Desmoplastic stroma and cholangiocarcinoma: Clinical implications and therapeutic targeting

holangiocarcinomas are usually characterized by a prominent desmoplastic and hypovascularized stroma. However, the biological significance and clinical impact of the desmoplastic stroma in cholangiocarcinoma is only just beginning to be addressed at the cellular and molecular levels. Nevertheless, there is now increasing evidence to suggest that the desmoplastic reaction, marked by a dramatic accumulation of a-smooth muscle actin positive cancerassociated fibroblasts (a-SMA1CAFs) with increased production of extracellular matrix proteins, proinvasive growth factors and cytokines, antiangiogenic factors, and matrix modifying enzymes may be playing a crucial role in promoting enhanced malignant behavior and therapeutic resistance in cholangiocarcinoma. We also describe recent experimental approaches to prevent cholangiocarcinoma by reducing hepatic fibrosis. Last, we discuss the potential merits and challenges of a-SMA1CAF depletion as a novel strategy for cholangiocarcinoma therapy.