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Gene expression profiling of tumor stroma in human intrahepatic cholangiocarcinoma

ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling we demonstrated that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 non-redundant genes that significantly discriminate the tumor stroma from non tumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix and Transforming Growth Factor beta (TGFβ) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increase expression of Collagen 4, Laminin, Osteopontin/SPP1, KIAA0101 and TGFβ2 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of Osteopontin, TGFβ2 and Laminin in the stroma of ICC was significantly correlated with patient overall survival. More importantly, multivariate analysis demonstrated that the stromal expression of Osteopontin was an independent prognostic marker for overall and disease-free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidates biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE45001 | GEO | 2013/06/21

SECONDARY ACCESSION(S): PRJNA192813

REPOSITORIES: GEO

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Project description:Intrahepatic cholangiocarcinoma (ICC) is the second most common type of primary cancer in the liver. ICC is an aggressive cancer with poor prognosis and limited therapeutic strategies. The identification of new drug targets and prognostic biomarkers is an important clinical challenge for ICC. The presence of an abundant stroma is a histological hallmark of ICC. Given the well established role of the stromal compartment in the progression of cancer diseases, we hypothesized that relevant biomarkers could be identified by analyzing the stroma of ICC. By combining laser capture microdissection and gene expression profiling we demonstrated that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 non-redundant genes that significantly discriminate the tumor stroma from non tumor fibrous tissue. Functional analysis of differentially expressed genes demonstrated that up-regulated genes in the stroma of ICC were related to cell cycle, extracellular matrix and Transforming Growth Factor beta (TGFM-NM-2) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increase expression of Collagen 4, Laminin, Osteopontin/SPP1, KIAA0101 and TGFM-NM-22 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of Osteopontin, TGFM-NM-22 and Laminin in the stroma of ICC was significantly correlated with patient overall survival. More importantly, multivariate analysis demonstrated that the stromal expression of Osteopontin was an independent prognostic marker for overall and disease-free survival. Conclusion: The study identifies clinically relevant genomic alterations in the stroma of ICC, including candidates biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression. 20 RNA samples were analyzed, from 10 patients with ICC. For each patient, RNA were isolated from laser capture microdissected (LCM) stroma from tumor and non tumor areas.

Project description:Background & Aims: Intrahepatic cholangiocarcinoma (ICC) is known to heterogeneous with diverse etiology, morphology, and clinical outcomes. Recently, cholangiolar differentiation of ICC has been suggested to associate with prognostic outcomes, however, its molecular patho-biological features and clinical significances were not evaluated extensively. Methods:Integrative analysis was performed using transcriptomic profiles (n=27) and tissue microarrays (n=142) from ICC specimens. Results:ICCs were classified into ICC with cholangiolar differentiation (ICC-CD, n=20) and ICC with bile duct differentiation (ICC-BD, n=122). ICC-CD showed favorable overall survival (OS) compared to ICC-BD (Hazard Ratio=0.38, P=0.020, log-rank test). Transcriptomic profiling of ICC-CD and ICC-BD revealed a cholangiolar differentiation signature (CD signature, n=794), which could predict prognostic outcomes of ICC in an independent data. Interestingly, the expression of CD signature demonstrated that the ICC-BD but not ICC-CD harbored pancreatic ductal adenocarcinoma (PDAC) like expression trait, implying its cellular origin from multipotent biliary tree stem cells or the cells committed to differentiate into pancreatic lineage cells. The CD signature might be a key determinant for ICC heterogeneity indicating spectral continuum of cellular differentiation of ICC-CD → ICC-BD → PDAC. In addition, we identified four genes (i.e., CRP, CDH2, TFF1, and S100P) from integrated analysis of tissue microarrays and transcriptome profiles as prognostic as well as differential histologic markers for ICC-CD and ICC-BD. Strikingly, combined expression status of the four genes were more beneficial in predicting prognostic outcomes of ICC. Conclusions:Our integrative genomic-pathologic analysis could reveal new molecular and clinical significance of cholangiolar differentiation in association with PDAC-like expression traits, which might play pivotal roles in heterogeneous progression of ICC.

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Gene expression profiling of tumor stroma in human intrahepatic cholangiocarcinoma

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