Gallbladder Cancer Carcinogenesis Research Articles

Arsenic may be a carcinogenic determinant of a subset of gallbladder cancer: A pilot study

Gallbladder cancer (GBC) is one of the deadliest malignancy and treatment options are deplorably limited. Better strategies of prevention are urgently needed but knowledge on risk factors remains scarce. Recent data suggested that arsenic (As) may be involved in GBC carcinogenesis but the question remains debated. To date, there are no data on As measurement in GBC samples. This pilot study aimed to measure As concentrations in tissue samples from patients with GBC compared to non-cancerous gallbladder (NCGB). Included patients underwent cholecystectomy at Hospital Clinico Universidad de Chile, Santiago in Chile, a country with high As exposure, between 2001 and 2020. Tissue samples were preserved in formalin-fixed, paraffin-embedded blocks. Selected samples were retrieved, processed and submitted to inductively coupled plasma mass spectrometry (ICP-MS) to determine As concentrations. A total of 77 patients were included, including 35 GBC and 42 NCGB. The two groups were comparable, except for age (68 vs. 49 years, p < 0.001). Measured in 11 GBC and 38 NCGB, total As was detected in 5 GBC (14%) compared to 0 NCGB samples (p < 0.001). GBC group also showed higher median values of As compared to NCGB (p < 0.001). This pilot study provided a proof-of-concept to measure As concentrations in gallbladder samples and showed higher level of As in GBC samples compared to NCGB, paving the way for future studies aiming to investigate the impact of As on GBC, which may contribute to the prevention of this deadly disease.

Environmental and Lifestyle Risk Factors in the Carcinogenesis of Gallbladder Cancer.

Gallbladder cancer (GBC) is an aggressive neoplasm that in an early stage is generally asymptomatic and, in most cases, is diagnosed in advanced stages with a very low life expectancy because there is no curative treatment. Therefore, understanding the early carcinogenic mechanisms of this pathology is crucial to proposing preventive strategies for this cancer. The main risk factor is the presence of gallstones, which are associated with some environmental factors such as a sedentary lifestyle and a high-fat diet. Other risk factors such as autoimmune disorders and bacterial, parasitic and fungal infections have also been described. All these factors can generate a long-term inflammatory state characterized by the persistent activation of the immune system, the frequent release of pro-inflammatory cytokines, and the constant production of reactive oxygen species that result in a chronic damage/repair cycle, subsequently inducing the loss of the normal architecture of the gallbladder mucosa that leads to the development of GBC. This review addresses how the different risk factors could promote a chronic inflammatory state essential to the development of gallbladder carcinogenesis, which will make it possible to define some strategies such as anti-inflammatory drugs or public health proposals in the prevention of GBC.

Jab1-siRNA Induces Cell Growth Inhibition and Cell Cycle Arrest in Gall Bladder Cancer Cells via Targeting Jab1 Signalosome.

The aberrant alteration in Jab1 signalosome (COP9 Signalosome Complex Subunit 5) has been proven to be associated with the progression of several carcinomas. However the specific role and mechanism of action of Jab1 signalosome in carcinogenesis of gall bladder cancer (GBC) are poorly understood. The main objective of our study was to elucidate the role and mechanism of Jab1 signalosome in gall bladder cancer by employing siRNA. Jab1 overexpression was identified in gall bladder cancer tissue sample. The role of Jab1-siRNA approach in cell growth inhibition and apoptotic induction was then examined by RT-PCR, Western Blotting, MTT, ROS, Hoechst and FITC/Annexin-V staining. In the current study, we have shown that overexpression of Jab1 stimulated the proliferation of GBC cells; whereas downregulation of Jab1 by using Jab1-siRNA approach resulted incell growth inhibition and apoptotic induction. Furthermore, we found that downregulation of Jab1 induces cell cycle arrest at G1 phase and upregulated the expression of p27, p53 and Bax gene. Moreover, Jab1-siRNA induces apoptosis by enhancing ROS generation and caspase-3 activation. In addition, combined treatment with Jab1-siRNA and gemicitabine demonstrated an enhanced decline in cell proliferation which further suggested increased efficacy of gemcitabine at a very lower dose (5μM) in combination with Jab1-siRNA. In conclusion, our study strongly suggests that targeting Jab1 signalosome could be a promising therapeutic target for the treatment of gall bladder cancer.

