Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies

Abstract

Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with very poor prognosis. Genome-wide, high-throughput technologies have made major advances in understanding the molecular basis of this disease, although important mechanisms are still unclear. Recent data have revealed specific genetic mutations (for example, KRAS, IDH1 and IDH2), epigenetic silencing, aberrant signaling pathway activation (for example, interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3), tyrosine kinase receptor-related pathways) and molecular subclasses with unique alterations (for example, proliferation and inflammation subclasses). In addition, some ICCs share common genomic traits with hepatocellular carcinoma. All this information provides the basis to explore novel targeted therapies. Currently, surgery at early stage is the only effective therapy. At more advanced stages, chemotherapy regimens are emerging (that is, cisplatin plus gemcitabine), along with molecular targeted agents tested in several ongoing clinical trials. Nonetheless, a first-line conclusive treatment remains an unmet need. Similarly, there are no studies assessing tumor response related with genetic alterations. This review explores the recent advancements in the knowledge of the molecular alterations underlying ICC and the future prospects in terms of therapeutic strategies leading towards a more personalized treatment of this neoplasm.

Figure 1

Summary of key molecular alterations involved in ICC carcinogenesis. Despite the absence of clear etiological risk factors or underlying disease, external stimuli (for example, liver fluke or hepatitis viral infection) favor the induction of proinflammatory signals mediated by several cellular types lying in the microenvironment. The release of growth-promoting factors and cytokines during chronic inflammation (for example, IL-6, tumor growth factor β) promotes cholangiocytes’ proliferation. This phenomenon along with the accumulation of genetic and epigenetic alterations in oncogenes and oncosuppressors leads to the malignant transformation of normal cholangiocytes and to the deregulation of main signaling pathways (for example, EGFR, ERBB2, HGF/MET, VEGFR) involved in the hallmarks of cancer, such as proliferation, survival, invasion and enhanced angiogenesis.

Figure 2

Signaling pathways and molecular therapies in ICC. Major deregulated oncogenic signaling pathways identified for ICC and targeted molecular drugs evaluated in preclinical and clinical studies are represented. Activation of tyrosine kinase receptors (for example, EGFR, VEGFR, MET, and so on) and also others, such prostaglandin receptor 4 (EP4), triggers the activation of two major signaling pathways including the RAS/MAPK and PI3K/AKT pathways. These pathways implicate sequential activation of downstream tyrosine kinases, which lead to the regulation of gene expression through the activation of specific transcription factors. COX-2 is a key enzyme implicated in inflammation and cell growth through the biosynthesis of prostaglandin E2 (PGE2). In IL-6/STAT3 signaling, the binding of IL-6 to the receptor leads to gp130 receptor dimerization and associated JAK phosphorylation. These then provide a docking place for the transcription factor STAT3, which also is phosphorylated and dimerized. Activated STAT3 is translocated to the nucleus and induces the transcription of targeted genes implicated in cell processes, such as proliferation, cell growth and differentiation.