Stroma is an important BAY 80-6946 nmr histological hallmark of ICC, suggesting that it may greatly influence tumor progression. However, few studies have specifically investigated the alterations of the stroma in ICC, particularly at a genomic scale. Notably, a genome-wide comparative analysis of tumor epithelia and stroma from 23 cholangiocarcinomas was recently reported.[25] Tumor epithelium was characterized by the dysregulation of the HER2 network and frequent overexpression of EGFR, whereas the stroma was enriched in inflammatory cytokines.[25] This study provided not only an important insight into the pathogenesis of cholangiocarcinoma but also novel therapeutic targets. However, these
studies were not designed to investigate the molecular heterogeneity of the stroma or to define specific gene dysregulations Smoothened Agonist nmr in the stromal compartment of ICC. Herein, we specifically
addressed these issues by performing gene expression profiling of microdissected stroma from human ICC. Also, while previous studies analyzed several types of cholangiocarcinomas with different prognoses (e.g., peri-hilar, infiltrating, and mass-forming type), our study exclusively focused on the mass-forming type of ICC. The robustness of the results was evaluated using two independent cohorts of patients with ICC. Importantly, the cases included representatives of all groups of ICC, as defined by the staging system of the UICC classification (Table 1; Supporting Table 2). The validating set was also equally distributed in cases with or without recurrence. Thus, although the cohort is small, we believe that the cases are likely representative of ICC. A good agreement was found for all genes evaluated at the mRNA level in the testing set and at the protein level in the validating set. Univariate and multivariate statistical analysis of protein expression and clinical features demonstrated that an overexpression of osteopontin in the stroma was closely associated with a poor prognosis in ICC. Osteopontin 上海皓元医药股份有限公司 is a multifunctional
secreted glycoprotein also known as the secreted phosphoprotein 1 (SPP1), which interacts with CD44 and integrins. Although initially discovered in bone tissue,[34] osteopontin is equally present in the liver, especially in the epithelium of the bile ducts and in stellate and Küpffer cells.[35] Osteopontin plays a pivotal role in mediating tumor-stroma interactions and in modulating cell adhesion, tissue remodeling, and tumor invasiveness, as previously described in colon and liver cancers.[36-39] In HCC, several studies have demonstrated that osteopontin blockade resulted in the inhibition of tumor growth, migration, and invasion, both in vitro and in vivo.[40, 41] Besides a functional role in cancer, osteopontin also exhibits great potential as a diagnostic and/or prognostic biomarker. Indeed, the plasma level of osteopontin was shown to correlate with poor prognosis in several cancers, including HCC.