Browsing by Author "Roy, Sukanya"

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    Targeting Lymphangiogenesis and Lymph Node Metastasis in Liver Cancer
    (Elsevier, 2021) Roy, Sukanya; Banerjee, Priyanka; Ekser, Burcin; Bayless, Kayla; Zawieja, David; Alpini, Gianfranco; Glaser, Shannon S.; Chakraborty, Sanjukta; Surgery, School of Medicine
    Increased lymphangiogenesis and lymph node metastasis, the important prognostic indicators of aggressive hepatobiliary malignancies such as hepatocellular cancer and cholangiocarcinoma, are associated with poor patient outcome. The liver produces 25% to 50% of total lymphatic fluid in the body and has a dense network of lymphatic vessels. The lymphatic system plays critical roles in fluid homeostasis and inflammation and immune response. Yet, lymphatic vessel alterations and function are grossly understudied in the context of liver pathology. Expansion of the lymphatic network has been documented in clinical samples of liver cancer; and although largely overlooked in the liver, tumor-induced lymphangiogenesis is an important player, increasing tumor metastasis in several cancers. This review aims to provide a detailed perspective on the current knowledge of alterations in the hepatic lymphatic system during liver malignancies, as well as various molecular signaling mechanisms and growth factors that may provide future targets for therapeutic intervention. In addition, the review also addresses current mechanisms and bottlenecks for effective therapeutic targeting of tumor-associated lymphangiogenesis.
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    Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma
    (MDPI, 2021-11-09) Roy, Sukanya; Kumaravel, Subhashree; Banerjee, Priyanka; White, Tori K.; O’Brien, April; Seelig, Catherine; Chauhan, Rahul; Ekser, Burcin; Bayless, Kayla J.; Alpini, Gianfranco; Glaser, Shannon S.; Chakraborty, Sanjukta; Surgery, School of Medicine
    Cholangiocarcinoma (CCA), or cancer of bile duct epithelial cells, is a very aggressive malignancy characterized by early lymphangiogenesis in the tumor microenvironment (TME) and lymph node (LN) metastasis which correlate with adverse patient outcome. However, the specific roles of lymphatic endothelial cells (LECs) that promote LN metastasis remains unexplored. Here we aimed to identify the dynamic molecular crosstalk between LECs and CCA cells that activate tumor-promoting pathways and enhances lymphangiogenic mechanisms. Our studies show that inflamed LECs produced high levels of chemokine CXCL5 that signals through its receptor CXCR2 on CCA cells. The CXCR2-CXCL5 signaling axis in turn activates EMT (epithelial-mesenchymal transition) inducing MMP (matrix metalloproteinase) genes such as GLI, PTCHD, and MMP2 in CCA cells that promote CCA migration and invasion. Further, rate of mitochondrial respiration and glycolysis of CCA cells was significantly upregulated by inflamed LECs and CXCL5 activation, indicating metabolic reprogramming. CXCL5 also induced lactate production, glucose uptake, and mitoROS. CXCL5 also induced LEC tube formation and increased metabolic gene expression in LECs. In vivo studies using CCA orthotopic models confirmed several of these mechanisms. Our data points to a key finding that LECs upregulate critical tumor-promoting pathways in CCA via CXCR2-CXCL5 axis, which further augments CCA metastasis.