Signaling and molecular networks related to development and inflammation involved in CCA initiation and progression

Abstract

Intrahepatic cholangiocarcinoma (iCCA) is a rare neoplasm of the bile ducts with a low survival rate, whose incidence is continuously increasing and is associated with a rich and varied tumor microenvironment (TME). Although the main mutations characterizing iCCA are known, there are several unresolved issues regarding the processes leading to the accumulation of mutations in the normal cholangiocyte. The inflammatory mediators and the molecular pathways involved in cholangiocarcinogenesis, which regulate the transition from normal to dysplastic cells, resulting in neoplastic cholangiocytes, are poorly understood. Moreover, once the tumor is established, it is unclear which effects of the interaction between the tumor and TME constituent cells, in particular cancer-associated fibroblasts (CAFs), are responsible for stimulating the malignant behavior of iCCA. In this review, we described the main mutations affecting the bile ducts leading to iCCA development as well as the putative inflammatory mediators and morphogenetic pathways involved in the establishment of the malignant transition of the bile ducts. We also described the main signaling pathways involved in TME-tumor cell interactions, with particular emphasis on the effect of CAFs in cancer. Finally, we wanted to analyze possible new therapeutic approaches aimed at modifying the composition of TME and the possible role of immunotherapy in improving the treatment of this cancer.

Tumor Microenvironment Composition and Related Therapy in Hepatocellular Carcinoma

“…Moreover, they release ECM-degrading enzymes, including MMPs, which not only bolster CAF migration but also expedite ECM degradation, setting the stage for tumor cell infiltration. 81 HSCs are activated when the liver is damaged or subjected to extracellular stimuli. Activated HSCs participate in ECM remodeling by synthesizing ECM molecules and secreting MMPs.…”

Advances in The Treatment of Intrahepatic Cholangiocarcinoma-ICLCA

“…Mutant IDH develops a new capacity to create the oncometabolite 2-hydroxyglutarate (2-HG), which may be recruited in the blood and tumor while losing its usual enzymatic function. IDH inhibitors have been revealed to limit proliferation in tumor cell lines that carry certain IDH mutations 32 . These findings suggest that targeting mutant IDH with IDH inhibitors may be a promising therapeutic approach.…”