Molecular profiling of stroma identifies osteopontin as an independent predictor of poor prognosis in 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 demonstrate that ICC stromal cells exhibit dramatic genomic changes. We identified a signature of 1,073 nonredundant genes that significantly discriminate the tumor stroma from nontumor 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 (TGFb) pathways. Tissue microarray analysis using an independent cohort of 40 ICC patients validated at a protein level the increased expression of collagen 4A1/COL4A1, laminin gamma 2/LAMC2, osteopontin/SPP1, KIAA0101, and TGFb2 genes in the stroma of ICC. Statistical analysis of clinical and pathological features demonstrated that the expression of osteopontin, TGFb2, and laminin in the stroma of ICC was significantly correlated with overall patient survival. More important, 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 candidate biomarkers for prognosis, supporting the idea that tumor stroma is an important factor for ICC onset and progression. (HEPATOLOGY 2013;58:1992-2000 I ntrahepatic cholangiocarcinomas (ICC) account for 5%-10% of liver primary cancers. 1 ICC usually arise from epithelial cells of the intrahepatic small bile ducts, although a recent report in mice suggested that ICC might also originate from the conversion of mature hepatocytes. 2 Over the last decade, the incidence of ICC has increased significantly in Western countries. 3,4 This trend could be related to a better histological diagnosis of ICC and/or to the rising incidence of the main risk factors for ICC: cholangitis, chronic hepatitis B and C, diabetes, and obesity. 5 Liver resection remains the only curative treatment for ICC but is associated with a high rate of recurrence. 6 Recently, we showed that hilar lymph node metastasis,

Osteopontin-a splice variant is overexpressed in papillary thyroid carcinoma and modulates invasive behavior

“…These data are in accordance with OPN as a glycoprotein secreted in the extracellular matrix, both in tumor and non-tumoral tissues [28]. OPN is also known to be upregulated in the tissue stroma in different conditions, such as salivary pleomorphic adenomas [29] and intrahepatic cholangiocarcinoma [30]. It is well known that the interplay between epithelial cells and the microenvironment may contribute to keep the epithelial polarity and to modulate growth inhibition [31].…”

Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

“…The stroma of CCA undergoes profound changes in its composition during cholangiocarcinogenesis with an upregulation of genes related to the cell cycle, extracellular matrix, TGFβ pathway and inflammation 172,173 . Stromal signature was found to be significantly associated with poor CCA prognosis (enrichment score = 0.52), consistent with a major contribution of the microenvironment to tumour progression 173 .…”

New insights into molecular diagnostic pathology of primary liver cancer: Advances and challenges

“…Sulpice et al showed that stromal cells of ICC can present characteristic gene changes. For example, the expression of osteopontin (OPN), TGF-β2, and laminin is closely associated with the overall survival of patients and that OPN is an independent prognostic factor for ICC [32]. Studies have shown that 41% of ICC cases have a mutation in PTPN3, a protein tyrosine phosphatase family member.…”