The role of bile acids in carcinogenesis

Abstract

Bile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis.

New Insights into Bile Acids Related Signaling Pathways in the Onset of Colorectal Cancer

“…Continuous inflammation was involved in the CRC pathogenesis due to barrier disruption, and bacterial translocation resulted in the inflammation and neoplastic transformation of colonic epithelial cells [ 163 ]. TGR5 activation by UDCA and LCA may also exert anti-inflammatory reactions through TLR4 activation or by reducing pro-inflammatory cytokines in the colon, which can decrease the frequency of developing CRC [ 164 ].…”

Hepatocellular carcinoma: Novel understandings and therapeutic strategies based on bile acids (Review)

“…TGR5. The secondary BAs DCA and LCA are the most potent natural ligands for TGR5 (49). TGR5 participates in the regulation of nutrient metabolism and energy consumption after activation.…”

“…The high expression of TGR5 in monocytes and macrophages was indicated to decrease the phagocytic activity of these cells and inhibit the production of numerous proinflammatory cytokines induced by lipopolysaccharide, such as TNF-α, IL-1, IL-6 and IL-8 (53). Most studies point to TGR5-dependent immunosuppression partly due to the suppression of the Toll-like receptor 4/NF-κB pathway (49). Since these inflammatory signals are closely related to HCC, the downregulation of TGR5 may be an important factor in the progression of HCC.…”

“…In conclusion, numerous studies suggest that the application of UDCA is an effective strategy for the management of advanced hepatobiliary diseases in the future. Based on the anti-inflammatory, antioxidant and cytoprotective activities, UDCA may be useful to improve treatments of advanced liver diseases, notably in combination with other drugs such as sorafenib, to enhance the therapeutic efficacy of targeting drugs for HCC (49,85,86). Furthermore, based on UDCA, monoclonal antibodies may be designed at the key sites of these inflammatory signaling pathways to achieve the purpose of targeted therapy.…”

Bile Acids in Intrahepatic Cholestasis of Pregnancy

“…The osmotic pressure gradient that arises during the secretion of BAs into the bile ducts is one of the most important factors ensuring the proper flow of bile through the liver [ 45 , 57 ]. Due to their detergent properties, BAs can damage the cell membranes of the biliary epithelium and, consequently, damage the liver parenchyma [ 67 , 68 , 69 , 70 ].…”