Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive epithelial malignancy still carrying a dismal prognosis and striking resistance to conventional chemotherapy. The development of a reactive tumor microenvironment (TME) is a functional hallmark in iCCA progression. However, in respect to other aggressive epithelial malignancies characterized by a TME with abnormal vascular networks, iCCA TME is hypovascularized, with a prominent development of lymphatic vessels. This leads to a rapid metastatic spread into regional lymph nodes and the liver parenchyma, precluding curative treatments. Recently, to gain insights into factors modulating iCCA angiogenesis, we demonstrated that the expression of thrombospondin 1 (THBS1), thrombospondin 2 (THBS2) and pigment epithelium-derived factor (PEDF) in the extracellular fluid of the iCCA microenvironment leads to a downregulation of the vascular network and increased levels of lymphangiogenesis. We believe that these data strongly support the idea that a strategy targeting THBS1-, THBS2-, and PEDF-mediated lymphangiogenesis may be a double-edged sword to counteract the iCCA. On the one hand, it may inhibit the tumor-associated lymphangiogenesis thus hampering the spreading of cancer cells into regional lymph nodes and within the liver parenchyma. On the other hand, it may enhance the delivery of chemotherapeutic agents to tumor sites. Therefore, driven by our preliminary results, we designed the present proposal to define the molecular mechanisms of action of THBS1, THBS2 and PEDF in promoting the iCCA-associated lymphangiogenesis in order to unveil most specific and selective targets for therapeutics. In particular, this proposal aims to study (i) the role of THBS1, THBS2 and PEDF in promoting lymphatic endothelial cells migration, (ii) the interplay among THBS1, THBS2 and PEDF and the pro-lymphangiogenic VEGF-C signaling, (iii) the interactome of THBS1, THBS2, PEDF with TME-associated proteins.
iCCA is usually asymptomatic in early stages and, therefore, often diagnosed when the disease is already in advanced stages, which highly compromises therapeutic options, resulting in a dismal prognosis [21]. Tumour resection is still the only potentially curative option for iCCA patients, although only a small percentage of patients are eligible and the percentage recurrence is high. For patients with advanced-stage or unresectable cholangiocarcinoma, the available systemic therapies are of limited effectiveness: the median overall survival with the current standard-of care chemotherapy regimen is
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