VEGF Polymorphisms in Gall Bladder Cancer

Purpose: Gall bladder cancer (GBC) is common in Chile and in north India. Angiogenesis plays an important role in carcinogenesis. Vascular endothelial growth factors (VEGF) at 6p12 play an important role in carcinogenesis. VEGF overexpression has been found in many cancers. We studied VEGF single nucleotide polymorphisms (SNPs) in GBC and gall stone associated benign diseases viz. chronic cholecystitis (CC) and xantho-granulomatous cholecystitis (XGC). Methods: DNA was extracted from blood in patients with GBC (n=195), CC (n=140), XGC (n=47), and normal controls (n=300). VEGF polymorphism (-1154G/A, -2578C/A, +936C/T and 18 bp -2549I/D) was investigated using PCR-RFLP method. Results: -1154G/A heterozygous genotype GA and +936C/T genotype TT were risk associated with GBC (OR 1.65, p=0.01; OR 2.59, p=0.02) and CC (OR 1.68, p=0.01; OR 3.48, p=0.003). -2578C/A heterozygous genotype CA was protective for GBC (OR=0.6, p=0.01). Combitorial analysis revealed that ICGC, DTGC, DCAC, and DTGA were predisposing haplotypes for GBC, CC, and XGC. Haplotype DTGA, containing mutant alleles, showed highest risk for GBC (OR 15.15, p<0.0001), CC (OR 7.5, p=0.007), and XGC (OR 10.6, p=0.001). Haplotype DCGC was risk protective for GBC (OR 0.28, p<0.0001), CC (OR 0.39, p<0.0001), and XGC (OR 0.32, p=0.001). Haplotype ICAC was protective for GBC (OR 0.27, p=0.0001). Conclusion: Hsing et al (2008) also found VEGF polymorphism to be associated with GBC. VEGF polymorphism may play a role in carcinogenesis of GBC and needs further evaluation.

Comparison of p53, K-ras, and HER2/neu expression in nonneoplastic gall bladder epithelium and gall bladder cancer (GBC) epithelium: A pilot study.

e14511 Background: GBC carcinogenesis is a multi step process, involving increasing genetic disarray accumulated over a long time. In view of aggressive nature of GBC and lack of good therapeutics,...

Preliminary study of p53 and c-erbB-2 expression in gallbladder cancer in Indian patients manuscript id: 8962091628764582.

BackgroundThe inactivation of the tumour suppressor gene and activation of the proto-oncogene are the key steps in the development of the human cancer. The p53 and c-erbB-2 are the best examples of it. In the present study, our aim was to determine the role of these genes in the carcinogenesis of gallbladder by immunohistochemistry.MethodsIn all 78 consecutive patients of gall bladder diseases were studied for p53 and c-erbB-2 expression immunohistochemically and their expression was correlated with the age, grades and stages of the disease and presence of stone. An informed consent was obtained in each case. Chi square and z test were applied to see the association of p53 and c-erbB-2 over expression with other clinicopathological factors.ResultsEight (20%) patients of gall bladder cancer were positive for p53 expression and 10 (25%) patients for c-erbB-2. The p53 positivity increased with increasing grade while cerbB-2 positivity decreased with increasing grade of gall bladder cancer. Mean age in cerbB-2 positive cases were lesser as compared to negative cases while p53 did not show such association with age.ConclusionOnly one case of gall bladder cancer co-expressed the p53 and c-erbB-2, thereby suggesting that p53 and c-erbB-2 may have independent role in carcinogenesis of gall bladder cancer. c-erbB-2 over expression in adenoma and younger age group indicates its role as an early event in carcinogenesis of gallbladder. However study of larger sample is required to further validate the results.