A systems biology perspective on cholangiocellular carcinoma development: focus on MAPK-signaling and the extracellular environment.
OBJECTIVE
Multiple genes have been implicated in cholangiocellular carcinoma (CCC) development. However, the overall neoplastic risk is likely associated with a much lower number of critical physiological pathways.


METHODS
To investigate this hypothesis, we extracted all published genetic associations for the development of CCC from PubMed (genetic association studies, but also studies associating genes and CCC in general, i.e. functional studies in cell lines, genetic studies in humans, knockout mice etc.) and integrated CCC microarray data.


RESULTS
We demonstrated the MAPK pathway was consistently enriched in CCC. Comparing our data to genetic associations in HCC often successfully treated by a multityrosine kinase inhibitor, sorafenib, we demonstrated a similar overrepresentation of MAPK. In contrast, most cancer-related genetic studies focusing on genes related to transcription and cell cycle control, we consistently found genes coding for products in the extracellular environment to be significantly enriched. Thus, CCC must be regarded as developing in the context of an altered extracellular environment.


CONCLUSIONS
Our study suggests the liver microenvironment holds essential functions and structures key to CCC progression. Furthermore, we identified the MAPK signaling pathway consistently enriched, pointing towards a critical role in CCC development. These data may provide a rationale for treatment of CCC with sorafenib.
Wang
Chunxia
C
Central Laboratory, Shandong Provincial Hospital, Jinan, PR China.
Maass
Thorsten
T
Krupp
Markus
M
Thieringer
Florian
F
Strand
Susanne
S
Wörns
Marcus A
MA
Barreiros
Ana-Paula
AP
Galle
Peter R
PR
Teufel
Andreas
A
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000627:therapeutic use; D001650:Bile Duct Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics; D001653:Bile Ducts, Intrahepatic; D005075:Biological Evolution; D018281:Cholangiocarcinoma / Q000188:drug therapy / Q000201:enzymology* / Q000209:etiology* / Q000235:genetics; D019295:Computational Biology; D030541:Databases, Genetic; D005110:Extracellular Space / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics; D051379:Mice; D005810:Multigene Family; D009536:Niacinamide / Q000031:analogs & derivatives; D020411:Oligonucleotide Array Sequence Analysis; D010671:Phenylurea Compounds; D011725:Pyridines / Q000627:therapeutic use; D000077157:Sorafenib; D049490:Systems Biology
D000970:Antineoplastic Agents; D001557:Benzenesulfonates; D010671:Phenylurea Compounds; D011725:Pyridines; D009536:Niacinamide; D000077157:Sorafenib