Genetic heterogeneity in cholangiocarcinoma: a major challenge for targeted therapies.

Figure 1

Overview of the main potential factors driving genetic heterogeneity in CC

Genetic variability in CC could be the result of a complex interplay among several factors including: a. the existence of two genetically distinct stem cell niches along the biliary tree (the canals of Hering with hepatic stem cells and the peribiliary glands with biliary tree stem/progenitor cells), with a different susceptibly to risk factors; b. tumor clonal heterogeneity. Genetically distinct tumor cell sub-clones can coexist with founder cells harboring most of the tumor-borne genetic mutations, either in the primary tumor (intratumoral heterogeneity), or in the same metastasis (intrametastatic heterogeneity). Genetic variability can also occur among metastases derived from the same primary tumor, as the different sub-clones of the primary tumor can give rise to genetically distinct lesions at the metastatic site (intermetastatic heterogeneity); c. stochastic mutations and genomic instability. The large number of cell divisions required for cancer growth makes tumor cells prone to accumulate genomic alterations with a high frequency, due to random mutations occurring during DNA replication and deficiencies in the mechanisms involved in DNA repair; d) tumor microenvironment and cancer treatment. The tumor microenvironment and cancer therapy can induce fluctuations in tumor sub-clonal architecture and genetic profile by promoting the selective growth of sub-clones with a survival advantage within a given tumor microenvironment or a given therapeutic setting and by eradicating those with a less favorable survival advantage.

Oncotarget. 2015 June 20;6(17):14744-14753.

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