Cholangiocarcinoma(CCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis, owing to early lymph node metastatic dissemination and striking resistance to conventional chemotherapy. Although...Cholangiocarcinoma(CCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis, owing to early lymph node metastatic dissemination and striking resistance to conventional chemotherapy. Although mechanisms underpinning CCA progression are still a conundrum, it is now increasingly recognized that the desmoplastic microenvironment developing in conjunction with biliary carcinogenesis, recently renamed tumor reactive stroma(TRS), behaves as a paramount tumor-promoting driver. Indeed, once being recruited, activated and dangerously co-opted by neoplastic cells, the cellular components of the TRS(myofibroblasts, macrophages, endothelial cells and mesenchymal stem cells) continuously rekindle malignancy by secreting a huge variety of soluble factors(cyto/chemokines, growth factors, morphogens and proteinases). Furthermore, these factors are long-term stored within an abnormally remodeled extracellular matrix(ECM), which in turn can deleteriously mold cancer cell behavior. In this review, we will highlight evidence for the active role played by reactive stromal cells(as well as by the TRS-associated ECM) in CCA progression, including an overview of the most relevant TRS-derived signals possibly fueling CCA cell aggressiveness. Hopefully, a deeper knowledge of the paracrine communications reciprocally exchanged between cancer and stromal cells will steer the development of innovative, combinatorial therapies, which can finally hinder the progression of CCA, as well as of other cancer types with abundant TRS, such as pancreatic and breast carcinomas.展开更多
Cholangiocarcinoma(CCA),an aggressive tumor originating from both intra-and extra-hepatic biliary cells,represents an unmet need in liver oncology,as treatment remains largely unsatisfactory.A typical feature of CCA i...Cholangiocarcinoma(CCA),an aggressive tumor originating from both intra-and extra-hepatic biliary cells,represents an unmet need in liver oncology,as treatment remains largely unsatisfactory.A typical feature of CCA is the presence of a complex tumor microenvironment(TME)composed of neoplastic cells,a rich inflammatory infiltrate,and cancer-associated fibroblasts and desmoplastic matrix that makes it extremely chemoresistant to traditional chemotherapeutic drugs.In this review,we describe the cell populations within the TME,in particular those involved in the innate and adaptive immune response and how they interact with tumor cells and with matrix proteins.The TME is crucial for CCA to mount an immune escape response and is the battlefield where molecularly targeted therapies and immune therapy,particularly in combination,may actually prove their therapeutic value.展开更多
文摘Cholangiocarcinoma(CCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis, owing to early lymph node metastatic dissemination and striking resistance to conventional chemotherapy. Although mechanisms underpinning CCA progression are still a conundrum, it is now increasingly recognized that the desmoplastic microenvironment developing in conjunction with biliary carcinogenesis, recently renamed tumor reactive stroma(TRS), behaves as a paramount tumor-promoting driver. Indeed, once being recruited, activated and dangerously co-opted by neoplastic cells, the cellular components of the TRS(myofibroblasts, macrophages, endothelial cells and mesenchymal stem cells) continuously rekindle malignancy by secreting a huge variety of soluble factors(cyto/chemokines, growth factors, morphogens and proteinases). Furthermore, these factors are long-term stored within an abnormally remodeled extracellular matrix(ECM), which in turn can deleteriously mold cancer cell behavior. In this review, we will highlight evidence for the active role played by reactive stromal cells(as well as by the TRS-associated ECM) in CCA progression, including an overview of the most relevant TRS-derived signals possibly fueling CCA cell aggressiveness. Hopefully, a deeper knowledge of the paracrine communications reciprocally exchanged between cancer and stromal cells will steer the development of innovative, combinatorial therapies, which can finally hinder the progression of CCA, as well as of other cancer types with abundant TRS, such as pancreatic and breast carcinomas.
基金supported in part by the Yale Liver Center award NIH P30 DK034989 Clinical-Translational core.
文摘Cholangiocarcinoma(CCA),an aggressive tumor originating from both intra-and extra-hepatic biliary cells,represents an unmet need in liver oncology,as treatment remains largely unsatisfactory.A typical feature of CCA is the presence of a complex tumor microenvironment(TME)composed of neoplastic cells,a rich inflammatory infiltrate,and cancer-associated fibroblasts and desmoplastic matrix that makes it extremely chemoresistant to traditional chemotherapeutic drugs.In this review,we describe the cell populations within the TME,in particular those involved in the innate and adaptive immune response and how they interact with tumor cells and with matrix proteins.The TME is crucial for CCA to mount an immune escape response and is the battlefield where molecularly targeted therapies and immune therapy,particularly in combination,may actually prove their therapeutic value.
