Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma

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 endoth...

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Autores principales:	Sukanya Roy, Subhashree Kumaravel, Priyanka Banerjee, Tori K. White, April O’Brien, Catherine Seelig, Rahul Chauhan, Burcin Ekser, Kayla J. Bayless, Gianfranco Alpini, Shannon S. Glaser, Sanjukta Chakraborty
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	chemokines liver cancer lymphatic metastasis inflammation bioenergetics Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/d07c1d18d4ff4f769fd2064703464d10
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spelling	oai:doaj.org-article:d07c1d18d4ff4f769fd2064703464d102021-11-25T17:11:25ZTumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma10.3390/cells101130932073-4409https://doaj.org/article/d07c1d18d4ff4f769fd2064703464d102021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3093https://doaj.org/toc/2073-4409Cholangiocarcinoma (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.Sukanya RoySubhashree KumaravelPriyanka BanerjeeTori K. WhiteApril O’BrienCatherine SeeligRahul ChauhanBurcin EkserKayla J. BaylessGianfranco AlpiniShannon S. GlaserSanjukta ChakrabortyMDPI AGarticlechemokinesliver cancerlymphatic metastasisinflammationbioenergeticsBiology (General)QH301-705.5ENCells, Vol 10, Iss 3093, p 3093 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	chemokines liver cancer lymphatic metastasis inflammation bioenergetics Biology (General) QH301-705.5
spellingShingle	chemokines liver cancer lymphatic metastasis inflammation bioenergetics Biology (General) QH301-705.5 Sukanya Roy Subhashree Kumaravel Priyanka Banerjee Tori K. White April O’Brien Catherine Seelig Rahul Chauhan Burcin Ekser Kayla J. Bayless Gianfranco Alpini Shannon S. Glaser Sanjukta Chakraborty Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma
description	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.
format	article
author	Sukanya Roy Subhashree Kumaravel Priyanka Banerjee Tori K. White April O’Brien Catherine Seelig Rahul Chauhan Burcin Ekser Kayla J. Bayless Gianfranco Alpini Shannon S. Glaser Sanjukta Chakraborty
author_facet	Sukanya Roy Subhashree Kumaravel Priyanka Banerjee Tori K. White April O’Brien Catherine Seelig Rahul Chauhan Burcin Ekser Kayla J. Bayless Gianfranco Alpini Shannon S. Glaser Sanjukta Chakraborty
author_sort	Sukanya Roy
title	Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma
title_short	Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma
title_full	Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma
title_fullStr	Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma
title_full_unstemmed	Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma
title_sort	tumor lymphatic interactions induce cxcr2-cxcl5 axis and alter cellular metabolism and lymphangiogenic pathways to promote cholangiocarcinoma
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/d07c1d18d4ff4f769fd2064703464d10
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Tumor Lymphatic Interactions Induce CXCR2-CXCL5 Axis and Alter Cellular Metabolism and Lymphangiogenic Pathways to Promote Cholangiocarcinoma

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