Pima Indians suggests the presence of high penetrating lithogenic genes in these populations [14]. The most studied lithogenic polymorphisms correspond to the ABCG8-DH19 transporter gene in the ABCG5/G8 heterodimer pattern and that simultaneously could be related to a greater risk of developing cancer in certain ethnic populations like in the Chinese population [15]. These genes would participate in the generation of cholesterol stones, expressing abnormal molecular mechanisms in the secretion and/or solubility of cholesterol that would be present in women and is influenced by environmental factors like obesity [14].…”

“…Multiple polymorphisms in genes associated with the immune system, inflammation, and oxidative stress that have been linked to the development of gallbladder cancer like PTGS2, TLR2, TLR4, IL1RN, IL10, IL8, CCR5, LXRB, and OGG1. The use of some anti-inflammatories such as aspirin has been linked to a reduction in the risk of gallbladder cancer [15]. …”

IL-1β promotes proliferation and migration of gallbladder cancer cells via Twist activation

“…IL-1β may promote proliferation and migration of GBC cells via Twist activation. The correlation between chronic inflammation and gallbladder carcinogenesis has been described previously (45,46), although the exact inflammatory mediators involved has yet to be elucidated. To the best of our knowledge, the present study is the first to implicate IL-1β in the tumorigenesis of GBC.…”