Abstract
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.
Highlights
IntroductionCCA is the second most common type of liver cancer that involves the extra- and intrahepatic bile ducts
We found that a dense network of lymphatic endothelial cells (LECs) and lymphatic vessels were present surrounding CCA tumor cells (Figure 1A)
We found that the expression level of multiple genes like PFKP, GLUT3, FASN, hexokinase 2 (HK2), c oxidase subunit I (CO I), ATP synthase membrane subunit 6 (ATP6) was increased (p ≤ 0.001) in CCA-conditioned medium (CM) treated LECs (Figure 6E)
Summary
CCA is the second most common type of liver cancer that involves the extra- and intrahepatic bile ducts. CCA is very aggressive with a dismal prognosis and a post-metastasis diagnosis five-year survival rate of only 2% [1]. Diagnosis of CCA is challenging and treatment options are limited [2,3]. Tumor-associated growth of new lymphatic vessels (i.e., lymphangiogenesis) predicts unfavorable prognosis of CCA with tumor metastasis to the draining LNs as the primary prognostic indicator of tumor aggressiveness [4]. A high degree of both peri- and intra-tumoral lymphangiogenesis in the early stages of CCA indicates greater LN metastasis that makes surgical resection a significant challenge [5]
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