Abstract
BackgroundIntrahepatic cholangiocarcinoma (iCCA) is a malignancy that arises from the intrahepatic biliary tree, showing high mortality rates due to its late clinical presentation and limited treatment options. iCCA is characterized by a dense, reactive desmoplastic stroma marked by a dramatic accumulation of extracellular matrix (ECM). Although recent results strongly suggest a relationship between increasing desmoplastic stroma and the enhanced malignant behaviour of iCCA, the importance of ECM proteins in the pathogenesis of iCCA still have to be addressed.MethodsiCCA ECM fibrillar structural organization was characterized by histological analysis. ECM proteome profiles from decellularized iCCA and surrounding noncancerous tissues were analysed by nLC coupled to MALDI-TOF/TOF analysis.ResultsiCCA tissues displayed high levels of collagen fibers and low abundance of reticular and elastic fibers, suggesting stiffness and loss of polarity. The ECM proteome profiles of iCCA samples, when compared to those obtained from the surrounding noncancerous tissues showed a dismantling of the basement membrane, a reduced angiogenesis and a downregulation of oncosuppressive activity. In particular, we focused on the effects of the overexpression of collagen type III alpha 1 chain (COL3A1) in iCCA, thus providing evidences that COL3A1 promotes iCCA cells migration and is a component of tumor-associated aligned collagen.ConclusionsOverall, this study contributes to the understanding of molecular basis underlying desmoplasia in iCCA and indicates the type III collagen as a promising therapeutic target.
Highlights
Intrahepatic cholangiocarcinoma is a malignancy that arises from the intrahepatic biliary tree, showing high mortality rates due to its late clinical presentation and limited treatment options. iCCA is characterized by a dense, reactive desmoplastic stroma marked by a dramatic accumulation of extracellular matrix (ECM)
Intrahepatic cholangiocarcinoma is a highly lethal primary liver cancer that originates from the intrahepatic biliary tree [1]. iCCA represents the second most common hepatic malignancy after hepatocellular carcinoma (HCC), accounting for 10% of all primary liver malignant neoplasms
Results iCCA has an altered ECM fiber composition in respect to non-cancerous liver tissue (NCT) Tissue specimens were obtained from surgical resections of 9 patients (Additional file 1)
Summary
Intrahepatic cholangiocarcinoma (iCCA) is a malignancy that arises from the intrahepatic biliary tree, showing high mortality rates due to its late clinical presentation and limited treatment options. iCCA is characterized by a dense, reactive desmoplastic stroma marked by a dramatic accumulation of extracellular matrix (ECM). During iCCA carcinogenesis, the desmoplastic reaction originates by the accumulation of many α-smooth muscle actin (α-SMA)positive cancer associated fibroblasts (CAFs) which in turn lead to an increased of an aberrant extracellular matrix (ECM) production [6, 7]. This fibrogenic response causes histopathological lesions that surround neoplastic bile ducts where CAFs promote tumor progression and invasiveness via ECM molecular components [8]. The tissue inhibitor of metalloproteinases 3 (TIMP3) has been observed to be downregulated [12, 13] Dysregulations of these ECM regulators are usually associated with primary liver tumors [13]. We focused on the collagen type III alpha 1 chain (COL3A1) stromal overexpression, demonstrating its involvement in iCCA cells migration and in the tumor-associated collagen re-organization
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