Presentation Information
[1AFOB-05]Molecular Mechanisms of Gallbladder Carcinogenesis: Oxysterol Signalling, Microbial Dysbiosis, and Metal-Induced Genotoxicity
Asmita Kumari1, Rajani Sharma2, Ratnakar Shukla3, Vinay Kumar Kapoor4, Takao Asai5, Yasuo Tsuchiya6, ○Shubha Rani Sharma1 (1. Dept of Bioengineering & Biotechnology, Birla Institute of Technology, Mesra (India), 2. Amity Institute of Biotechnology, Amity University Jharkhand (India), 3. Sharda School of Allied Health Science, Sharda University, Greater Noida (India), 4. Mahatma Gandhi Medical College & Hospital, Jaipur (India), 5. Graduate School of Medicine, Kobe University, Kobe (Japan), 6. Graduate School of Medical and Dental Sciences, Niigata University (Japan))
Keywords:
gallbladder cancer,oxysterol,cholesterol,microbial dysbiosis,heavy metals
AbstractPurpose: Gallbladder cancer (GBC) ranks among the most lethal biliary tract malignancies, with chronic inflammation, gallstones, and environmental exposures driving its pathogenesis. This study examines three understudied causal factors—oxysterols, heavy metals, and bacteria.
Method: Investigating the technique by which oxysterols, oxidized cholesterol derivatives, accumulate in bile via leukocyte activity during inflammation or bacterial infection, promoting gallstone formation and biliary carcinogenesis. Oxysterol forms an endogenous ligand for nuclear receptors. Exploring the mechanisms by which heavy metals and microbiome alter the metabolic pathway leading to instigating their role in Gallbladder cancer.
Results: Studies show elevated oxysterol-binding proteins (OSBPs) like OSBP2 in cholangiocarcinoma sera, linking them to metastasis. Work to date includes bile analysis correlating oxysterols with pigment stones and inflammation, but causal validation remains limited to in vitro assays. Heavy metals such as cadmium, lead, chromium, arsenic, nickel, zinc and copper elevate in GBC tissues, serum, and bile compared to controls or gallstone patients, activating pathways like cholic acid synthesis, inflammation, angiogenesis, and cell cycle dysregulation. Indian endemic studies report electron-dense metal deposits in GBC tissues. The next most crucial instigating factor includes presence of microbes in GBC tissues. The microbial population of the intestinal tract and its relationship to specific diseases have been extensively studied during the past decade. There is growing evidence that the gallbladder bile contains an autochthonous microbiota, and its disturbance or imbalance may result in gallbladder disease, including gallbladder cancer. Different studies have been done on identifying the specific microbial species present in the bile of gallbladder cancer patients, often highlighting chronic inflammation as a key contributing factor to carcinogenesis. However, these studies are limited to a few cultivable species, and thus have a clear limitation. Previous studies have reported isolation of bacteria from bile ducts and gallbladder tissues, particularly Salmonella spp., as well as Pseudomonas spp., E. coli, Klebsiella spp., Enterococcus spp., and Helicobacter spp.
Considerations: Current literature provides associative evidence but lacks prospective designs, mechanistic depth, and interventions for these factors. Integrated studies combining presence of heavy metals, microbiome presence and oxysterols concentration in high-risk cohorts (e.g., gallstone patients) are critical.
Conclusion: Studying these factors interplay holds transformative significance and its potential as biomarker enable early detection in asymptomatic high-risk groups, improving GBC dismal prognosis via targeted screening and chemoprevention.
Method: Investigating the technique by which oxysterols, oxidized cholesterol derivatives, accumulate in bile via leukocyte activity during inflammation or bacterial infection, promoting gallstone formation and biliary carcinogenesis. Oxysterol forms an endogenous ligand for nuclear receptors. Exploring the mechanisms by which heavy metals and microbiome alter the metabolic pathway leading to instigating their role in Gallbladder cancer.
Results: Studies show elevated oxysterol-binding proteins (OSBPs) like OSBP2 in cholangiocarcinoma sera, linking them to metastasis. Work to date includes bile analysis correlating oxysterols with pigment stones and inflammation, but causal validation remains limited to in vitro assays. Heavy metals such as cadmium, lead, chromium, arsenic, nickel, zinc and copper elevate in GBC tissues, serum, and bile compared to controls or gallstone patients, activating pathways like cholic acid synthesis, inflammation, angiogenesis, and cell cycle dysregulation. Indian endemic studies report electron-dense metal deposits in GBC tissues. The next most crucial instigating factor includes presence of microbes in GBC tissues. The microbial population of the intestinal tract and its relationship to specific diseases have been extensively studied during the past decade. There is growing evidence that the gallbladder bile contains an autochthonous microbiota, and its disturbance or imbalance may result in gallbladder disease, including gallbladder cancer. Different studies have been done on identifying the specific microbial species present in the bile of gallbladder cancer patients, often highlighting chronic inflammation as a key contributing factor to carcinogenesis. However, these studies are limited to a few cultivable species, and thus have a clear limitation. Previous studies have reported isolation of bacteria from bile ducts and gallbladder tissues, particularly Salmonella spp., as well as Pseudomonas spp., E. coli, Klebsiella spp., Enterococcus spp., and Helicobacter spp.
Considerations: Current literature provides associative evidence but lacks prospective designs, mechanistic depth, and interventions for these factors. Integrated studies combining presence of heavy metals, microbiome presence and oxysterols concentration in high-risk cohorts (e.g., gallstone patients) are critical.
Conclusion: Studying these factors interplay holds transformative significance and its potential as biomarker enable early detection in asymptomatic high-risk groups, improving GBC dismal prognosis via targeted screening and chemoprevention.
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